Selective senolytic cell penetrating peptide compositions and uses

Abstract

The technology relates in part to compositions containing a cell penetrating peptide that can be used to selectively reduce a senescent cell population. The technology also relates to methods of treatment of ageing and ageing-associated diseases using a cell penetrating peptide to selectively reduce a senescent cell population.

Description

[0001] ATTORNEY DOCKET: 05336.0007WO01

[0002] SELECTIVE SENOLYTIC CELL PENETRATING PEPTIDE COMPOSITIONS AND USES

[0003] Cross-Reference to Related Applications

[0004] This application claims priority to, and is a non-provisional of, U. S. Patent Applications 63 / 719,899 (filed November 13, 2024), 63 / 749,376 (filed January 24, 2025), 63 / 763,206 (filed February 25, 2025), 63 / 889,340 (filed September 27, 2025) and 63 / 895,071 (filed October 7, 2025), the entirety of which are incorporated herein by reference.

[0005] Reference to a Sequence Listing

[0006] This application contains a Sequence Listing in computer readable form. The computer readable form is incorporated herein by reference. The computer readable file is named Seqeuence.xml and was created on November 11, 2025 (1,240 kB). The content of this file is hereby incorporated by reference.

[0007] Field

[0008] The technology relates in part to compositions containing a cell penetrating peptide that can be used to selectively reduce a senescent cell population. The technology also relates to methods of treatment of ageing and ageing-associated diseases using a cell penetrating peptide to selectively reduce a senescent cell population.

[0009] Background

[0010] Senescence is a process of cellular aging, in which cells lose their ability to divide but do not die. During senescence, these cells transform into an inflammatory phenotype, secreting pro-inflammatory molecules, including certain cytokines and chemokines, altogether termed the Senescence-Associated Secretory Phenotype (“SASP”). During a subject’s youthful years, specific cells in our immune system continuously remove unwanted senescent cells (“SCs”). The immune system’s rate of SC clearance mostly keeps up with the rate of SC formation, leaving few SCs persistently present. As subjects continue to age, SCs begin to accumulate as the immune system becomes less efficient at ATTORNEY DOCKET: 05336.0007WO01

[0011] removing SCs. Chronic inflammation from SCs further impairs the immune system and cellular stresses increase the rate of formation of SCs, leading to progressive accumulation of SCs. Organ function begins to deteriorate due to this adverse cellular and tissue microenvironment. As subjects continue to age, SCs continue to accumulate even further. Widespread “inflammaging”, the chronic, low-grade inflammation that occurs as people age that is not caused by infections but is a result of the aging process itself, reaches critical levels, leading to organ dysfunction and causing widespread aging-related diseases e.g. cognitive decline, sarcopenia and frailty, cataracts, and glucose metabolic disorders like obesity and diabetes.

[0012] Thus, over the lifetime of a subject, a growing population of senescent cells can build up in tissues throughout the body contributing to the process of aging. These cells remain active and release harmful SASP factors that cause inflammation and damage to nearby nonsenescent cells, which may lead to organ dysfunction. The accumulation of senescent cells may contribute to the development of many diseases that commonly occur during aging, including cancer. Furthermore, the elimination of senescent cells has been shown in pre-clinical animal models to be a safe and effective method of preventing or even reversing many of these aging-related diseases. A safe, effective, and selective method to reduce the proportion of senescent cells, relative to non-senescent cells, in an organ, tissue or whole organism, is therefore desirable.

[0013] Geroscience is the study of mechanisms that make aging a major risk factor for common chronic conditions and diseases of aging. Geroscience research seeks to understand how aging affects the disease process and to use that knowledge to slow the rate of aging, reverse its effects, and delay or even cure age-related diseases.

[0014] The primary goal of geroscience is to extend the healthy years of life by targeting the underlying biological processes of aging. Research areas encompass genetics, molecular biology, cellular biology, and physiology to study how aging contributes to diseases like cancer, diabetes, Alzheimer’s, and cardiovascular diseases. By understanding common pathways that drive both aging and age-related diseases, interventions can be developed to delay and / or prevent these conditions. Geroscience therapeutics (“gerotherapeutics”) have the potential to improve healthspan (the period of life spent in good health) and reduce the burden of chronic diseases on individuals and healthcare systems. One theory of geroscience holds that the accumulation of senescent cells is a primary driver of aging ATTORNEY DOCKET: 05336.0007WO01

[0015] and age-related diseases and that a therapeutic that reduces or eliminates these senescent cells would be an effective gerotherapeutic.

[0016] Summary

[0017] In an embodiment, a method comprises administering a cell penetrating peptide to a patient in an amount sufficient to selectively eliminate senescent cells.

[0018] In an embodiment, a method comprises administering a cell penetrating peptide to a patient in an amount sufficient to reduce inflammation and improve tissue and organ health by the elimination of senescent cells.

[0019] In an embodiment, a method comprises administering a cell penetrating peptide to a patient in an amount sufficient to reduce the effects of aging and improve the overall health and functioning of the patient by the elimination of senescent cells.

[0020] In an embodiment, a composition comprises a senolytic cell penetrating peptide in an amount sufficient to selectively reduced a senescent cell population.

[0021] Brief Description of the Drawings

[0022] The drawings illustrate certain implementations of the technology and are not limiting. For clarity and ease of illustration, the drawings are not made to scale, and, in some instances, various aspects may be shown exaggerated or enlarged to facilitate an understanding of particular implementations.

[0023] FIG. 1 A shows quantification of senescence-associated beta-galactosidase (“SA-p-Gal”) percent levels, a marker of senescent cells, in various tissues of naturally aged untreated mice at specified, increasing ages e.g. 6 weeks old, 30 weeks old, 60 weeks old, 75 weeks old and 90 weeks old.

[0024] FIG. 1 B shows quantification of SCs by uPAR and p16 immunohistochemistry in gastrocnemius in 75 week old naturally aged untreated mice.

[0025] FIG. 1 C shows quantification of SCs by uPAR and p16 immunohistochemistry in the prostate gland of 75 week old naturally aged untreated mice. ATTORNEY DOCKET: 05336.0007WO01

[0026] FIG. 2A illustrates an experimental scheme for testing senolytic activity of peptides in 75 week old naturally aged mice.

[0027] FIG. 2B and FIG. 2C show post-treatment reduction of senescent cell populations in inguinal adipose tissue of 75 week old naturally aged mice.

[0028] FIG. 2D shows post-treatment reduction of senescent cell populations in spleen, lung, and brain tissue in 75 week old naturally aged mice.

[0029] FIG. 2E shows post-treatment surface area quantification of brain CA1 and brain CA3 in 75 week old naturally aged mice.

[0030] FIG. 2F and FIG. 2G show post-treatment reduction of senescent cell populations in brain tissue in 75 week old naturally aged mice.

[0031] FIG. 2H shows post-treatment oligodendrocyte co-localization in 75 week old naturally aged mice.

[0032] FIG. 2I shows post-treatment co-localization of cell-type specific markers in 75 week old naturally aged mice.

[0033] FIG. 2J shows post-treatment adipocyte area in inguinal adipose tissue in 75 week old naturally aged mice.

[0034] FIG. 2K shows a side-by-side comparison of post-treatment reduction of senescent cell population (P-gal+ staining in spleen) with post-treatment reduction in intermyocyte space in gastrocnemius and in adipocyte area in inguinal adipose tissue in 75 week old naturally aged mice after no (saline) or 4, 6 and 8 weeks of peptide treatment.

[0035] FIG. 3A illustrates an experimental scheme for testing the phenotypic effects resulting from the senolytic activity of peptides in 75 week old naturally aged mice.

[0036] FIG. 3B shows body weight improvement in 75 week old naturally aged mice treated with GPP compared to no (saline) peptide treatment.

[0037] FIG. 3C shows post-CPP treatment body composition in 75 week old naturally aged mice compared to no (saline) peptide treatment.

[0038] FIG. 3D shows post-CPP treatment body composition in 75 week old naturally aged mice compared to no (saline) peptide treatment. ATTORNEY DOCKET: 05336.0007WO01

[0039] FIG. 3E shows post-CPP treatment rotarod testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0040] FIG. 3F shows post-CPP treatment treadmill endurance testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0041] FIG. 3G shows post-CPP treatment forelimb grip strength testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0042] FIG. 3H shows post-CPP treatment water-motivated Stone T-maze testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. FIG. 3I shows post-CPP treatment measurement of anti-inflammatory (M2) macrophage in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. FIG. 3J shows post-CPP treatment characterization of pro-inflammatory (M1) v. antiinflammatory (M2) macrophage in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0043] FIG. 4A shows post-CPP treatment reduction of senescent cell populations in spleen tissue in 75 week old naturally aged mice.

[0044] FIG. 4B shows post-CPP body weight improvement in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0045] FIG. 4C and FIG. 4D show body weight composition in naturally aged 75 week old mice treated with CPP compared to no (saline) peptide treatment.

[0046] FIG. 4E shows post-CPP treatment rotarod testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0047] FIG. 4F shows post-CPP treatment forelimb grip strength testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. ATTORNEY DOCKET: 05336.0007WO01

[0048] FIG. 4G depicts data associated with the phenotypic changes of PTGS2, HSPA8, IRS2, EGR1, JAG1.

[0049] FIG. 4H shows data associated with the phenotypic change of PHB2.

[0050] FIG. 4I shows data associated with anti-inflammatory effects and PTGS2.

[0051] FIG. 4J shows data associated with mitochondrial effects and PHB2.

[0052] FIG. 4K shows data associated with metabolic effects and HSPA8, IRS2 and JAG1. FIG. 5A shows post-CPP body weight improvement in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0053] FIG. 5B shows post-CPP overall survival and cancer-specific survival in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0054] FIG. 5C shows post-CPP body weight composition in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0055] FIG. 5D shows post-CPP treatment rotarod testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0056] FIG. 5E shows post-CPP treatment forelimb grip strength testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0057] FIG. 5F shows post-CPP treatment y-Maze cognition testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0058] FIG. 6A shows post-CPP body weight improvement in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0059] FIG. 6B shows post-CPP overall survival and cancer-specific survival in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0060] FIG. 6C shows post-CPP body weight composition in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0061] FIG. 6D shows post-CPP treatment rotarod testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0062] FIG. 6E shows post-CPP treatment forelimb grip strength testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. ATTORNEY DOCKET: 05336.0007WO01

[0063] FIG. 6F shows post-CPP treatment y-Maze cognition testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0064] FIG. 7A shows post-CPP body weight improvement in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0065] FIG. 7B shows post-CPP overall survival and cancer-specific survival in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0066] FIG. 7C shows post-CPP body weight composition in 75 week old naturally aged mice compared to results after no (saline) peptide treatment.

[0067] FIG. 8A illustrates an experimental scheme for testing senolytic activity of peptides in an accelerated skin aging model in rats.

[0068] FIG. 8B shows SA-[3-galactosidase staining of rat skin tissue.

[0069] FIG. 8C shows quantification of SCs by SA-[3-galactosidase staining of rat skin tissue. FIG. 9A illustrates an experimental scheme to test the senolytic activity of peptides in an accelerated systemic aging model in mice.

[0070] FIG. 9B shows representative SA- -gal-stained tissues.

[0071] FIG. 9C shows results from quantification of SCs as measured by percent SA-[3-gal+ area in the liver, kidneys, and spleen.

[0072] FIG. 10A illustrates an experimental scheme for testing senolytic activity of peptides in accelerated systemic aged mice.

[0073] FIG. 10B shows results from quantification of SCs as measured by percent SA-[3-gal+ area and p16 percent area by immunohistochemistry in spleen and lung in accelerated systemically-aged mice.

[0074] FIG. 10C, FIG. 10D, FIG. 10E, FIG. 10F, FIG. 10G and FIG. 10H shows SASP cytokine levels in the plasma taken from mice at different timepoints during peptide treatment compared to no (saline) control treatment.

[0075] FIG. 11 A illustrates an experimental scheme for testing senotherapeutic activity of peptides in accelerated systemically-aged mice.

[0076] FIG. 11 B shows prevention of late (3 to 6 months) radiation-induced toxicity in peptide-treated mice as demonstrated by body weight and percent survival. ATTORNEY DOCKET: 05336.0007WO01

[0077] FIG. 12A and FIG. 12B show cytotoxicity curves of peptides against proliferating and nonproliferating (senescent) cells.

[0078] FIG. 13 shows cytotoxicity curves of select peptides in proliferating and senescent cells. FIG. 14 shows cytotoxicity curves of select peptides in proliferating and senescent cells. FIG. 15A shows cytotoxicity curves of select peptides in proliferating and senescent cells. FIG. 15B shows percentage of apoptotic cells in proliferating and senescent cells.

[0079] FIG. 16 illustrates an experimental scheme for testing senotherapeutic activity of peptides in 75 week old naturally aged mice.

[0080] FIG. 17A shows cytotoxicity of peptides in cancer cells as demonstrated by characterization of peptide treatment in CML and ALL ABL1 wt cell lines.

[0081] FIG. 18A shows survival of peptide-treated mice in a TOM-1 (IV) tumor animal model FIG. 18B shows terminal flow cytometry in TOM-1 (IV) tumor animal model.

[0082] FIG. 19 shows TMRM staining in peptide-treated p- / s-IMR-90 cells normalized to mitochondrial mass.

[0083] FIG. 20 shows annexin V staining in peptide-treated p- / s-IMR-90 cells.

[0084] FIG. 21 A shows results of MS imaging of vehicle treatment areas and peptide treatment areas.

[0085] FIG. 21 B shows post-CPP cytokine reduction compared to results after no (vehicle) treatment.

[0086] FIG. 21 C shows post-CPP treatment rotarod testing results compared to results after no (vehicle) peptide treatment.

[0087] FIG. 21 D shows post-CPP treatment forelimb grip strength testing results compared to results after no (vehicle) peptide treatment.

[0088] FIG. 22 illustrates mitochondrial mass, membrane potential, and mitochondrial reactive oxygen species in young fibroblasts compared to senescent fibroblasts.

[0089] FIG. 23 illustrates a mitochondrial-mediated apoptosis pathway. ATTORNEY DOCKET: 05336.0007WO01

[0090] Detailed Description

[0091] Compositions containing certain components can reduce the quantity and proportion of senescent cells in an organ, tissue or whole organism. A component that selectively eliminates senescent cells is referred to as a “senolytic”.

[0092] Provided in certain aspects is a composition containing a senolytic cell penetrating peptide (“CPP”) in an amount sufficient to reduce a senescent cell population, referred to as a “CPP composition.”

[0093] In the conventional art, GPPs have been used to provide a carrier or transporter function, for example, to deliver an additional active component into a cell, across a cell membrane, etc. However, CPPs have not been known to provide a direct senolytic effect on their own, irrespective of this carrier function.

[0094] In certain aspects, a CPP composition contains an active ingredient containing, consisting essentially of, consisting of, or comprising the CPP itself. In certain aspects, a CPP composition is used to reduce a senescent cell population. In certain aspects, provided is a method for determining the senolytic cell quantity or proportion in a tissue, organ or animal, including a human, and monitoring the efficacy and persistence of senescent-cell elimination, after senolytic treatment administered to an aged animal, including an aged human. Certain implementations are described further in the following description, examples and claims, and in the drawings.

[0095] Described herein are CPP compositions, comprising the CPPs themselves and uses of such CPP compositions that demonstrate safe, effective, and selective senolytic activity. Also described are methods for determining the senolytic cell quantity or proportion and monitoring the efficacy and persistence of senescent-cell elimination, after senolytic treatment administered to an aged animal, including an aged human.

[0096] In certain aspects, provided is a composition comprising, consisting essentially of, or consisting of a CPP in an amount sufficient to reduce a senescent cell population. The senescent cell population can be identified using tissue-staining methods that detect (i) an SA-p-galactosidase-positive cell population; or (ii) a p16-positive cell population; or (iii) a urokinase plasminogen activator receptor (uPAR)-positivecell population; or (iv) a p-21 positive cell population; or (v) a combination of one or more of (i), (ii), (iii), and (iv).). SA-p-galactosidase, p21, and p16 are naturally occurring proteins that can be expressed at a ATTORNEY DOCKET: 05336.0007WO01

[0097] higher level in senescent cells than in non-senescent cells (Valieva et al., Diagnostics'^: 2309 (2022) Word Wide Web URL address doi.org / 10.3390 / diagnostics12102309). A p16 protein can be a p16INK4a protein. Senescent cell populations may also be identified using other markers for example, laminate B1, dsDNA breaks, 53BP1 and yH2AX which indicate telomere-associated DNA damage (TAF), lysosomal lipofuscin, Ki67, Phosphorylated RPS6, p53, and RB. SASP molecules may also indicate senescent cell populations, for example, MMP3, MMP9, Chemokines like 0XCR2, Cytokines like IL-6 and IL-8, IGFBP7, and others. Still further, Histone H2A. J and senescence associated heterochromatin foci SAHF may be used.

[0098] Overview of Senescent Cell Accumulation

[0099] Example 1: Senescent Cell Accumulation in Naturally Aged Mice

[0100] Senescent cells are known to accumulate as animals age. FIG. 1 A shows a representative increase in senescent cells throughout various tissues over the lifespan of naturally aged untreated mice.

[0101] Naturally aged C57BL / 6J mice were surveyed at 6, 30, 60, 75, and 90 weeks old. As a note, 75 week old mice are considered analogous to middle aged humans, approximately 50-55 years of age. Tissues from organs were stained and analyzed (using SA-[3-gal+ staining methods as will be discussed in more detail below) to quantify senescent cells. As shown in FIG. 1 A, a general increase in senescent cells occurs throughout the body correlated with increasing age.

[0102] FIG. 1 A depicts representative organs and analysis showing accumulation of senescent cell populations in a survey of naturally aged mice. As shown therein, the survey demonstrated a general increase in senescent cells throughout the body correlated with age.

[0103] FIG. 1 B shows quantification results of uPAR and p16 survey in gastrocnemius in naturally aged untreated mice. FIG. 1C shows quantification results of uPAR and p16 survey in prostate gland in naturally aged untreated mice. Both figures further demonstrate increase in senescent cells throughout the body correlated with age. ATTORNEY DOCKET: 05336.0007WO01

[0104] Overview of Senolytic Activity and Geroscientific / Gerotherapeutic Effect Elimination / reduction of such senescent cells will now be discussed with respect to the following examples. Frequently used peptides from various examples are listed in the following table:

[0105] Peptide Sequence

[0106] P1 WEARLARALARALARHLARALARALRACEA (SEQ ID NO: 5)

[0107] Itlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg (SEQ ID NO: 12) (FOXO4-DRI available from CLEARA Biotech).

[0108] *P2 is used in the examples as an additional control peptide because it has been suggested by others to have senolytic activity (Baar MP,

[0109] P2 Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis

[0110] in Response to Chemotoxicity and Aging, Cell, 2017 Mar

[0111] 23; 169(1): 132-147). As used in this Specification, P2 is not to be construed as a CPP and demonstrates minimal senolytic activity in the Examples.

[0112] P3 CRRLRHLRHHYRRRWHRFRC (SEQ ID NO: 15)

[0113] P4 RQIKIWFQNRRMKWKK (SEQ ID NO: 16)

[0114] LLIILRRRIRKQAHAHSK (SEQ ID NO: 13) (derived from murine VE- P5

[0115] Cadherin and referred to as murine pVEC (“m-pVEC”)

[0116] P6 WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 18)

[0117] P8 WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO: 19)

[0118] P9 WEARLARALARALARHLAHALAHALHACEA (SEQ ID NO: 20)

[0119] P10 LLIFLRRRLRKQARAHGK (SEQ ID NO: 14)

[0120] P11 kshahaqkrirrrliill (SEQ ID NO: 1009)

[0121] P12 kgharaqkrlrrrlfill (SEQ ID NO: 1010)

[0122] P13 aecahlahalahalhralaralaralraew (SEQ ID NO: 1077)

[0123] P14 wearlaralaralarhlahalahalhacea (SEQ ID NO: 1078)

[0124] aecahlahalaralhralaralaralraew (SEQ ID NO: 1079)

[0125] P15

[0126] lliilrrrirkqahahsk (SEQ ID NO: 1080)

[0127] P16

[0128] wearlaralaralarhlaralahalhacea (SEQ ID NO: 1081)

[0129] P17

[0130]

[0131] As discussed in more detail below, in certain embodiments, a senolytic CPP may have a logP measure lower than 0.1 (with log P measurements extending into the negative range), may have a net positive charge, one or more positively charged amino acids, an Arg (R) or ATTORNEY DOCKET: 05336.0007WO01

[0132] Lys(K) residue, and combinations thereof. These criteria are evaluated for the frequently used peptides P1 -P17 in the table below.

[0133] Peptide Length Number Percent Number LogP LogD Origin Category Number of + of + of - Charged Charged Charged

[0134] AA's AA's AA's

[0135] (K, R, H) (D, E)

[0136] P1 30 8 26.7% 2 -3.99 -10.15 Synthetic Amphipathic

[0137] P2 46 13 28.3% -10.81 -34.74

[0138] P5 18 8 44.4% -0.27 -10.73 Protein Amphipathic Derived

[0139] P6 30 8 26.7% 2 -3.03 -7.73 Synthetic Amphipathic P8 30 8 26.7% -2.55 -6.52 Synthetic Amphipathic P9 30 8 26.7% -2.55 -6.52 Synthetic Amphipathic P10 18 8 44.4% 0.04 -11.13 Protein Amphipathic Derived

[0140] P11 18 8 44.4% -0.27 -10.73 Protein Amphipathic Derived

[0141] P12 18 8 44.4% 0.04 -11.13 Protein Amphipathic Derived

[0142] P13 30 8 26.7% -2.55 -6.52 Synthetic Amphipathic P14 30 8 26.7% -2.55 -6.52 Synthetic Amphipathic P15 30 8 26.7% 2 -3.03 -7.73 Synthetic Amphipathic P16 18 8 44.4% -0.27 -10.73 Protein Amphipathic Derived

[0143] P17 30 8 26.7% 2 -3.03 -7.73 Synthetic Amphipathic

[0144]

[0145] In embodiments, a senolytic CPP may have a logP lower than 0.1, a charge of at least positive 1, one or more positively charged amino acids, and / or one or more of Arg(R) and / or Lys(K) residues. In some embodiments, a senolytic CPP may have a logP lower ATTORNEY DOCKET: 05336.0007WO01

[0146] than 0.1, a charge of at least positive 1, one or more positively charged amino acids, and one or more of Arg(R) and / or Lys(K) residues.

[0147] Still further, in embodiments a senolytic CPP may have a length greater than four amino acids and fewer than 60 amino acids.

[0148] Examples 2-7

[0149] Examples 2 through 7 discussed below were studies performed in naturally aged 75 week old mice (analogous to approximately 50-55 year old humans), not a potentially flawed transgenic or other artificial model.

[0150] As shown in Examples 2-7, P1, P5, P6, and P15 target senescent cells for elimination by approximately 8 weeks of treatment. Senescent cells play a widely recognized role in aging while having a limited role in the normal, healthy biology of organs in mammals, including mice and humans. Targeted elimination of senescent cells avoids potentially more toxic approaches that target or cellular mechanisms that play more diverse and key roles in cellular biology. Further, elimination of senescent cells may require only episodic, not continuous, therapy, to exert a beneficial effect thus further limiting the risk of toxicity. The examples demonstrate the following proof of concept in geroscience:

[0151] P1, P5, P6, and P15 effectively and safely eliminate senescent cells in all organs of the body. These peptides also demonstrate ability to cross the blood brain barrier by way of their effective senolytic activity demonstrated in the brain after intraperitoneal administration, for example, including in key areas of the brain associated with neurodegenerative disorders like Alzheimer’s Disease and Chronic Traumatic Encephalopathy (Hippocampus-CA1 and CA3, Cerebral Cortex) and Parkinson’s Disease (Substantia Nigra and Basal Ganglia).

[0152] P1 and P5 effectively reduce plasma level of key cytokine components of the SASP. P1 and P5 effectively reduce the intermyocyte space and adipocyte area in treated mice, indicating improved tissue morphometry and health.

[0153] P1, P5, P6, and P15 prevent or reduce the weight loss associated with aging-associated sarcopenia. P1, P5, P6, and P15 add lean body and bone mass at the expense of fat compared with control animals. ATTORNEY DOCKET: 05336.0007WO01

[0154] P5 and P6 improve performance of treated mice on the Rotarod, a device measuring a combination of cognitive ability, balance, and exercise capacity. Mice treated with P1, P5 and P6 also showed decreased fatigue on the motorized treadmill test, increased forelimb grip strength on the grip strength test and improved cognitive performance on the water motivated Stone T-maze test.

[0155] P5 and P6 demonstrate the above stated effects in a dose-dependent manner. This is predominantly seen with weight loss or weight gain prevention, fat loss, and muscle gain. Examples 2 through 7 are now discussed in detail.

[0156] Example 2: Senolytic CPP In Naturally Aged Mice

[0157] 75 week old naturally aged (female C57BL / 6J) mice (analogous to middle aged 50-55 year old humans) were administered three peptides: P1, P2, and P5 (see FIG. 2A). Saline was used as a negative control. Peptides were administered 3X per week intraperitoneally (“IP”) at a dose of 1.5E-3 pmoles / kg.

[0158] Group Peptide Dose

[0159] 1a (n=4) P1 - 2 weeks 1.5E-3 pmoles / kg (5 mg / kg IP)

[0160] 1b (n=4) P1 - 4 weeks 1.5E-3 pmoles / kg (5 mg / kg IP)

[0161] 1c (n=4) P1 - 6 weeks 1.5E-3 pmoles / kg (5 mg / kg IP)

[0162] 1d (n=4) P1 - 8 weeks 1.5E-3 pmoles / kg (5 mg / kg IP)

[0163] 2a (n=4) P5 - 2 weeks 1.5E-3 pmoles / kg (3.3 mg / kg IP)

[0164] 2b (n=4) P5 - 4 weeks 1.5E-3 pmoles / kg (3.3 mg / kg IP)

[0165] 2c (n=4) P5 - 6 weeks 1.5E-3 pmoles / kg (3.3 mg / kg IP)

[0166] 2d (n=4) P5 - 8 weeks 1.5E-3 pmoles / kg (3.3 mg / kg IP)

[0167] 3a (n=4) P2 - 2 weeks 1.5E-3 pmoles / kg (8.1 mg / kg IP)

[0168] 3b (n=4) P2 - 4 weeks 1.5E-3 pmoles / kg (8.1 mg / kg IP)

[0169] 3c (n=4) P2 - 6 weeks 1.5E-3 pmoles / kg (8.1 mg / kg IP)

[0170] 3d (n=4) P2 - 8 weeks 1.5E-3 pmoles / kg (8.1 mg / kg IP)

[0171] 4a (n=4) Saline

[0172] 4b (n=4) Saline

[0173] 4c (n=4) Saline

[0174] 4d (n=4) Saline

[0175]

[0176] 4e (n=4) Saline ATTORNEY DOCKET: 05336.0007WO01

[0177] Senescent cells were quantified in harvested organs at baseline, 2, 4, 6 and 8 weeks by three different staining methods: SA-β-Gal+ staining and p16 and uPAR immunohistochemistry.

[0178] Post-treatment senescent cell populations in inguinal adipose tissue (IAT) are shown in FIG. 2B and FIG. 20. Results are shown after 8 weeks. Senescent cells were quantified in harvested organs by uPAR and p16 immunohistochemical staining methods.

[0179] As shown in FIG. 2B and FIG. 20, P1 demonstrated reduction of senescent cells by over 43% (uPAR staining) and over 50% (p16 staining) in IAT. P5 demonstrated reduction of senescent cells by 67% (uPAR staining) and over 53% (p16 staining). These results were statistically significant even though the studies were not powered to show significance. IAT SA-p-Gal Re ative Change (relative to saline)

[0180] Peptide uPAR P P16 P

[0181] P1 -43.7% P<0.01 -50.2% PcO.0001 P5 -67.8% PcO.0001 -53.8% PcO.0001

[0182]

[0183] P2 +1.73% n.s. -13.5% n.s.

[0184] In summary, P1 and P5 demonstrated effective senolytic activity in IAT in naturally aged mice compared with both the saline control and the control peptide P2.

[0185] Post-treatment senescent cell populations in spleen, lung, and brain (CA1 and CA3 regions) are shown in FIG. 2D. Results are shown after 8 weeks. Senescent cells were quantified in harvested organs by SA-β-Gal+ staining methods.

[0186] As shown in FIG. 2D, P1 demonstrated reduction of senescent cells by 39% in spleen and 78% in lung. P5 demonstrated reduction of senescent cells by 67% in spleen and 77% in lung. Further, P5 demonstrated reduction of senescent cells by 35% and 32% in two key regions of the brain associated with memory consolidation (hippocampus CA1) and pattern completion and episodic memory (hippocampus CA3). These results were statistically significant for P5 even though the studies were not powered to show significance.

[0187] In summary, P1 and P5 demonstrated effective senolytic activity in spleen and lung of naturally aged mice compared with the saline control.

[0188] Importantly, P1 and P5 also demonstrated ability to cross the blood brain barrier and provide effective senolytic activity in regions of the brain, including the hippocampus CA1 and CA3 regions involved in key memory functions. ATTORNEY DOCKET: 05336.0007WO01

[0189] Additionally, there was no apparent loss of volume in these two regions during treatment indicating on evidence of off target toxicity as shown in FIG. 2E.

[0190] Additionally, post-treatment senescent cell populations in tissues from certain areas of the brain associated with various neurodegenerative diseases e.g. Alzheimer’s Disease and Chronic Traumatic Encephalopathy (Hippocampus CA1 and 0A3, Cerebral Cortex) and Parkinson’s Disease (Basal Ganglia) are shown in FIG. 2F and FIG. 2G. Results are shown after 8 weeks. Senescent cells were quantified in harvested organs by p16 staining methods (relative to DAPI).

[0191] P16 %Area Relative Change (Relative to Saline)

[0192] Peptide CA1 (P) CA3 (P) Cerebral Basal Ganglia Cortex (P) (P)

[0193] P1 -63.3% (n.s.) -55.3% (n.s.) -80.9% (n.s.) -82.9%

[0194] (<0.01 ))

[0195] P5 -46.1% (n.s.) -63.8% (n.s.) -51.6% (n.s.) -64.4 (<0.05)

[0196]

[0197] P2 +65.4% (n.s.) -24.2% (n.s.) -64.5% (n.s.) -35.9% (n.s.)

[0198] P21 %Area Relative Change (Relative to Saline)

[0199] Peptide CA1 (P) CA3 (P) Cerebral Basal Ganglia Cortex (P) (P)

[0200] P1 -72.9% (n.s.) -62.1% (n.s.) -53.5% (n.s.) -61.3% (n.s.) P5 -79.3% (n.s.) -54.5% (n.s.) -52.8% (n.s.) -21.2 (n.s.)

[0201]

[0202] P2 +63.8% (n.s.) -54.7% (n.s.) -25.0% (n.s.) +8.41% (n.s.)

[0203] Further cell type-specific immunohistochemistry and co localization studies were performed to assess which specific cell types were preferentially eliminated. As shown in FIG. 2H and FIG. 2I, P1 and P5 have minimal effects on neurons, as one would hope, while demonstrating a modest reduction of p16+ senescent oligodendrocytes, primarily in the CA-3 and basal ganglia regions of the brain.

[0204] Oligodendrocyte Percent Reduction - Bulk vs p16+

[0205] Peptide CA1 CA1 -p16% Tl

[0206] P1 -27.2% +44.5% 0.39

[0207] P5 -25.2% +24.7% 0.5

[0208] P2 -12.2% -33.9% 2.78

[0209] CA3 CA3-p16% Tl

[0210] P1 +33.3% -39.7% >50

[0211] P5 +4.94% -52.7% >50

[0212] P2 +9.90% -33.5% >50

[0213]

[0214] ATTORNEY DOCKET: 05336.0007WO01

[0215] BG BG-p16% Tl

[0216] P1 -4.34% -11.2% 2.58

[0217] P5 -7.14% -18.8% 2.63

[0218]

[0219] P2 0%

[0220] Improved tissue morphometry and adipose tissue health as a result of the elimination of senescent cells is also demonstrated by reduction of adipocyte area. Previous studies have also shown reduction of adipocyte area in visceral adipose tissue when senescent cells are genetically eliminated. (Palmer, Allyson K. et al. “Targeting senescent cells alleviates obesity-induced metabolic dysfunction.” Aging Cell 8 (2019)).

[0221] Post-treatment adipocyte area quantification in IAT is shown in FIG. 2J. Results are shown after 8 weeks.

[0222] IAT Adipocyte Area Relative change (Relative to Saline) Peptide %Change P

[0223] P1 -48.05% PcO.0001

[0224] P5 -10.6% n.s.

[0225]

[0226] P2 -11.38 n.s.

[0227] As shown in FIG. 2J, a reduction of 48.05% in adipocyte area was also demonstrated by P1. These results were statistically significant even though the studies were not powered to show significance.

[0228] Post-treatment results also show a dose response curve having shared kinetics across the elimination of senescent cells and resulting tissue morphometric effects in diverse tissues, e.g. muscle (intermyocyte space) and fat (adipocyte area). For example, reduction of senescent cell populations correlates with other beneficial tissue morphometric phenotypic changes.

[0229] As discussed above, senolytic effect was measured by post-treatment reduction of senescent cell populations in spleen (along with other tissues) as shown in FIG. 2D. An additional measure to assess pathological effect of aging on muscle tissue is to measure an intermyocyte space. In this example, the intermyocyte space was measured in the gastrocnemius at baseline and at 2, 4, 6, and 8 weeks of peptide treatment and showed a 12.2% reduction at 8 weeks, a sign of improved muscle health. ATTORNEY DOCKET: 05336.0007WO01

[0230] FIG. 2K shows a side-by-side comparison of post-treatment reduction of senescent cell population (SA-β-Gal+ staining in spleen) with post-treatment reduction in intermyocyte space in gastrocnemius and in adipocyte area in inguinal adipose tissue in naturally aged mice. As can be seen, reduction in all three can be seen with the same dose response kinetics, beginning at 6 weeks and are accelerating at 8 weeks. These results with P for Intermyocyte Space at 6 weeks and for Adpipocyte Area at 8 weeks were statistically significant even though the studies were not powered to show significance.

[0231] Spleen SA- / ?-Gal Gastrocnemius IAT Adipocyte Area (Change Relative to Intermyocyte Space (Change Relative to Saline) (Change Relative to Saline)

[0232] Saline)

[0233] Peptide 6-week 8-week 6-week 8-week 6-week 8-week (P) (P) (P) (P) (P) (P) P1 -12.7% -39.2% -2.99% -12.2% -21.9% -33.9%

[0234] (n.s.) (<0.05) (<0.01 ) (n.s.) (n.s.) (<0.001 ) P5 -16.4% -67.1% -4.99% -3.20% -12.0% +5.25% (n.s.) (<0.01 ) (n.s.) (n.s.) (n.s.) (n.s.) P2 -13.6% -27.9% -6.88% -8.47% -15.2% -26.7%

[0235]

[0236] _ (TLSj _ _ (ILSJ _ _ QLSJ _ _ (LLSJ _ _ QLSJ _ _ QLSJ _

[0237] Further, SASP levels were monitored through the 8-weeks of peptide treatment for a range of cytokines. P1 and P5 showed a reduction in or maintenance of levels of components of the SASP compared to saline controls. In many cases, P1 and P5 treated groups maintained cytokine levels at approximately 0. In several components of the SASP, treatment with P2 led to elevated plasma levels compared to treatment with saline controls and to treatment with P1 and P5. Finally, P5 treated groups performed equal to or better than control groups in every case.

[0238] Plasma Levels Compared to Saline Control-Treated Group

[0239] Peptide -Equal -0 pg / mL Lower Higher P1 IL-18, CCL4, CXCL2, TNF IL-9, IL-15, IL-22, IL- IL-9, IL-15, IL-1 beta, IL- alpha, IFN gamma, IL-1 23, IL-27, LIF, IL-18, IL-28, IL-22, 2, IL-6 alpha, IL-3, IL-4, IL-5, IL- CCL3, CXCL2, TNF IL-23, IL-27,

[0240] 10, IL-12p70, IL-13, IL-31, alpha, IFN gamma, IL- LIF, CCL3,

[0241] 1 alpha, IL-3, IL-4, IL- CCL5, IL-9

[0242] 5, IL-9, IL-10, IL- 12p70, IL-13, IL-31

[0243] P5 IL-18, CCL4, CXCL2, TNF IL-9, IL-15, IL-28, IL- IL-9, IL-15,

[0244]

[0245] alpha, IFN gamma, IL-1 22, IL-23, IL-27, LIF, IL-28, IL-22, ATTORNEY DOCKET: 05336.0007WO01

[0246] alpha, IL-1 beta, IL-2, IL-3, IL-18, CCL3, CXCL2, IL-23, IL-27,

[0247] IL-4, IL-5, IL-6, IL-10, IL- TNF alpha, IFN LIF, CCL3,

[0248] 12p70, IL-13, IL-31 gamma, IL-1 alpha, CCL5, IL-9

[0249] IL-1 beta, IL-2, IL-3,

[0250] IL-4, IL-5, IL-6, IL-9,

[0251] IL-10, IL-12p70, IL-13,

[0252] IL-31

[0253] P2 IL-22, IL-18, CCL3, IL-23, IL-27, LIF, IL- IL-23, IL-27, IL-9, IL-15, CXCL2, CCL5, IL-9, IL-10 18, CXCL2, IL-10 LIF IL-28, CCL4,

[0254] TNF-alpha, IFN-gamma, IL-1 alpha, IL- 1 beta, IL-2, IL-3, IL-4, IL- 5, IL-6, IL-31, IL-12p70, IL-

[0255]

[0256] 13

[0257] Example 2 shows that P1 and P5 safely and effectively reduce / eliminate senescent cells quantified by four different methods of histological quantification (SA-β-Gal, uPAR, p16, and p21 ) in various organs of the naturally aged 75 week old mice including in key areas of the brain associated with neurodegenerative disorders, for example, Alzheimer's Disease and Chronic Traumatic Encephalopathy (Hippocampus-CA1 and CA3, Cerebral Cortex) and Parkinson’s Disease (Basal Ganglia). In the brain, these peptides also preferentially eliminated senescent microglial cells and oligodendrocytes compared to neurons.

[0258] Through 8 weeks of treatment, both P1 and P5 treated groups showed either a reduction in or maintenance of plasma levels of components of the SASP-associated cytokines compared to saline controls. In many cases, P1 and P5 treated groups maintained cytokine levels at Opg / mL.

[0259] Elimination of senescent cells is seen beginning after approximately 6 weeks of peptide therapy and increases at 8 weeks of therapy.

[0260] Further, gastrocnemius intermyocyte space and IAT adipocyte area both decreased over time with P1 and P5 treatment, demonstrating improved tissue morphology and health with peptide treatment. This improvement also followed the same kinetics as seen with senescent cell elimination.

[0261] No apparent toxicity was observed in this example. ATTORNEY DOCKET: 05336.0007WO01

[0262] Example 3: Senotherapeutic CPP in Naturally Aged Mice

[0263] This example is substantially similar to Example 2 except in that male C57BL / 6J mice were used and different peptide compositions were employed. Further, additional phenotypic measurements in treated mice were measured and / or monitored. See FIG. 3A.

[0264] 75 week old naturally aged (male C57BL / 6J) mice (analogous to middle aged humans) were administered three peptides: P1, P5, and P6.

[0265] Saline was used as a negative control. Peptides were administered 3X per week IP at a dose of 1.5E-3 pmoles / kg. Phenotypic analysis was performed at 12 / 13 weeks.

[0266] Group Peptide Dose

[0267] A (n=8) P1 1.5E-3 pmoles / kg (5 mg / kg IP) B (n=8) P5 1.5E-3 pmoles / kg (3.3 mg / kg IP) C (n=8) P6 1.5E-3 pmoles / kg (5 mg / kg IP)

[0268]

[0269] D (n=8) Saline n / a

[0270] Body weights of mice were tracked weekly throughout the study.

[0271] Senotherapeutic effect may be demonstrated by reduction or prevention of weight loss, or even weight gain, in naturally aging 75 week old mice. Previous studies have shown that naturally aged mice experience a reduction in weight (age-associated weight loss or sarcopenia). Further, previous studies have shown a reduction or prevention of weight loss, or even weight gain when senescent cells are eliminated using a genomic ablation model (Ogrodnik, Mikolaj et al. “Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.” Aging cell vol. 20,2 (2021 ): e13296. doi:10.1111 / acel.13296). Weight gain, rather than expected weight loss, after 13 weeks of peptide treatment of treated naturally aged mice is shown (see FIG. 3B) for P1 and P5 peptide treated mice, and a reduction in weight loss in P6 treated mice compared to control saline-treated mice in FIG. 3B.

[0272] % Body Weight Change

[0273] Relative to initial Timepoint Relative to Saline Cohort 1, Latest Time Point Peptide Relative % Relative % p

[0274] P1 101% +5.18% n.s.

[0275] P5 102% +6.04% n.s

[0276] P6 98.8% +3.07% n.s.

[0277]

[0278] Saline 95.9% - - ATTORNEY DOCKET: 05336.0007WO01

[0279] Higher weights, compared to saline-treated controls, were observed in P1, P5, or P6 treated mice compared to saline control-treated mice. The reduction or prevention of age-associated sarcopenia demonstrates the beneficial health effects of cell penetrating peptides compositions in aging animals.

[0280] In addition to weight, body composition was also measured at designated time points. DEXA Scanning was performed at 13 weeks of peptide treatment. Results are shown in FIG. 30 and FIG. 3D as well as the tables below.

[0281] Body Composition - %Change Rela ive to Saline

[0282] Fat P Lean P Bone P Bone P Total P Mass Mass Mass Density Mas

[0283] P1 -1.95% n.s. +1.01% n.s. -3.15% n.s. -1.24% n.s. +4.56% n.s. P5 -18.4% n.s. -8.49% n.s. +6.26% n.s. -1.57% n.s. -6.71% n.s.

[0284]

[0285] P6 -20.3% n.s. +9.48% n.s. +2.99% n.s. +0.10% n.s. -0.17% n.s.

[0286] Body Composition - %Change Relative to Saline

[0287] Fat P Lean P Bone P Bone P Total P Mass Mass Mass Density Mass

[0288] P1 -1.95% n.s. +1.01% n.s. -3.15% n.s. -1.24% n.s. +4.56% n.s. P5 -18.4% n.s. +8.49% n.s. +6.26% n.s. -1.57% n.s. -6.71% n.s.

[0289]

[0290] P6 -20.3% n.s. +9.48% n.s. +2.99% n.s. +0.10% n.s. -0.17% n.s.

[0291] Mice treated with P5 and P6 peptides experienced an improved body composition, with a -20% reduction in fat mass offset by a -10% increase in lean body mass and a 3-6% increase in bone mass, compared to control saline-treated mice.

[0292] Senotherapeutic effect is also evaluated by mouse “Olympiad” testing in which mice were also monitored for additional aging phenotypic measurements. For example, in addition to body composition analysis using DEXA, motor coordination, balance and endurance were tested with Rotarod, strength and endurance were tested with motorized treadmill, strength was tested with the grip strength testing device, and spatial learning and memory was tested using the water-motivated Stone T-Maze.

[0293] Instrument Metric Indication Motorized Treadmill strength, endurance Sarcopenia Rotarod motor coordination, Sarcopenia, Brain balance, and endurance (cognition for balance)

[0294]

[0295] ATTORNEY DOCKET: 05336.0007WO01

[0296] Water-Motivated spatial learning and Alzheimer's, TBI Stone T-maze memory

[0297] Grip-strength strength Sarcopenia DEX A body composition Sarcopenia / Obesity

[0298]

[0299] FIG. 3E shows results of balance / exercise capacity testing using the Rotarod testing device. Rotarod testing parameters included maximum time of 300 seconds, maximum distance of 100 meters, and maximum RPM of 40. Observers were blinded to the treatment groups and all data was captured automatically by the Rotarod.

[0300] Rotarod Activity - Percent Change Relative to Saline

[0301] Peptide Time at P Total P Maximum P

[0302] Fall Distance Speed

[0303] P1 -3.24% n.s. -8.17% n.s. +3.78% n.s.

[0304] P5 +15.8% n.s. +37.2% n.s. +22.5% n.s.

[0305]

[0306] P6 +13.3% n.s. +27.3% n.s. +15.0% n.s.

[0307] As shown, after 13 weeks of treatment, Rotarod testing showed a greater result for time at fall, total distance, and maximum speed for P5 and P6 treated mice compared with control saline-treated mice, indicating more youthful and healthier functioning.

[0308] FIG. 3F shows results of strength and endurance testing using a motorized treadmill test after 14 weeks of peptide treatment. Testing parameters included maximum time of 1920 seconds, maximum distance of 552 meters, and maximum speed 24 m / s. Observers were blinded to the treatment groups and all data captured automatically by the treadmill.

[0309] Endurance Tes ting - Warnings

[0310] Peptide # of Mice <50 # of Mice >50 % of Mice <50 % of Mice >50 warnings warnings warnings warnings Saline 2 5 28.6% 71.4%

[0311] P1 6 2 75% 25%

[0312] P5 6 2 75% 25%

[0313]

[0314] P6 5 3 62.5% 37.5%

[0315] “Warnings” or “warning rate” reports each time the mouse stops running and enters a “fatigue zone”.

[0316] The warning rate, representative of time in the fatigue zone, can help identify when a mouse is reaching fatigue and indicates a mouse’s stamina and endurance levels. ATTORNEY DOCKET: 05336.0007WO01

[0317] This can then provide insight into a mouse's exercise capability and overall health.

[0318] Thus, these results show improved exercise capability after 14 weeks of peptide treatment with P1 P5-, and P6-peptide treated mice compared to control saline-treated mice.

[0319] FIG. 3G shows results of forelimb grip strength testing after 14 weeks of peptide treatment. Hand grip strength is widely accepted as a measurement for diagnosing sarcopenia. In humans, it is a simple, non-invasive test that provides valuable information about muscle function and overall physical capability, especially in older adults. Low hand grip strength is associated with an increased risk of adverse outcomes such as falls, fractures, physical disability, and mortality.

[0320] Forelimb Grip Strength - %Relative to Saline

[0321] Peptide Percent Change P

[0322] P1 +3.47% n.s.

[0323] P5 +16.7% n.s.

[0324]

[0325] P6 +2.72% n.s.

[0326] P1-, P5-, and P6-peptide treated mice showed increased hand grip strength compared to control saline-treated mice.

[0327] FIG. 3H shows results of Water-Motivated Stone T-maze testing after 15 weeks of peptide treatment. Water-motivated Stone T-maze testing tests a mouse’s spatial learning and memory.

[0328] Maze Testing -%Change Relative to Saline

[0329] Peptide Total % Change Total Error Rate % Change Completion (8 Relative to (8 runs) per Relative to runs) Time per Saline (P) Mouse Saline (P) Mouse (sec)

[0330] Saline 446.9 - 33.9 /

[0331] P1 334.4 -25.2% (n.s.) 25.0 -26.3%

[0332] (P<0.05) P5 436.8 -2.26% (n.s.) 49.4 +45.7% (n.s.)

[0333]

[0334] P6 325.9 -27.1% (n.s.) 30.7 -9.44% (n.s.)

[0335] P1-, P5- and P6-peptide treated mice showed reduced time to navigate through the maze compared to control saline-treated mice, indicating improved memory and cognitive function. ATTORNEY DOCKET: 05336.0007WO01

[0336] Anti-inflammatory macrophage measurements were also taken in inguinal adipose tissue (IAT), perirenal adipose tissue (PRAT), and gonadal adipose tissue (GAT) after 17 weeks of peptide treatment. Results are shown in FIG. 3I.

[0337] IAT %Area Relative PRAT %Area Relative GAT %Area Relative Change Change Change (Relative to Saline) (Relative to Saline) (Relative to Saline) Peptide %Change P %Change P %Change P P1 +44.3% 0.0766 +89.2% 0.0885 +17.5% 0.5377 P5 +60.6% 0.250 +59.7% 0.1392 +80.2% 0.0339 P6 +56.4% 0.0490 +76.6% 0.0859 -1.3% 0.9547

[0338]

[0339] Further, the proportion of pro-inflammatory (M1) v. anti-inflammatory (M2) macrophage was compared. Results are shown in FIG. 3J.

[0340] As shown, after 17 weeks of peptide treatment, the proportion of M2 Anti-Inflammatory Macrophage subtype increased in all three types of adipose tissue

[0341] Example 3 shows that treatment of naturally aged 75 week old mice with P1, P5, and P6 prevented or reduced weight loss associated with aging-associated sarcopenia expected and observed with control saline treated mice (which lost weight as expected, a sign of aging-associated sarcopenia). Further and importantly, mice treated with P5 and P6 added lean body and bone mass at the expense of fat compared to control saline-treated animals as determined by DEXA scanning. Preservation of lean body mass at the expense of fat body mass is an important yet elusive goal of weight loss therapies for the treatment of obesity in humans.

[0342] After 13 weeks of peptide treatment, Rotarod testing, which tests a combination of cognitive ability, balance and exercise capacity, showed a greater magnitude for time at fall, total distance and maximum speed for mice treated with P5 and P6 peptides compared to control saline-treated mice demonstrating more youthful and healthier functioning.

[0343] After 14 weeks of treatment, motorized treadmill testing, which tests a mouse’s strength and endurance, showed reduced fatigue for P1-, P5-, and P6-peptide treated mice ATTORNEY DOCKET: 05336.0007WO01

[0344] compared to control saline-treated mice, demonstrating improved exercise capability and overall health.

[0345] After 14 weeks of treatment, forelimb hand grip strength, a standard test in sarcopenia / frailty clinical trials, showed increased hand grip strength for P1 P5-, and P6-peptide treated mice compared to control saline-treated mice.

[0346] After 15 weeks of treatment, Water Motivated Stone T-maze testing, which tests a mouse’s spatial learning and memory, showed reduced time to navigate through the maze for P1-, P5- and P6-peptide treated mice compared to control saline-treated mice, demonstrating improved memory and cognitive function.

[0347] Further, after 17 weeks of peptide treatment, P1, P5, and P6 treated mice demonstrated increased anti-inflammatory (M2) macrophage in IAT and PRAT. P1 and 5 treated mice also demonstrated increased anti-inflammatory (M2) macrophage in GAT. Still further, the proportion of M2 Anti-Inflammatory Macrophage subtype increased in all three types of adipose tissue based on treatment with each of P1, P5, and P6.

[0348] No apparent toxicity was observed in any of the treatment groups in this example.

[0349] Prophetic Example 3’: Additional Studies Involving the Senotherapeutic CPP in Naturally Aged Mice of Example 3

[0350] Example 3 is ongoing. Results testing these mice for plasma SASP are pending.

[0351] Senescent cell quantification is to be performed upon sacrifice of mice. Once the complete array of phenotyping studies has been performed, the mice are to be sacrificed, and senescent cells are to be quantified by SA-B-Gal in the spleen and brain, and by uPAR / p16 in all fat tissues. Gastrocnemius morphology for intermyocyte space and IAT for adipocyte area are to be measured as well.

[0352] Additional embodiments may include monitoring additional aging phenotypic measurements. In embodiments, aging phenotypic measurements may include but are not limited to glucose tolerance testing, insulin tolerance testing, and / or blood chemistry (for example, fasting glucose, kidney, liver, cardiac, and the like).

[0353] Mice treated with P1 and P5 demonstrate reduced senescent cell populations and resulting reduced plasma SASP levels. Furthermore, mice treated with P1, P5, and P6 show ATTORNEY DOCKET: 05336.0007WO01

[0354] improved results and function with most of the phenotypic measurements made. Those improved results appear to be correlated with the reduction in senescent cell population and the reduction in plasma SASP levels seen with CPP peptide treatment.

[0355] Example 4: Senotherapeutic CPP in Naturally Aged Mice

[0356] 75 week old naturally aged (female C57) mice (analogous to middle aged 50-55 year old humans) were administered P6 peptide. Saline was used as a negative control. Peptides were administered subcutaneously (“SC”) at varying dosages as shown in the following table:

[0357] Group Peptide Administration Dose

[0358] 1(n=5) P6 SC 3X Weekly 50mg / kg

[0359] 2 (n=5) P6 SC 3X Weekly 25mg / kg

[0360] 3 (n=5) P6 SC 3X Weekly 10mg / kg

[0361] 4 (n=5) P6 SC 3X Weekly 5mg / kg

[0362] 5 (n=5) P6 SC 3X Weekly 2.5mg / kg

[0363] 6 (n=5) P6 SC 1X Weekly 50mg / kg

[0364]

[0365] 7 (n=5) Saline SC 3X Weekly

[0366] Tissues for all animals were harvested. Tissues were analyzed for those mice where reduction in SASP cytokines was seen. Tissues were analyzed by histology for uPAR / p16: spleen, iWAT, gastrocnemius, interscapular brown adipose tissue, subcutaneous adipose tissue, perigonadal, and perinephric fat, liver, lung, brain, and heart.

[0367] Brain, heart, kidney, liver, and lung were stained by H& E and sent for toxicity analysis. FIG. 4A shows post-treatment reduction of senescent cell populations in spleen tissue in naturally aged 75 week old mice. Data is also shown in the table below. Treated mice showed elimination / reduction of senescent cells.

[0368] Treatment / Dosage % Change P

[0369] Saline - - P6 (25mg / kg, 3X / week) -33.0% 0.0025

[0370] P6 (50mg / kg, 3X / week) -52.0% 0.0009

[0371]

[0372] P6 (50mg / kg, 1X / week) -59.6% <0.0001 ATTORNEY DOCKET: 05336.0007WO01

[0373] FIG. 4B shows body weight improvement in naturally aged 75 week old mice treated with CPP compared to no (saline) peptide treatment. Data is also shown in the table below. Treated mice showed reduction in body weight.

[0374] 20 Weeks Treatment

[0375] P6 % Body Weight Change

[0376] Relative to Initial Timepoint Relative to Saline, Latest Time Point

[0377] Dose (Route, Relative% P Relative% P mg / kg)

[0378] Saline 98.2% 0.5592 - - SC, 2.5mg / kg 97.8% 0.7940 -0.41% 0.9628 SC, 5mg / kg 97.5% 0.2861 -0.71% 0.8804 SC, 10mg / kg 100.6% 0.7649 2.44% 0.5989 SC, 25 mg / kg 92.8% 0.1599 -5.50% 0.3180 SC, 50mg / kg 78.2% 0.0045 -20.37% 0.0023 SC, 50mg / kg 89.3% 0.0410 -9.06% 0.1557

[0379]

[0380] (1X / week)

[0381] FIG. 4C and FIG. 4D show body weight composition in naturally aged 75 week old mice treated with CPP compared to no (saline) peptide treatment. Data is also shown in the following table. Treated mice showed reduction of fat mass and increase in lean mass.

[0382] 20 Weeks Treatment

[0383] P6 Fat Mass Lean Mass

[0384] Dose (Route, A Saline P A Saline P mg / kg) (Latest Time (Latest Time

[0385] Point) Point)

[0386] SC, 2.5mg / kg -24.12% 0.2999 -3.04% 0.3907 SC, 5mg / kg -15.29% 0.4207 3.92% 0.2544 SC, 10mg / kg -9.06% 0.6112 3.00% 0.1682 SC, 25 mg / kg -24.65% 0.2309 6.27% 0.2033 SC, 50mg / kg -64.04% 0.0261 14.76% 0.0550 SC, 50mg / kg -40.34% 0.1642 9.817% 0.0828

[0387]

[0388] (1X / week)

[0389] FIG. 4E shows post-CPP treatment rotarod testing results in naturally aged 75 week old mice compared to results after no (saline) peptide treatment. Data is also shown in the following table. Treated mice showed improvement in all three categories, namely, improved latency, distance, and speed. ATTORNEY DOCKET: 05336.0007WO01

[0390] Rotarod - 20 Weeks Treatment

[0391] P6 Latency Distance Speed

[0392] Dose A Saline P A Saline P A Saline P (Route, (Latest (Latest (Latest

[0393] mg / kg) Time Time Time

[0394] Point) Point) Point)

[0395] SC,

[0396] 28.62% 0.3356 55.12% 0.3757 24.29% 0.482 2.5mg / kg

[0397] SC, 5mg / kg 11.26% 0.648 17.17% 0.7447 16.44% 0.5516 SC,

[0398] 0.81% 0.9682 7.92% 0.8548 6.09% 0.7981 10mg / kg

[0399] SC, 25

[0400] 20.08% 0.2738 36.34% 0.381 10.10% 0.6621 mg / kg

[0401] SC,

[0402] 26.95% 0.3033 54.44% 0.3473 17.21% 0.6068 50mg / kg

[0403] SC,

[0404] 50mg / kg 19.64% 0.5091 44.577% 0.5048 18.190% 0.581

[0405]

[0406] (1X / week)

[0407] FIG. 4F shows post-CPP treatment forelimb grip strength testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. Data is also shown in the following table.

[0408] P6 Grip Strength - 20 Weeks Treatment

[0409] Dose (Route, A Saline (Latest Time P

[0410] mg / kg) Point)

[0411] IP, 5mg / kg,

[0412] -6.10% 0.4186

[0413] 3X / week

[0414] SC, 2.5mg / kg 12.88% 0.5657

[0415] SC, 5mg / kg 7.83% 0.7503

[0416] SC, 10mg / kg -14.83% 0.0636

[0417] SC, 25 mg / kg 7.13% 0.4201

[0418] SC, 50mg / kg 8.77% 0.6601

[0419] SC, 50mg / kg

[0420] -15.18% 0.0424

[0421]

[0422] (1X / week)

[0423] P6 Treatment in naturally aged mice (75 weeks old at study initiation) affected 1,260 biological processes including fatty acid metabolism, T cell immunity, and muscle development. Genes in the table below represent those most prevalent in those processes revealed by RNAseq pathway analysis from mouse splenocytes.

[0424] Gene Fold- Primary Function Relevance to Enrichment Phenotypic Change

[0425]

[0426] (Median) ATTORNEY DOCKET: 05336.0007WO01

[0427] Inflammatory

[0428] Anti-inflammatory Prostaglandin enzyme,

[0429] effects may improve PTGS2 G / H synthase 7.30 mitochondrial

[0430] muscle function and 2 (COX-2) dysfunction

[0431] body composition marker

[0432] Enhanced protein Heat shock Protein folding, quality control HSPA8 protein family 7.06 mitochondrial supports muscle

[0433] A member 8 protein import function and metabolic health Insulin / IGF-1 Improved insulin Insulin

[0434] signaling, sensitivity drives fat IRS2 receptor 5.44

[0435] metabolic loss and lean mass substrate 2

[0436] regulation gain

[0437] Transcription Coordinates adaptive Early growth

[0438] EGR1 8.15 factor, stress responses to improve response 1

[0439] response cellular function Jagged Notch signaling, Promotes tissue JAG1 canonical 7.15 cell fate regeneration and Notch ligand 1 determination muscle development Mitochondrial Direct mitochondrial PHB2 Prohibitin 2 5.54 chaperone, cristae target improving

[0440]

[0441] structure energy metabolism

[0442] Connections between these biological processes, associated genes, and phenotypic effect are shown in the table below and FIG. 4G, FIG. 4H, FIG. 41, FIG. 4J and FIG. 4K. The phenotypic changes of PTGS2, HSPA8, IRS2, EGR1, JAG1 are associated with the data of FIG. 4H. The phenotypic change of PHB2 is associated with FIG. 4G.

[0443] Gene Fold- Primary Function Relevance to Enrichment Phenotypic changes (median)

[0444] PTGS2 Prostaglandin 7.30 Inflammatory Anti-inflammatory G / H synthease enzyme, effects may improve 2 (COX-2) mitochondrial muscle function and dysfunction marker body composition HSPA8 Heat shock 7.06 Protein folding Enhanced protein protein family A mitochondrial quality control member 8 protein import supports muscle function and metabolic health IRS2 Insulin receptor 5.44 Insulin / IGF-1 Improved insulin substrate 2 signaling, sensitivity drives fat metabolic loss and lean mass

[0445]

[0446] regulation gain ATTORNEY DOCKET: 05336.0007WO01

[0447] EGR1 Early growth 8.15 Transcription Coordinates adaptive response 1 factor, stress responses to improve response cellular function JAG1 Jagged 7.15 Notch signaling, Promotes tissue canonical Notch cell fate regeneration and ligand 1 determination muscle development PHB2 Prohibitin 2 5.54 Mitochondrial Direct mitochondrial chaperone cristae target improving

[0448]

[0449] structure energy metabolism

[0450] Example 5: Senotherapeutic CPP in Naturally Aged Mice

[0451] 75 week old naturally aged (male C57BL / 6J) mice (analogous to middle aged 50-55 year old humans) were administered peptides: P5. Saline was used as a negative control. Peptides were administered subcutaneously (“SC”) at varying dosages as shown in the following table:

[0452] Group Peptide Administration Dose

[0453] 1 (n=10) P5 SC 1X Weekly 2.5mg / kg

[0454] 2 (n=10) P5 SC 1X Weekly 5mg / kg

[0455] 3 (n=10) P5 SC 1X Weekly 10mg / kg

[0456] 4 (n=10) P5 SC 1X Weekly 25mg / kg

[0457] 5 (n=10) P5 SC 1X Weekly 50mg / kg

[0458]

[0459] 6 (n=10) Saline SC 1X Weekly

[0460] FIG. 5A shows body weight improvement in naturally aged 75 week old mice treated with P5 compared to no (saline) peptide treatment. Data is also shown in the table below. Treated mice showed reduction in body weight.

[0461] 20 Weeks Treatment

[0462] P5 % Body Weight Change

[0463] Relative to Initial Timepoint Relative to Saline, Latest Time Point

[0464] Dose (Route, Relative% P Relative% P

[0465] mg / kg)

[0466] SC, 2.5mg / kg 3.60% 0.7077 -14.16% 0.0015 SC, 5mg / kg 9.22% 0.3251 -8.54% 0.1424 SC, 10mg / kg 10.06% 0.1444 -7.71 % 0.0769 SC, 25 mg / kg 3.83% 0.6565 -13.93% 0.0009 SC, 50mg / kg 0.68% 0.7492 -17.08% 0.0047

[0467]

[0468] Saline 17.76% 0.0944 - ATTORNEY DOCKET: 05336.0007WO01

[0469] FIG. 5B shows overall survival and cancer-specific survival n naturally aged 75 week old mice treated with P5 compared to no (saline) peptide treatment. Data is also shown in the following table:

[0470] P5 Survival Injection Site Reactions Cancer- Dose (Route, ISR-Related Total Deaths Specific Incidence

[0471] mg / kg) Deaths Deaths

[0472] 2.5 mg / kg,

[0473] 1 / 10 0 / 1 0 / 10 0 / 1

[0474] 1 X / week

[0475] 5 mg / kg,

[0476] 1 / 10 1 / 1 0 / 10 0 / 1

[0477] 1 X / week

[0478] 10 mg / kg,

[0479] 1 / 10 1 / 1 0 / 10 0 / 1

[0480] 1 X / week

[0481] 25 mg / kg,

[0482] 1 / 10 1 / 1 2 / 10 0 / 1

[0483] 1 X / week

[0484] 50 mg / kg,

[0485] 4 / 10 1 / 4 3 / 10 0 / 4

[0486] 1 X / week

[0487]

[0488] Saline 0 / 10 N / A 0 / 10 NA

[0489] FIG. 5C shows body weight composition in naturally aged 75 week old mice treated with GPP compared to no (saline) peptide treatment. Data is also shown in the following table. Treated mice showed reduction of fat mass and increase in lean mass.

[0490] P5 Fat Mass Lean Mass

[0491] Dose A P A p A P A p (Route, Baseline Saline Baseline Saline mg / kg) (Latest (Latest (Latest (Latest Time Time Time Time Point) Point) Point) Point)

[0492] SC,

[0493] 11.37% 0.9408 0.3684 3.89% 0.1925 -8.58% 0.0698 2.5mg / kg 12.30%

[0494] SC,

[0495] 22.49% 0.4256 -1.18% 0.9603 7.59% 0.1368 -4.88% 0.3888 5 mg / kg

[0496] sc,

[0497] 16.87% 0.2742 -6.80% 0.5838 10.13% 0.151 -2.34% 0.6544 10mg / kg

[0498] SC, 25

[0499] -9.01% 0.3319 0.0155 8.43% 0.014 -4.04% 0.2829 mg / kg 32.68%

[0500] SC,

[0501] -8.51% 0.9586 0.0486 4.16% 0.278 0.0842 50mg / kg 32.17% 8.316%

[0502]

[0503] Saline 23.67% 0.2012 - - 12.47% 0.0035 - - ATTORNEY DOCKET: 05336.0007WO01

[0504] FIG. 5D shows post-CPP treatment rotarod testing results in naturally aged 75 week old mice compared to results after no (saline) peptide treatment. Data is also shown in the following table.

[0505] P5 Time of Fall Distance Traveled Maximum Speed Dose A P A p A P A p A P A p (Rou Base Sali Base Sali Base Sali te, line ne line ne line ne mg / k (Late (Lat (Late (Lat (Late (Lat g) st est st est st est Time Tim Time Tim Time Tim Point e Point e Point e

[0506] ) Poi ) Poi ) Poi nt) nt) nt) SC,

[0507] 0.3 0.8 0.5 1.19 0.9 0.4 0.9 2.5m 10.12 2.59 4.87 7.55 1.71

[0508] 913 920 379 % 722 429 352 g / kg % % % % % sc,

[0509] 0.4 2.08 0.9 1.55 0.5 7.62 0.8 0.4 1.58 0.9 5mg / 5.45 4.26

[0510] 326 % 043 % 139 % 520 726 % 381 kg % %

[0511] SC,

[0512] 0.1 0.7 0.1 0.8 0.2 0.8 10mg 14.19 6.67 15.34 9.28 10.13 4.29

[0513] 081 029 282 186 165 340 / kg % % % % % % SC,

[0514] 25 7.99 0.8 15.5 0.3 29.04 0.8 35.1 0.3 12.06 0.6 17.9 0.3 mg / k % 328 1% 507 % 624 0% 198 % 984 0% 115 g

[0515] SC,

[0516] 0.0 0.2 0.0 0.1 0.0 0.2 50mg 25.57 18.0 44.17 38.1 23.55 17.7

[0517] 192 097 290 595 376 444 / kg % 4% % 1% % 1% Salin

[0518] 0.1 0.2 0.1

[0519] e 7.53 - - 6.06 - - 5.84 - - 446 086 295

[0520]

[0521] % % %

[0522] FIG. 5E shows post-CPP treatment forelimb grip strength testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. Data is also shown in the following table.

[0523] P5 Average Force / BW

[0524] Dose (Route, A Baseline P A Saline P

[0525] mg / kg) (Latest Time (Latest Time

[0526] Point) Point)

[0527] SC, 2.5mg / kg -2.51% 0.4269 19.71% 0.0850 SC, 5mg / kg -26.12% 0.0154 -3.90% 0.7851

[0528]

[0529] SC, 10mg / kg -25.53% 0.0026 -3.30% 0.7624 ATTORNEY DOCKET: 05336.0007WO01

[0530] SC, 25 mg / kg -19.92% 0.0074 2.31% 0.8307 SC, 50mg / kg 7.11% 0.9908 29.34% 0.0440

[0531]

[0532] Saline -22.22% 0.0165 - -

[0533] FIG. 5F shows post-CPP treatment y-Maze cognition testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. Data is also shown in the following table.

[0534] P5 Spontaneous Alterations

[0535] Dose (Route, A Baseline P A Saline p mg / kg) (Latest Time (Latest Time

[0536] Point) Point)

[0537] SC, 2.5mg / kg 37.22% 0.7865 69.10% 0.1690 SC, 5mg / kg 32.17% 0.7421 64.05% 0.0316 SC, 10mg / kg -16.38% 0.1870 15.51% 0.6201 SC, 25 mg / kg 41.48% 0.4234 73.36% 0.2176 SC, 50mg / kg 29.17% 0.5613 61.05% 0.2307

[0538]

[0539] Saline -31.88% 0.0128 - -

[0540] Example 6: Senotherapeutic CPP in Naturally Aged Mice

[0541] 75 week old naturally aged (male C57BL / 6J) mice (analogous to middle aged 50-55 year old humans) were administered peptides: P5, P6, P11, P15. Saline was used as a negative control. Peptides were administered as shown in the following table:

[0542] Group Peptide Dose

[0543] 1 (n=10) P5 25mg / kg 1X / Week

[0544] 2 (n=10) P11 25mg / kg 1X / Week

[0545] 3 (n=5) P6 25mg / kg 1X / Week

[0546] 4 (n=5) P15 25mg / kg 1X / Week

[0547]

[0548] 5 (n=10) Saline

[0549] FIG. 6A shows body weight improvement in naturally aged 75 week old mice treated with CPP compared to no (saline) peptide treatment. Data is also shown in the table below. Treated mice showed reduction in body weight.

[0550] 20 Weeks Treatment

[0551] P5 % Body Weight Change

[0552] Relative to Initial Timepoint Relative to Saline, Latest Time Point

[0553] Dose (Route, Relative% P Relative% P

[0554]

[0555] mg / kg) ATTORNEY DOCKET: 05336.0007WO01

[0556] P5 -0.66% 0.6801 -3.66% 0.3511

[0557] P11 -6.56% 0.1342 -9.56% 0.0228

[0558] P6 -7.38% 0.3399 -10.37% 0.2261

[0559] P15 -3.30% 0.7652 -6.30% 0.2973

[0560]

[0561] Saline 3.00% 0.5510 - -

[0562] FIG. 6B shows overall survival and cancer-specific survival n naturally aged 75 week old mice treated with GPP compared to no (saline) peptide treatment. Data is also shown in the following table:

[0563] Survival Injection Site Reactions

[0564] P5 3 / 20 1 / 3 2 / 20 0 / 3

[0565] P11 5 / 10 3 / 5 10 / 10 0 / 5

[0566] P6 1 / 5 0 / 1 0 / 5 N / A

[0567] P15 0 / 5 N / A 0 / 5 N / A

[0568]

[0569] Saline 2 / 20 1 / 2 0 / 20 0 / 2

[0570] FIG. 6C shows body weight composition in naturally aged 75 week old mice treated with GPP compared to no (saline) peptide treatment. Data is also shown in the following table. Treated mice showed reduction of fat mass and increase in lean mass.

[0571] P5 Fat Mass Lean Mass

[0572] Dose A P A p A P A p (Route, Baseline Saline Baseline Saline mg / kg) (Latest (Latest (Latest (Latest Time Time Time Time Point) Point) Point) Point)

[0573] P5 10.85% 0.7029 1.50% 0.9319 2.16% 0.6138 1.889% 0.6369 P11 -13.25% 0.4635 -22.60% 0.2579 -1.12% 0.6318 -1.39% 0.7508 P6 -1.80% 0.5784 -11.16% 0.6523 -0.71% 0.8889 -0.97% 0.8221 P15 -1.06% 0.9978 -10.41% 0.6330 2.60% 0.4573 2.33% 0.5786

[0574]

[0575] Saline 9.35% 0.6451 - - 0.27% 0.9886 - -

[0576] FIG. 6D shows post-CPP treatment rotarod testing results in naturally aged 75 week old mice compared to results after no (saline) peptide treatment. Data is also shown in the following table.

[0577] P5 Time of Fall Distance Traveled Maximum Speed Dos A P A P A P A P A P A P e Base Sali Base Sali Base Sali (Ro line ne line ne line ne

[0578]

[0579] ute, (Late (Lat (Late (Lat (Late (Lat ATTORNEY DOCKET: 05336.0007WO01

[0580] mg / st est st est st est kg) Time Tim Time Tim Time Tim Point e Point e Point e

[0581] ) Poin ) Poin ) Poin t) t) t)

[0582] P5

[0583] 2.82 0.69 0.74 16.05 0.48 0.96 7.73 0.45 1.85 0.89

[0584] 4.36 1.12

[0585] % 05 11 % 92 83 % 46 % 45

[0586] % %

[0587] P11

[0588] 0.55 0.52 8.82 0.31 0.79 0.50 0.59 1.37 8.54 8.35 1.69 7.56

[0589] 11 95 % 83 14 11 87 % % % % %

[0590] P6

[0591] 0.56 0.14 0.50 0.19 0.63 0.18 11.78 18.9 22.26 39.4 12.70 18.5

[0592] 67 39 24 96 31 70 % 5% % 3% % 8% P15

[0593] 0.46 0.17 0.48 0.24 0.32 0.17 10.52 17.6 19.28 36.4 12.17 18.0

[0594] 39 77 43 17 31 18 % 9% % 5% % 4% Sali 7.17 0.71 17.17 0.64 5.88 0.83

[0595] - - - - - -

[0596]

[0597] ne % 16 % 78 % 95

[0598] FIG. 6E shows post-CPP treatment forelimb grip strength testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. Data is also shown in the following table.

[0599] Average Force / BW

[0600] Dose (Route, A Baseline P A Saline p

[0601] mg / kg) (Latest Time (Latest Time

[0602] Point) Point)

[0603] P5 -15.33% 0.0770 18.15% 0.0237 P11 -18.29% 0.0104 15.19% 0.0934

[0604] P6 -25.65% 0.0359 7.83% 0.1013 P15 -15.40% 0.1909 18.08% 0.3651

[0605]

[0606] Saline -33.48% 0.0031 - -

[0607] FIG. 6F shows post-CPP treatment y-Maze cognition testing results in 75 week old naturally aged mice compared to results after no (saline) peptide treatment. Data is also shown in the following table.

[0608] Spontaneous Alterations

[0609] Dose (Route, A Baseline P A Saline P

[0610] mg / kg) (Latest Time (Latest Time

[0611] Point) Point)

[0612] P5 194.25% 0.0648 65.55% 0.5362

[0613]

[0614] P11 146.88% 0.2988 18.17% 0.8013 ATTORNEY DOCKET: 05336.0007WO01

[0615] P6 253.33% 0.0169 124.63% 0.2529

[0616] P15 97.33% 0.0084 -31.37% 0.6909

[0617]

[0618] Saline 128.70% 0.0593 - -

[0619] Example 7: Senotherapeutic CPP in Naturally Aged Mice

[0620] 75 week old naturally aged (female C57BL / 6J) mice (analogous to middle aged 50-55 year old humans) were administered peptides: P5, P6, and P11. Saline was used as a negative control. Peptides were administered as shown in the following table:

[0621] Group Peptide Dose

[0622] 1 (n=10) P5 2.5mg / kg 1X / Week

[0623] 2(n=10) P5 10mg / kg 1X / Week

[0624] 3(n=10) P5 25mg / kg 1X / Week

[0625] 4(n=10) P6 2.5mg / kg 1X / Week

[0626] 5(n=10) P6 10mg / kg 1X / Week

[0627] 6(n=10) P6 25mg / kg 1X / Week

[0628] 7(n=10) P11 2.5mg / kg 1X / Week

[0629] 8(n=10) P11 10mg / kg 1X / Week

[0630] 9(n=10) P11 25mg / kg 1X / Week

[0631]

[0632] 10 (n=10) Saline 1X / Week

[0633] FIG. 7A shows body weight improvement in naturally aged 75 week old mice treated with CPP compared to no peptide (saline) after 8 weeks of treatment. Data is also shown in the table below. Treated mice showed reduction in body weight.

[0634] % Body Weight Change

[0635] Relative to Initial Relative to Saline, Latest Timepoint Time Point

[0636] Dose (Route, mg / kg) Relative% P Relative% P

[0637] P52.5mg / kg 3.02% 0.5368 -6.73% 0.1220 P5 10mg / kg 3.12% 0.3185 -6.63% 0.2117 P525mg / kg -13.14% 0.8736 -22.89% 0.0737 P62.5mg / kg 3.74% 0.6018 -6.01% 0.1424 P6 10mg / kg 2.77% 0.7382 -6.98% 0.1754 P625mg / kg -2.90% 0.725 -12.66% 0.0168 P11 2.5mg / kg -5.31% 0.6423 -15.06% 0.0028 P11 10mg / kg 1.88% 0.2992 -7.87% 0.0676 P11 25mg / kg -10.16% 0.7990 -19.91% 0.0056

[0638]

[0639] Saline 9.75% 0.2586 - ATTORNEY DOCKET: 05336.0007WO01

[0640] FIG. 7B shows overall survival and cancer-specific survival n naturally aged 75 week old mice treated with GPP compared to no peptide (saline) after 8 weeks of treatment. Data is also shown in the following table:

[0641] Survival Injection Site Reactions Cancer- Overall Incidence ISR-Deaths Specific

[0642] P52.5mg / kg 0 / 9 NA 0 / 9 0 / 0

[0643] P5 10mg / kg 1 / 9 0 / 9 0 / 9 0 / 1

[0644] P525mg / kg 1 / 9 1 / 1 9 / 9 0 / 1

[0645] P62.5mg / kg 0 / 10 NA 0 / 9 0 / 0

[0646] P6 10mg / kg 0 / 10 NA 0 / 9 0 / 0

[0647] P625mg / kg 1 / 13 0 / 1 5 / 13 0 / 0

[0648] P11 2.5mg / kg 1 / 9 0 / 1 0 / 9 0 / 0

[0649] P11 10mg / kg 1 / 13 0 / 1 9 / 13 0 / 0

[0650] P11 25mg / kg 2 / 10 1 / 2 10 / 10 1 / 2

[0651]

[0652] Saline 0 / 10 NA 0 / 10 0 / 0

[0653] FIG. 7C shows body weight composition in naturally aged 75 week old mice treated with GPP compared to no peptide (saline) after 8 weeks of treatment. Data is also shown in the following table. Treated mice showed reduction of fat mass and increase in lean mass.

[0654] Body Composition Score

[0655] Body Composition A Saline Group Score (Latest Time (Latest Timepoint) Point)

[0656] Group BCS ABCS p P52.5 mg / kg -10.87 22.50 0.4775 P5 10 mg / kg -1.52 31.85 0.2613 P5 25 mg / kg 13.55 42.36 0.1123 P62.5 mg / kg -21.81 11.56 0.6841 P6 10 mg / kg 3.34 36.71 0.1962 P6 25 mg / kg 3.88 37.25 0.1347 P11 2.5 mg / kg -7.66 25.71 0.4284 P11 10 mg / kg 1.17 34.54 0.1843 P11 25 mg / kg 40.78 74.15 0.0396

[0657]

[0658] Saline -33.37 - -

[0659] Overview of CPPs and CPP Compositions

[0660] In certain embodiments, a CPP in a composition is in an amount sufficient to reduce a senescent cell population in vitro. In certain instances, a CPP in a composition is in an ATTORNEY DOCKET: 05336.0007WO01

[0661] amount sufficient to reduce the senescent cell population in vivo, in a tissue or organ. In certain embodiments, a GPP in a composition is in an amount sufficient to reduce the senescent cell population in a subject.

[0662] A CPP can contain naturally occurring amino acids. There are different amino acid isomers, and a CPP can contain D-amino acids, L-amino acids, or a combination of D-amino acids and L-amino acids. In certain embodiments, all amino acids of a CPP are L-amino acids or D-amino acids. A CPP in certain embodiments can contain a peptidomimetic portion and an amino acid portion. In certain instances, a CPP is a peptidomimetic containing no naturally occurring amino acids.

[0663] In certain embodiments, a CPP contains:

[0664] WEARLARALARALARHLARALARALRACEA (SEQ ID NO: 5).

[0665] In certain embodiments, a CPP contains:

[0666] WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6);

[0667] WEARLARALARALARELARALARALRACEA (SEQ ID NO: 8);

[0668] WEAHLAHALARALARHLARALARALRACEA (SEQ ID NO: 17) WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 18) WEAHLAHALARALARHLARALARALRACEA (SEQ ID NO: 19) WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 20) REARLARALARALARLARALARALRACEA (SEQ ID NO: 9);

[0669] REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); or REARLARALARALARELARALARALRAREA (SEQ ID NO: 11).

[0670] In certain embodiments, a CPP contains: LLIILRRRIRKQAHAHSK (SEQ ID NO: 13), derived from murine VE-Cadherin and referred to as murine pVEC (“m-pVEC”), or LLIFLRRRLRKQARAHGK (SEQ ID NO: 14), derived from human VE-Cadherin and referred to as a human pVEC (“hu-pVEC”).

[0671] In certain embodiments, a CPP contains RKKRRQRRR (SEQ ID NO: 21), or RRRRRRRR (SEQ ID NO: 22), or RKKRRRESRKKRRRES (SEQ ID NO: 23), or GRPRESGKKRKRKRLKP (SEQ ID NO: 24), or GRRRRRRRRRPPQ (SEQ ID NO: 25), or RVRVFVVHIPRLT (SEQ ID NO: 26), or GALFLGFLGAAGSTMGAWSQPKKKRKV (SEQ ID NO: 27), or KLALKLALKALKAALKLA (SEQ ID NO: 28), or GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 29), or VSALK (SEQ ID NO: 30), or ATTORNEY DOCKET: 05336.0007WO01

[0672] CSIPPEVKFNPFVYLI (SEQ ID NO: 31), or GIGAVLKVLTTGLPALISWIKRKRQQ (SEQ ID NO: 32) or HGLASTLTRWAHYNALIRAF (SEQ ID NO: 33).

[0673] In certain embodiments, a GPP contains kshahaqkrirrrliill (SEQ ID NO: 1009), kgharaqkrlrrrlfill (SEQ ID NO: 1010), aecahlahalahalhralaralaralraew (SEQ ID NO: 1077 ), Wearlaralaralarhlahalahalhacea (SEQ ID NO: 1078 ), aecahlahalaralhralaralaralraew (SEQ ID NO: 1079 ), lliilrrrirkqahahsk (SEQ ID NO: 1080 ), or wearlaralaralarhlaralahalhacea (SEQ ID NO: 1081).

[0674] In certain embodiments a CPP may be selected from those in Table 1 included below.

[0675] As discussed above, in the conventional art, cell penetrating peptides have been used to provide a carrier or transporter function, for example, to deliver a different active component into a call, across a cell membrane, etc.

[0676] In embodiments of the present invention, a CPP may itself provide a senolytic effect irrespective of any carrier function. That is, the CPP may provide the senolytic effect separate and apart from acting as carrier or transporter for a different active component. Thus, in certain embodiments, a CPP composition contains no cargo nucleic acid. In certain embodiments, a CPP composition contains no nucleic acid. In certain instances, a CPP composition contains no cargo component that reduces a senescent cell population. In certain embodiments, a CPP composition contains no component (for example, no cargo component) having one or more of the following activities: (i) having JAK2 protein kinase inhibition activity; (ii) having proinflammatory molecule reduction activity; (iii) having interleukin reduction activity (for example, having IL-6 reduction activity); (iv) having senomorphic activity; or (v) a combination of (i) and (ii); (i) and (iii); (i) and (iv); (ii) and (iii); (ii) and (iv); (iii) and (iv); (i), (ii) and (iii); (i), (iii) and (iv); (ii), (iii) and (iv); or (i), (ii), (iii) and (iv). In certain instances, a CPP composition contains no cargo agent. In certain embodiments, a CPP composition contains no additive capable of reducing a senescent cell population. In certain embodiments, a CPP composition contains no fluorescent labels, fluorescein, fluorescein derivatives, GFP, or EGFP. In certain embodiments, a CPP composition contains no biotin.

[0677] In certain embodiments, a CPP composition contains an active ingredient, and the active ingredient contains, consists essentially of, or consists of the CPP. The term “consists essentially of” with reference to an active ingredient containing a CPP means there is no ATTORNEY DOCKET: 05336.0007WO01

[0678] other component in the active ingredient that materially affects the characteristics of the active ingredient. An active ingredient, for example, can include one or more components other than the CPP that enhance senescent cell population reduction activity by not more than 5%. For example, an active ingredient can contain another component so long as the senescent cell population reduction activity of the active ingredient containing the CPP and other component is increased by no more than 5% compared to the active ingredient containing the CPP but not containing the other component.

[0679] Senescent cell population reduction activity of an active ingredient can be assessed by determining the amount of (i) SA-beta-galactosidase; or (ii) p16 (p16INK4a for example); or (iii) urokinase plasminogen activator receptor (uPAR); or (iv) a p-21 positive cell population; or (v) a combination of one or more of (i), (ii), (iii), and (iv) or other markers as discussed above. Senescent cell population reduction activity of an active ingredient can be assessed by a process described in the Examples disclosed herein. In embodiments, a senescent cell population reduced by a CPP composition contains cells located in any and / or every organ in a body of the patient. As examples and without limitation, a senescent cell population reduced by a CPP composition contains cells in one or more organs, including but not limited to the brain, kidneys, liver, lungs, eyes, inguinal adipose tissue, gastrocnemius, skin and spleen. In certain embodiments, a senescent cell population reduced by a CPP composition is the skin, containing skin cells, and the skin cells can include epidermis cells, dermis cells, or epidermis cells and dermis cells. In certain embodiments, a senescent cell population reduced by a CPP composition are in any organ of the body, containing the cells located in those organs. In certain embodiments, a senescent cell population reduced by a CPP composition contains fibroblast cells. In certain embodiments, a CPP composition contains a senescent cell population in addition to a CPP, and sometimes a senescent cell population contains one or more skin cells and / or system cells, including cell types described herein.

[0680] A CPP composition can be prepared as a pharmaceutically acceptable composition containing a CPP as described herein along with one or more pharmaceutically acceptable excipients, referred to as a CPP pharmaceutical composition. A CPP pharmaceutical composition can be prepared for a suitable route of administration, including topical or systemic administration, for example. In certain embodiments, a CPP pharmaceutical composition is formulated as a topical cream. In certain instances, a CPP pharmaceutical ATTORNEY DOCKET: 05336.0007WO01

[0681] composition is prepared for injection (for example, for subcutaneous, intramuscular or intravenous administration). In certain instances, a CPP cosmetic composition is prepared for application topically or by penetration of the skin using microneedles, intradermal or subcutaneous injection or other methods of skin penetration.

[0682] Additional Examples and Models

[0683] Examples 1 through 7 have been discussed above. Additional testing models and examples, providing further support for the embodiments described and claimed, will now be discussed. It will be understood that some of the testing models may be applicable to the previous examples and vice versa and that testing models and examples may be combined and / or used together.

[0684] The examples set forth below illustrate certain implementations and do not limit the technology.

[0685] As discussed above, frequently used peptides common to various examples are listed in the following table: ATTORNEY DOCKET: 05336.0007WO01

[0686] Peptide Sequence

[0687] P1 WEARLARALARALARHLARALARALRACEA (SEQ ID NO: 5)

[0688] P2 Itlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg (SEQ ID NO: 12)

[0689] P3 CRRLRHLRHHYRRRWHRFRC (SEQ ID NO: 15)

[0690] P4 RQIKIWFQNRRMKWKK (SEQ ID NO: 16)

[0691] P5 LLIILRRRIRKQAHAHSK (SEQ ID NO: 13) (m-PVEC)

[0692] P6 WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 18)

[0693] P8 WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO: 19)

[0694] P9 WEARLARALARALARHLAHALAHALHACEA (SEQ ID NO: 20)

[0695] P10 LLIFLRRRLRKQARAHGK (SEQ ID NO: 14)

[0696] P11 kshahaqkrirrrliill (SEQ ID NO: 1009)

[0697] P12 kgharaqkrlrrrlfill (SEQ ID NO: 1010)

[0698] P13 aecahlahalahalhralaralaralraew (SEQ ID NO: 1077)

[0699] P14 wearlaralaralarhlahalahalhacea (SEQ ID NO: 1078)

[0700] aecahlahalaralhralaralaralraew (SEQ ID NO: 1079)

[0701] P15

[0702] lliilrrrirkqahahsk (SEQ ID NO: 1080)

[0703] P16

[0704] wearlaralaralarhlaralahalhacea (SEQ ID NO: 1081)

[0705] P17

[0706]

[0707] *P2 is composed of D amino acids and P1, P3, P4, P5, and P6 each is composed of L amino acids. P11, P2, P13, P14, P15, P16, and P17 are composed of D amino acids.

[0708] Example 8: Cell penetrating peptide senolytic activity in skin

[0709] Senoiytic activity of peptides was assessed by an accelerated skin aging model in rats. Male CD-IGS (Sprague Dawley) rats (4-weeks old at study initiation) were exposed to a total of 20,000 mJ / cm2of UVB irradiation 5 days per week for eight weeks (i.e., Day -56 to Day 0, 500 mJ / cm2 / dose; a total of 40 doses) to induce senescence in the skin. A visual scheme of the experimental procedure Is shown below in FIG. 8A. Post-UVB irradiation, P1 and P2 (assessed in Example 1) were dosed intradermally to the rats. Peptides were dosed twice per week with a total of 50 pg peptide per dose for 21 days post-UVB Irradiation (Day 0 to Day 21 ). Sites of injection were marked with indelible ink to ensure the continuous treatment of the same area of skin. Rats were sacrificed on Days 0, 7, 14, and 21 and skin samples were harvested for senescence-associated SA-beta-galactosidase (SA-p-gal) analysis. SA-p-gal staining is a cytochemical staining method where the X-gal ATTORNEY DOCKET: 05336.0007WO01

[0710] chromogen (5-bromo-4-chloro-3-indoyl p-d-galactopyranoside) is applied directly to the tissues of interest. X-gal is a direct substrate for SA-f3-gal, which cleaves X-gal into galactose and 5-bromo-4-chloro-3-hydroxindole, the latter of which shows blue color, allowing for visualization using an inverted or upright light microscope. After detection by microscopy, data processing software, such as Imaged, was used to quantify the percentage of tissue that was SA-0-gal positive.

[0711] After staining and microscopy, skin sections were analyzed for percent SA-beta- galactosidase-positive (percent p-gal+) area of the epidermis and dermis using Imaged software. Values were then plotted using GraphPad Prism software. FIG. 8B shows representative SA-p-gal-stained skin tissues and FIG. 8C shows results from imaged quantification of percent [3-gal+area in the epidermis and dermis. SA-p-gal is blue, as indicated by dark portions, or spots on the eosin-stained background in the tissues shown in FIG. 8B. The included table of this Example shows the percent reduction of percent p-gal+area in the epidermis and dermis of the active senolytic peptide (P1) compared to the inactive peptide (P2). In all cases, P1 was more effective at reducing the percent P~gal+area than P2, and in some cases, It was as much as 95% more effective.

[0712] Percent Reduction of p-gal+area.

[0713] Time (Days Post-UVB)

[0714] Tissue

[0715] 7 14 21

[0716] Epidermis 95% 40% 12%

[0717]

[0718] Dermis 63% 38% 29%

[0719] Example 9: Senoiytic CPP in an Accelerated Systemic Aging Model Female Baib / c mice (4-weeks old at study initiation) were exposed to a total of 10 Gy of ionizing gamma-irradiation spread over a total of 10 doses over a 4-week period (i.e., Day -28 to Day 0, 0.5 Gy / dose, 10 total doses) to induce senescence systemically. A visual scheme of the experimental procedure is shown in FIG. 9A. For Group 1, P1 and P2 (assessed in Examples 1 and 2) were dosed intraperitoneally three times per week at a dose level of 5 mg / kg per dose during the gamma-irradiation treatment period (i.e., Day -28 to Day 0). For Group 2, P1 and P2 were dosed intraperitoneally three times per week at a ATTORNEY DOCKET: 05336.0007WO01

[0720] dose level of 5 mg / kg per dose after the gamma-irradiation treatment period (i.e., Day 0 to Day 56). Mice were sacrificed on Days 0, 28, and 56 and liver, spleen, and kidney tissues were harvested for both SA-p-gal analysis and p16 staining. SA-|3-gal staining was performed.

[0721] After staining and microscopy, organ sections were analyzed for percent [3-gal+area using imaged software. Values were then plotted using GraphPad Prism software. There was no significant SA-p-gal or p16 accumulation seen until Day 56, so only this data point is shown. FIG. 9B shows representative SA-p-gal-stained tissues and FIG. 90 shows results from Imaged quantification of percent [3-gal+area in the liver, kidneys, and spleen. SA- -gal is blue, as indicated by dark portions, or spots, in the tissues shown In FIG. 9B. The Included table of this Example shows the percent reduction of percent |3-ga area in the liver, kidneys, and spleen of the active senolytic peptide (P1) compared to the inactive peptide (P2) for both Group 1 and Group 2 (peptides injected during gamma-irradiation and peptides injected after gamma-irradiation, respectively).

[0722] In all cases, P1 was more effective at reducing the percent p-gab area than P2, in some cases, P1 was as much as 74% more effective.

[0723] Percent reduction of percent p-gal+area of P1 compared to P2.

[0724] Tissue Group 1 Group 2

[0725] Liver 72.4% 74.2%

[0726] Kidney 39.6% 39.0%

[0727] Spleen 38.7%

[0728]

[0729] 54.3%

[0730] Example 10: Senoiytic CPP in an Accelerated Systemic Aging Model

[0731] This example is substantially similar to Example 9 except in that different compositions were employed and plasma draws were included to measure circulation SASP. Treatment included P1, P2, and a negative saline control. The details of experimental groups are shown in the included table below.

[0732] Group Peptide Dose

[0733] 1a (n=5) P1 for 6 weeks 1.5E-3 pmoles / kg (5 mg / kg

[0734]

[0735] IP) ATTORNEY DOCKET: 05336.0007WO01

[0736] 1b (n=5) P1 for 8 weeks 1.5E-3 pmoles / kg (5 mg / kg IP)

[0737] 2a (n=5) P2 for 6 weeks 1.5E-3 pmoles / kg (8.1

[0738] mg / kg IP)

[0739] 2b (n=5) P2 for 8 weeks 1.5E-3 pmoles / kg (8.1

[0740] mg / kg IP)

[0741] 3a (n=5) Saline for 0 weeks n / a

[0742] 3b (n=5) Saline for 2 weeks n / a

[0743] 3c (n=5) Saline for 4 weeks n / a

[0744] 3d (n=5) Saline for 6 weeks n / a

[0745]

[0746] 3e (n=5) Saline for 8 weeks n / a

[0747] SA-[3-Gal and p16 levels were quantified as described previously.

[0748] SA-[3-Gal and p16 quantification

[0749] SA-p-Gal relative change (relative to P16 relative change (relative to Saline) Saline)

[0750] Peptide Spleen P Lung P Spleen P Lung P P1 -41% P<0.05 -26% n.s. -24% n.s. -35% n.s.

[0751]

[0752] P2 -37% P<0.05 +17% n.s. -37% n.s. +22% n.s.

[0753] As shown above, P1 demonstrates senolytic effect in both spleen and lungs compared to saline control.

[0754] Plasma cytokine levels were also monitored. See FIG. 10A, FIG. 10B, FIG. 10C, FIG. 10D, FIG. 10E, FIG. 10F, FIG. 10G and FIG. 10H. Many cytokines (e.g. IL-9, IL-10, IL-13, IL-15, IL-27, and MIP-1 a (CCL3)) were returned to ~0 upon treatment with P1 at almost all timepoints. In contrast, treatment with P2 was more variable with increases above controls seen with IL-31, GM-CSF, IL-18, IL-28, and IL-10.

[0755] Example 11: Senotherapeutic CPP in an Accelerated Systemic Aging Model Female Balb / c mice (12-weeks old at study initiation) were exposed to a total of 5.0 Gy of ionizing gamma-irradiation spread over a total of 10 doses over a 4-week period (i.e., Day - 28 to Day 0) (the final dose was skipped due to deteriorating health resulting in a total of 4.5 Gy over 9 doses) to induce senescence systemically. A visual scheme of the experimental procedure is shown below in FIG. 11 A. Certain groups were provided a high fat diet (HFD) while other groups were provided normal food.

[0756] Treatment included P5, P6, and a negative saline control. The details of experimental groups are shown in the table below. ATTORNEY DOCKET: 05336.0007WO01

[0757] Group Peptide Dose

[0758] 1a (n=10) HFD Gamma IR P6 1.5E-3 pmoles / kg (5 mg / kg IP)

[0759] 1b (n=10) HFD and Gamma IR Saline

[0760] 1c (n=10) HFD No Gamma IR Saline

[0761] 2a (n=10) Gamma IR P5 1.5E-3 pmoles / kg (3.3

[0762] mg / kg IP)

[0763] 2b (n=10) Gamma IR P6 1.5E-3 pmoles / kg (5 mg / kg IP)

[0764] 2c (n=10) Gamma IR Saline

[0765]

[0766] 2d (n=10) No Gamma IR Saline

[0767] Senolytic effects were to be analyzed using methods described herein, such as those used in previous examples. Likewise, senotherapeutic effects were to be analyzed using methods described herein, such as those listed in Example 3 and 3’.

[0768] However, Balb / c mice were unexpectedly more sensitive to gamma-irradiation and 37.5% of mice died of Acute Radiation Syndrome (ARS) approximately 1 week after the conclusion of irradiation treatment, from acute bone marrow failure. About 50 gamma¬ irradiate mice survived and were divided into two groups, HFD and normal chow fed, and treated with either P5 or P6. About 3 to 6 months later, these mice began to exhibit toxicity (e.g. weight loss) and death due to the effects of Late Radiation-Induced Toxicity (e.g. cardiac and Gl toxicity, tumors).

[0769] Peptide treatment, particularly P5 treatment, provided protective effects from weight loss and death due to Late Radiation-Induced Toxicity. See FIG. 11B.

[0770] Note that as mice die, there is a paradoxical increase in body weight in the remaining mice in the group as the sickest mice are the ones that typically die first. Thus, survival analysis became the key determinant of late radiation-induced toxicity.

[0771] Body Weight Analysis Relative to Initial Timepoint

[0772] Group Relative% P Saline, -5 Gys 112.7% 0.0312 Saline, +5 Gys 104.3% <0.0001

[0773] P5, +5 Gys 99.7% 0.8773 P6, +5 Gys 105.2% 0.0034

[0774]

[0775] ATTORNEY DOCKET: 05336.0007WO01

[0776] Body Weight Analysis Relative to Saline, -5 Gys

[0777] Group Relative% P Saline, -5 Gys -(-)

[0778] Saline, +5 Gys -7.45% 0.0243

[0779] P5, +5 Gys -11.5% 0.0029 P6, +5 Gys -6.65% 0.0258 Body Weight Analysis Relative to Saline, +5 Gys

[0780] Group Relative% P Saline, -5 Gys +8.05% 0.0243 Saline, +5 Gys -(-)

[0781] P5, +5 Gys -4.41% 0.1154 P6, +5 Gys +0.86% 0.7016 Survival - Statistical Analyses

[0782] Log-Rank Statistical Analysis P-value 0.0075

[0783] to Test Significance Between

[0784]

[0785] Survival Curves

[0786] Example 11 ’

[0787] Further, peptide treatment using peptides such as those described herein may provide increased efficacy and safety for various therapies, including radiotherapy and chemotherapy.

[0788] For example, gamma radiation therapy is often used for treatment of cancer, including glioblastoma, as primary therapy but also as adjuvant or salvage therapy. Similarly, chemotherapy is often used for primary therapy but also as adjuvant or salvage therapy for cancer.

[0789] Radiation-induced and / or chemotherapy-induced senescence of tumor cells can spur glioblastoma recurrence, driven by the senescence associated secretory phenotype (SASP). Direct elimination of senescent cells arising after radiotherapy and / or chemotherapy, along with a dampening of the tumor-promoting effects of SASP and ROS, using peptides such as those described herein, may increase tumor response rates while also alleviating some of the detrimental effects of chemotherapy and radiotherapy.

[0790] These benefits may be realized in various tumors currently treated (either primarily or as adjuvant or salvage therapy) with radiotherapy.

[0791] Peptides such as those described herein may, simultaneously, improve both the safety and efficacy of radiation therapy. Without being bound by theory, peptide treatment may ATTORNEY DOCKET: 05336.0007WO01

[0792] selectively eliminate senescent cells including both cancerous cells and non-cancerous cells as described further below.

[0793] This selective elimination may include cancerous cells (i.e., those to be directly treated by the radiation therapy) and may thereby directly contribute to cancer treatment.

[0794] Further, radiotherapy and chemotherapy are known to induce senescence in non-cancerous cells, for example, non-cancerous cells proximate to the treated cancerous cells that undergo DNA damage and activation of stress response pathways from the radiotherapy and / or chemotherapy. For example, senescence may be triggered in surrounding stromal and immune cells, contributing to adverse effects and potentially promoting tumor relapse via the SASP. These effects may be referred to as “therapy-induced senescence.”

[0795] In embodiments, peptide treatment with peptides such as those described herein may also treat such therapy-induced senescence, thereby improving both the efficacy and safety of the treatment. For example, peptides such as those described herein may selectively eliminate non-cancerous cells that have become senescent due to therapy-induced senescence, thereby reducing the SASP and reducing incidence of tumor relapse. These benefits may be realized across a variety of radiotherapy and chemotherapy options, including but not limited to gamma radiation therapy, treatment with doxorubicin, cisplatin, paclitaxel, cyclophosphamide, and other cancer treatments.

[0796] As examples, and without intending to be limiting, peptides such as P5, P8, P9, P13, and / or P14 may provide improved efficacy and safety of cancer treatments.

[0797] Example 12: CPP Senolytic Activity in Fibroblasts

[0798] Senolytic activity of peptides was assessed in an in vitro fibroblast accelerated-aging model. On Day 0, IMR-90 human fetal lung fibroblasts were plated in tissue culture (TC)-treated flasks and adhered overnight. To induce senescence, cells were exposed to 10 grays (Gy) of ionizing gamma-irradiation on Day 1. Cells were kept in culture from Days 2- 8 as both a recovery period and to allow cells to enter a senescent state. Cellular senescence was confirmed by senescence-associated SA-beta-galactosidase staining (SA-p-gal). On Day 9, various test peptides (the included table of this Example) and controls were titrated onto senescent IMR-90 fibroblasts and, as a control for senolytic ATTORNEY DOCKET: 05336.0007WO01

[0799] activity, proliferating IMR-90 fibroblasts. Test peptides and control peptides were added to cells starting at 100 micromolar (μM) along with additional half-log dilutions down to 3.16 nanomolar (nM). Cells were then incubated in the presence of peptides for a total of 5 days. Three days after initial addition of peptides (Day 12 of the assay), media was replaced with fresh media and peptides.

[0800] On the final day of the assay, Day 14, cell viability was analyzed using the CELLTITER- GLO® luminescent viability assay (Promega). Relative cell viability was normalized to the lowest peptide concentration and relative viability values were calculated. Relative viability values were then plotted and EC50 values calculated using GraphPad Prism Software. FIG.

[0801] 12A and FIG. 12B show plots of relative viability and the included table shows the calculated ECso values of four peptides analyzed using this cytotoxicity assay. The x-axis of FIG. 12A and FIG. 12B is cell penetrating peptide concentration, designated as “[CPP].” P1 showed senolytic activity, while P2 had an ECso value twice as high in healthy, proliferating cells than that observed in senescent cells. P1 was considered a relatively specific senolytic CPP according to the study.

[0802] Summary of EC50 Values from proliferating and senescent IMR-90 sells treated with peptides

[0803] EC50 (μM)

[0804] Peptide

[0805] Proliferating Senescent

[0806] P1 29.4 27.8

[0807] P2 90 ~41

[0808] P3 N / A >100

[0809]

[0810] P4 N / A >100

[0811] Example 13: CPP Senolytic Activity in Fibroblasts

[0812] EC50 values for peptides P1, P2, P5, and P4 were determined in senescent cells (S-IMR90) and proliferating (P-IMR90) cells. IMR90 senescent cells were prepared according to Example 12. See FIG. 13.

[0813] EC50 values of select peptides in proliferating and senescent cells

[0814] Peptide S-IMR90 EC50 (pM) P-IMR90 EC50 (μM)

[0815] P1 10.85 10.93

[0816]

[0817] P5 35.81 >100 ATTORNEY DOCKET: 05336.0007WO01

[0818] P4 (- control) >100 >100

[0819]

[0820] P2 (+ control) 0.9778 1.261

[0821] Example 14: CPP Senolytic Activity in Fibroblasts

[0822] EC50 values for peptides P1, P2, P5 and P6 were determined in senescent cells (S-IMR90) and proliferating (P-IMR90) cells. IMR90 senescent cells were prepared according to Example 8. See FIG. 14.

[0823] EC50 values of select peptides in proliferating and senescent cells

[0824] Peptide S-IMR90 EC50 (μM) P-IMR90 EC50 (μM) P1 7.912 12.06

[0825] P6 10.16 39.71

[0826] P5 n / a 77.13

[0827]

[0828] P2 8.430 21.48

[0829] Example 15: CPP Senolytic Activity in Fibroblasts

[0830] EC50 values for peptides P1, P2, P5, P6 and a combination of P2 + P5 were determined in senescent cells (S-IMR90) and proliferating (P-IMR90) cells. IMR90 senescent cells were prepared according to Example 8. See FIG. 15A.

[0831] EC50 values of select peptides in proliferating and senescent cells

[0832] Peptide S-IMR90 EC50 (μM) P-IMR90 EC50 (μM)

[0833] P1 32.98 -80

[0834] P6 -50 >100

[0835] P5 >100 >100

[0836] P2 44.07 23.35

[0837]

[0838] P2 + P5 ~100 >100

[0839] Apoptosis of cells was also analyzed. FIG. 15B shows percent of apoptosis in proliferating and senescent cells.

[0840] Example 16- Celt Penetrating Peptide Senotherapeutic Study in Naturally Aged Mice Analyzed Using IVIS

[0841] Naturally aged male and female p16-lnk4a-LUC mice (12-weeks old at study initiation) were administered peptides. Treatment included P6 and a negative saline control.

[0842] Animals are to be imaged using IVIS on a regular basis throughout the study, for example, on a monthly basis. The details of experimental groups are shown in the table below. ATTORNEY DOCKET: 05336.0007WO01

[0843] Group Peptide Dose

[0844] 1a (n=8) Male Saline

[0845] 1b (n=8) Male P6 1.5E-3 pmoles / kg (5 mg / kg IP)

[0846] 2a (n=10) Female Saline

[0847] 2b (n=11 ) Female P6 1.5E-3 pmoles / kg (5 mg / kg

[0848] IP)

[0849]

[0850] A visual scheme of the experimental procedure is shown in FIG. 16.

[0851] Senolytic effect will be analyzed using methods described herein, such as those used in previous examples. For example, animals may be sacrificed but will also be imaged on a regular basis throughout the study. Likewise, senotherapeutic effect will be analyzed using methods described herein, such as those listed in previous examples.

[0852] Example 16’: Cell Penetrating Peptide Senolytic Activity In the Brain

[0853] As discussed above, senescent cells may accumulate in tissue as a result of other injury, for example, senescent cells may accumulate in the brain as a result of mild traumatic brain injury or other damage. For example, as reported by Arun, Peethambaran et al. “Blast Exposure Leads to Accelerated Cellular Senescence in the Rat Brain.” Frontiers in neurology vol. 11 438. 21 May. 2020, doi:10.3389 / fneur.2020.00438, a wave of senescent cells appears in the brain within 24 hours of mild traumatic brain injury and may persist for months and even years after the initial injury. This wave of senescent cells may provide an opportunity for early intervention, for example, with a cell penetrating peptide such as those described herein. Cell penetrating peptides that cross the blood brain barrier, for example, P1, P5, P6, and others, may be especially effective.

[0854] Early treatment with cell penetrating peptides such as those described herein may eliminate such senescent cells and prevent progression to persistent symptoms and neurodegenerative disease. Cell penetrating peptides may thus provide effective treatment and / or prevention of post-concussive syndrome. Similarly, cell penetrating peptides may provide effective treatment and / or prevention of chronic traumatic encephalopathy. Still further, cell penetrating peptides may provide effective treatment and / or prevention of other diseases, such as Alzheimer’s disease and Parkinson’s disease. ATTORNEY DOCKET: 05336.0007WO01

[0855] Example 17: Cytotoxicity in Cancer

[0856] As discussed above, CPPs such as those discussed herein may be used to selectively eliminate cancer cells.

[0857] P1, P5, and P6 were tested for cytotoxicity against KCL-22-KM (CML ABL1 -T315I) and NALM-21 and TOM-1 (ALL ABL1 wt) human leukemia cell lines. EC₅₀ was calculated for each and is shown in FIG. 17A.

[0858] Day 4 - ECso Values (pM)

[0859] Cell Line P1 P5 P6

[0860] KCL22-KM >100 -100 >100

[0861] NALM-21 >100 >100 >100

[0862]

[0863] TOM-1 >100 ~90 4.38

[0864] P6 demonstrated activity against TOM-1 with an EC₅₀ of 4.38pM. For reference, ponatinib has an EC₅₀ of 2.7pM against TOM-1.

[0865] Without wishing to be bound to any particular theory, in embodiments, CPPs as described herein may demonstrate activity against and / or selectively eliminate cancer cells by selectively triggering apoptosis via a reduction in the Mitochondrial Membrane Potential (MMP) (A’+'m), exposing the cancer cells to prolonged mitochondrial transition pore opening and permeabilization of these mitochondria, leading to apoptosis and selective elimination of these cells as discussed in more detail below.

[0866] Cancer cells may also have a decreased capacity to maintain MMP compared with normal cells. Cancer cells may thus also be exposed to prolonged mPTP opening and possibly, to minority MOMP. Accordingly, MMP may provide a selective functional target for cancer cells, for example, a functional target for senolytic CPPs such as those described herein to target cancer cells.

[0867] Example 18: In Vivo Efficacy Against TOM-1 Tail Vein (IV) Tumor

[0868] NSG mice were injected with 0.75E6 TOM-1 cells through the tail vein. Three days after cell injection, drug administration was initiated. The table below indicates the dose levels and schedule for the test articles. ATTORNEY DOCKET: 05336.0007WO01

[0869] Group Test Article Dose ROA Frequency (5 animals

[0870] each)

[0871] 1 Saline — IP QD, M-F

[0872] 2 Ponatinib 10 mg / kg IP QD, M-F

[0873] 3 Venetoclax 25 mg / kg PO QD, M-F

[0874] 4 P9 50 mg / kg SC 1 X / week

[0875]

[0876] 5 P6 50 mg / kg SC 1 X / week

[0877] Mice were euthanized when moribund. Spleen and lungs were harvested and analyzed for the presence of TOM-1 cells by flow cytometry and hCD45+ antibodies, indicative of the presence of human B cells. Probability of survival is shown in FIG. 18A.

[0878] Group Survival is presented in the table below.

[0879] Group Survival (End of Study)

[0880] Group Dead / Total

[0881] Saline 5 / 5

[0882] Ponatinib 0 / 5

[0883] Venetoclax 5 / 5

[0884] P9 3 / 5

[0885]

[0886] P6 5 / 5

[0887] Median Survival for the P9-treated group was 26 days compared with 18 days for Saline-treated group (Log Rank - p = 0.0034). P9 shows significantly improved overall survival despite lower exposure to drug treatment (24 total doses of ponatinib compared with 5 total doses of P9 per animal).

[0888] Animals euthanized due to premorbid condition were subjected to flow cytometry of necropsied organs. Animals found dead in the morning were not subjected to flow cytometry of necropsied organs. On day 31, the study was terminated and the remaining animals alive were subjected to flow cytometry (5 / 5 ponatinib-treated and 2 / 5 P9-treated). The results are graphically depicted in the following table and FIG. 18B.

[0889] Test Article Lung % change relative to Spleen % change relative to saline (P) saline

[0890] Saline... (...)...(...)

[0891] Ponatinib (9 mg / kg QD) -95.03% (0.0010) -75.60% (0.0685) Venetoclax (25 mg / kg QD) -19.59% (0.5396) +134.9% (0.3125)

[0892] P9 (50 mg / kg 1 X / week) -92.40% (0.0460) -74.56 (0.2480)

[0893]

[0894] P6 (50 mg / kg 1 X / week) -73.75% (0.0286) -36.70% (0.4898) ATTORNEY DOCKET: 05336.0007WO01

[0895] In animals alive on Day 31 (End of Study), treatment with P9 exhibited almost complete control of tumor cells, equivalent to ponatinib-treated mice, as evidenced by flow cytometry of lung and spleen, despite significantly lower exposure to drug treatment (24 total doses of ponatinib compared with 5 total doses of P9 per animal).

[0896] Example 19: Mitochondrial Membrane Potential in IMR-90 Fibroblasts IMR90 human fibroblasts were cultured under standard conditions in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum and maintained at 37°C in a 5% CO2 atmosphere. To induce senescence, proliferating cells were exposed to 20 Gray of gamma, delivered at a dose rate of approximately 1.0 Gray per minute to ensure acute exposure that triggered DNA damage-induced senescence pathways. Following irradiation, cells were returned to standard culture conditions and allowed to develop senescent phenotype over a period of 7 days, during which morphological changes characteristic of senescence become evident, including cellular enlargement, flattening, and growth arrest. Senescence validation was performed through established senescence-associated biomarkers including SA-β-gal activity, p16 and p21 protein expression.

[0897] Senolytic peptide treatment was administered following senescence establishment. The senolytic peptide treatment protocol included incubation of both proliferating and senescent IMR90 cell populations with concentrations ranging from 5 picomolar to 500 nanomolar for 24 hours. Following senolytic peptide treatment, surviving cells were subjected to mitochondrial membrane potential quantification using TMRM, a lipophilic cationic fluorescent dye that accumulates in mitochondria in proportion to their membrane potential. Cells were washed thoroughly to remove peptide residues and dead cell debris, then incubated with TMRM phenol-red free medium for 30 minutes at 37°C, maintaining physiological temperature throughout the staining procedure to preserve mitochondrial function and membrane potential integrity. Concurrent staining with a mitochondrial mass marker allowed for normalization of TMRM signal to total mitochondrial content, thereby correcting for potential differences in mitochondrial abundance between treatment groups and accounting for any alterations in mitochondrial biogenesis that may have occurred following senolytic treatment. Flow cytometry was then used to quantity TMRM and mitochondrial mass, and TMRM values were normalized to mitochondrial mass for comparison. ATTORNEY DOCKET: 05336.0007WO01

[0898] Results are shown in FIG. 19.

[0899] As shown, senescent IMR90 cells exhibited reduced mitochondrial membrane potential compared to proliferating cells when normalized to mitochondrial mass, consistent with mitochondrial dysfunction as a hallmark of cellular senescence. Following senolytic peptide treatment, proliferating IMR90 cell populations showed increase of mitochondrial membrane potential, indicating an increase in mitochondrial function and energy biogenesis. In senescent cells, senolytic peptide treatment reduced mitochondrial membrane potential, indicative of membrane disruption which pushed the cells towards apoptosis, resulting in senolytic effect of peptides, particularly for P5, P6, and P10.

[0900] Example 20: Apoptosis in Proliferating and Senescent IMR-90 Fibroblasts IMR90 human fibroblasts were cultured using the protocol described in Example 16.

[0901] Senescence was also induced and validated using the protocol described in Example 16. Senolytic peptide treatment is administered following senescence establishment. The senolytic peptide treatment protocol included incubation of both proliferating and senescent IMR90 cell populations with concentrations ranging from 5 picomolar to 50 micromolar for 24 hours. Following senolytic peptide treatment, surviving cells were subjected to apoptotic state analysis via AnnexinV staining, a fluorescent molecule that binds to phosphatidylserine and indicates that cells are in an early apoptotic state. Saline-treated cells were used as negative controls. After flow cytometry analysis, the percentage of apoptotic cells, normalized to controls, were compared between senescent and proliferating IMR90 cells. This resulted in a ‘Senolytic Effect’, i.e., the relative amount of apoptotic senescent cells vs apoptotic proliferating cells.

[0902] Results are shown in FIG. 20.

[0903] As shown senescent IMR90 cells exhibited significantly increased apoptosis compared to proliferating cells, after senolytic peptide treatment, especially for P5, P6, and P10.

[0904] Example 21: Topical CPP Application

[0905] Senolytic activity of peptides was assessed by an accelerated skin aging model in mice. Female and male p16 INK4a-Fluc mice (12-weeks old at study initiation) were shaved and ATTORNEY DOCKET: 05336.0007WO01

[0906] exposed to 35 mJ / cm23X per week over 24 weeks. Peptides were administered 3X per week as curative therapy. A vehicle of 10% DMI, 20% propanediol, 20% Transcutol P in water was used with 1% peptide. Test groups are shown in the table below:

[0907] Group Treatment Administration

[0908] Female a (n=4) Vehicle

[0909] Female b (n=4) P5 Topical, 3X / week Female c (n=4) P11 Topical, 3X / week

[0910] Male a (n=5) Vehicle

[0911] Male b (n=8) P5 Topical, 3X / week

[0912]

[0913] Male c (n=7) P11 Topical, 3X / week

[0914] For each animal, vehicle was applied to the top half (“vehicle treatment area”) and peptide+vehicle was applied to the bottom half (“peptide treatment area”) of the animals. Separate ROIs were analyzed for vehicle treatment area and peptide treatment area. Results are shown in FIG. 21 A.

[0915] Blood was sampled from animals two weeks after completing UVB treatment (which was 2 weeks prior to initiating treatment) and two weeks after initiating treatment. Treatment was initiated at point 0 in FIG. 21 B. Blood levels were normalized to the pre-treatment blood SASP-level timepoint (-2) and percent change was graphed. As shown, treatment groups showed reduction in blood cytokines compared with vehicle.

[0916] Post-CPP treatment rotarod testing results compared to results after no (saline) peptide treatment are shown in FIG. 21 C and reported in the table below.

[0917] Rotarod Latency

[0918] Males Females ASaline ASaline (Latest Time Point) (Latest Time Point) Group A P A P Vehicle - - - - P5 -11.24% 0.1758 24.01% 0.0334 P11 -5.50% 0.4998 5.23% 0.4520

[0919]

[0920] Post-CPP treatment forelimb grip strength testing results compared to results after no (saline) peptide treatment are shown in FIG. 21 D and reported in the table below. ATTORNEY DOCKET: 05336.0007WO01

[0921] Grip Strength

[0922] Males Females ASaline ASaline (Latest Time Point) (Latest Time Point) Group A P A P Vehicle - - - - P5 -6.19% 0.4819 +5.21% 0.8148 P11 -17.59% 0.0608 -15.05% 0.4808

[0923]

[0924] Example 22: In Vitro Cancer Cell Line Screening

[0925] Exemplary Peptides were analyzed against leukemias and lymphomas. EC₅₀ values are shown in the table below (values given in nM).

[0926] Cell Line Cell Type P6 P8 P9 P13 P14

[0927] Acute

[0928] THP-1 monocytic 100,000 66,379

[0929] leukemia

[0930] Acute

[0931] HL-60 promyelocytic 198,584 100,000 88,568 94,752 22,471 leukemia

[0932] Acute

[0933] HL-60 / S4 myeloblastic 100,000 46,273

[0934] leukemia

[0935] Mantle cell (B

[0936] JeKo-1 cell) 100,000 100,000 81,113 8,347 6,317 lymphoma

[0937] B cell

[0938] Raji (Burkitt’s 1,987 100,000 267,453

[0939] lymphoma)

[0940] KCL-22- CML 100,000 100,000 100,000 100,000 100,000 KM KU-812 CML 100,000 125,777 76,232 100,000 100,000

[0941] Acute T cell

[0942] Loucy 100,000 100,000 100,000

[0943] leukemia

[0944] Acute T cell

[0945] Jurkat 100,000 100,000 100,000 100,000 84,310 leukemia

[0946] Ph “like” B

[0947] MHH- cell precursor 63,511 70,373 51,707 100,000 100,000 CALL-4

[0948] leukemia

[0949] Ph “like” B- MUTZ-5 100,000 12,447

[0950] ALL

[0951] Ph “like” B- HAL-01 100,000 6,145

[0952]

[0953] ALL ATTORNEY DOCKET: 05336.0007WO01

[0954] Ph “like” B- RCH-ACV 9,356 5,377

[0955] ALL NALM-21 Ph + B-ALL 100,000 100,000 100,000 100,000 100,000 TOM-1 Ph + B-ALL 2,442 15,786 4,054 100,000 100,000 SD-1 Ph + B-ALL 100,000 92,415

[0956] RT4 4,961 95,009 86,805

[0957] Bladder

[0958] T24 63,837 115,184

[0959] cancer

[0960] Bladder

[0961] TCCSUP 13,406

[0962] cancer

[0963] Bladder

[0964] UMUC3 22,933 100,000 45,765 18,842 1,845 cancer

[0965] Breast

[0966] T-47D 5,944 12,704 100,000

[0967] cancer

[0968] Breast

[0969] ZR-75-30 24,955

[0970] cancer

[0971] Colon

[0972] HCT116 10,941 100,000 14,788 17,109 1,659 carcinoma

[0973] SW620 Colon cancer 100,000 100,000 100,000 30,067 1,633

[0974] Colorectal

[0975] LS123 86,025 60,949

[0976] cancer

[0977] Epidermoid

[0978] A431 carcinoma

[0979] of the skin

[0980] Liver

[0981] HepG2 2,988 146,977 100,000

[0982] carcinoma

[0983] Liver

[0984] SNU-475 100,000 68,154

[0985] carcinoma

[0986] Lung

[0987] HCC-78 34,412 12,429

[0988] carcinoma

[0989] Lung

[0990] A549 172,380 44,744

[0991] carcinoma

[0992] Prostate

[0993] 22RV1 5,471 16,623 11,678 25,823 1,648 cancer (AR+)

[0994] Prostate

[0995] LnCAP 62,921 100,000 100,000 49,093 4,529 cancer (AR+)

[0996] MDA Pea Prostate

[0997] 100,000 100,000 100,000

[0998] 2b cancer (AR+)

[0999] Prostate

[1000] DU145 6,195 15,887

[1001] cancer (AR-)

[1002] Prostate

[1003] PC3 100,000 100,000 100,000

[1004]

[1005] cancer (AR-) ATTORNEY DOCKET: 05336.0007WO01

[1006] Summary of Examples and Demonstrated Senolytic and Senotherapeutic Effect

[1007] The examples above, for example, in vitro examples, demonstrate differential senolytic activity for GPPs, for example, for P1, P5, P6, P10, P15, P16, and P17 (e.g. higher activity in senescent IMR90 cells (S-IMR90) than in proliferating IMR90 cells (P-IMR90).

[1008] Furthermore, the in vivo examples evaluating GPPs demonstrate senolytic activity and correlated phenotypic effects resulting from the senotherapeutic activity of peptide treatment.

[1009] P1, P5, P6, and P15 effectively and safely eliminate senescent cells in all organs of the body. These peptides also demonstrate ability to cross the blood brain barrier by way of their effective senolytic activity demonstrated in the brain after intraperitoneal administration, for example, including in key areas of the brain associated with neurodegenerative disorders like Alzheimer’s Disease and Chronic Traumatic Encephalopathy (Hippocampus-CA1 and CA3, Cerebral Cortex) and Parkinson’s Disease (Substantia Nigra and Basal Ganglia).

[1010] P5, P6, and P10 demonstrate targeted apoptosis in senescent IMR90 cells.

[1011] P1 and P5 effectively reduce plasma level of key cytokine components of the SASP.

[1012] P1 and P5 effectively reduce the intermyocyte space and adipocyte area in treated mice. P1, P5, and P6 prevent or reduce the weight loss associated with aging-associated sarcopenia. P1, P5, and P6 add lean body and bone mass at the expense of fat compared with control animals.

[1013] Treatment with P1, P5, and P6 also results in increased M2 anti-inflammatory macrophage and in the proportion of M2 anti-inflammatory macrophage subtype increasing in three different type of adipose tissue (IAT, PRAT, and GAT).

[1014] P5 and P6 improve performance of treated mice on the Rotarod, a device measuring a combination of cognitive ability, balance, and exercise capacity. Mice treated with P1, P5, and P6 also showed decreased fatigue on the motorized treadmill, increased forelimb grip strength, and improved cognitive performance on the Water Motivated Stone T-maze. P5 also demonstrates protective effect against Late Radiation-Induced Toxicity. ATTORNEY DOCKET: 05336.0007WO01

[1015] Further, peptides, especially P6, P8, P9, P13, and P14, demonstrated cytotoxicity against various leukemia and lymphoma cancer cell lines.

[1016] P6 and P9 also demonstrated in vivo effect against TOM-1 Tail Vein (IV) Tumors.

[1017] CPPs such as those described herein selectively and preferentially kill senescent cells. In embodiments, and without being limited to a single method of action, CPPs demonstrate selective senolytic effect by apoptosis. For example, CPPs may demonstrate selective senolytic effect by apoptosis of senescent cells. As a further example, CPPs may demonstrate selective senolytic effect by apoptosis through disruption of a cell membrane. In embodiments, and without being limited to a single method of action, CPPs may have selective sensitivity to disruption of a senescent cell membrane.

[1018] Additionally or alternatively, CPPs may have selective sensitivity to disruption of a mitochondrial membrane. As an example, and again with being limited to single method of action, CPPs may selectively and / or preferentially bind to phosphatidylserine or cardiolipin or other negatively charged lipids in an external cell membrane and / or a mitochondrial membrane. Senescent cells may express higher levels of phosphatidylserine or cardiolipin or other negatively charged lipids than non-senescent cells.

[1019] Further, senescent cells may have a higher mitochondrial mass but lower membrane potential (lower mitochondrial membrane potential or ΔΨm) when compared with nonsenescent cells. The mitochondrial network may also be more fragmented in young cells, while mitochondria may be fused in senescent cells. Still further, mitochondrial superoxide levels may be elevated in senescent cells.

[1020] For example, as shown in FIG. 22, senescent fibroblasts may demonstrate a higher mitochondrial mass compared with non-senescent (young fibroblasts) as shown in green. Referring still to FIG. 22, despite the higher mitochondrial mass, senescent fibroblasts may demonstrate lower membrane potential when compared with non-senescent (young) fibroblasts as shown in red. Finally, mitochondrial superoxide levels may be elevated in senescent cells compared with younger, non-senescent cells as shown in pink.

[1021] Factors contributing to this lower membrane potential may include the following:

[1022] 1) Increased mitochondrial permeability transition pore (mPTP) activation. In senescent cells, the mPTP opens more frequently, leading to a loss of ΔΨm. This pore's activation ATTORNEY DOCKET: 05336.0007WO01

[1023] disrupts the mitochondrial membrane potential, inhibits oxidative phosphorylation, and releases calcium and reactive oxygen species (ROS).

[1024] 2) Decreased respiratory capacity. Senescent cells exhibit a reduced respiratory capacity per mitochondrion, which contributes to the decreased Aipm. This reduced capacity affects the cell's ability to generate ATP efficiently.

[1025] 3) Accumulation of mitochondrial DNA damage. Over time, mitochondrial DNA accumulates damage, leading to impaired mitochondrial function and a subsequent drop in Ai m.

[1026] 4) Enhanced Production of ROS. Senescent cells produce more ROS, which can damage mitochondrial components and further reduce Aipm.

[1027] CPPs such as those described herein, including, for example, cationic and amphipathic CPPs described herein, may target the mitochondrial membrane potential (MMP) through several mechanisms, including, for example:

[1028] 1) Electrostatic Attraction: Cationic GPPs, which contain positively charged amino acids like arginine and lysine, are attracted to the negatively charged mitochondrial membrane. This electrostatic interaction facilitates their binding and entry into the mitochondria.

[1029] 2) Amphipathic Nature: Amphipathic CPPs have both hydrophilic and hydrophobic regions, allowing them to interact with the lipid bilayer of the mitochondrial membrane. This dual nature helps them to penetrate the membrane more effectively.

[1030] 3) Membrane Potential Utilization: The mitochondrial membrane potential (MMP) creates an electrochemical gradient that cationic CPPs can exploit. The positive charge of the CPPs is drawn towards the negatively charged inner mitochondrial membrane, aiding in their translocation across the membrane.

[1031] 4) Mitochondrial Targeting: Some CPPs are specifically designed to target mitochondria by exploiting the Mitochondrial Membrane Potential (MMP).

[1032] In summary, senescent cells may have less capacity to maintain MMP compared with normal dividing cells and may thus be exposed to prolonged mPTP opening and, possibly, to minority mitochondrial outer membrane permeabilization MOMP. Permeabilization of a small number of mitochondria leads to apoptosis and selective elimination of these cells. ATTORNEY DOCKET: 05336.0007WO01

[1033] Thus, MMP may provide a selective functional target for senescent cells, for example a functional target for senolytic GPPs such as those described herein.

[1034] For example, senolytic GPPs such as those described herein may selectively eliminate senescent cells via mitochondrial-mediated apoptosis as is now described in more detail. The loss of mitochondrial membrane potential, or MMP (A^Pm) is a critical event in the process of apoptosis, often triggered by the opening of the mitochondrial permeability transition pore (mPTP) under various pathological conditions. A representative diagram of mitochondrial-mediated apoptosis is shown in FIG. 23.

[1035] Referring to FIG. 23, the following steps are depicted:

[1036] Opening of mPTP: Pathological conditions such as oxidative stress, calcium overload, or ischemia can trigger the opening of the mPTP.

[1037] Loss of AMJm: The opening of the mPTP disrupts the proton gradient across the inner mitochondrial membrane, leading to a loss of ΔΨm. This gradient is essential for ATP production through oxidative phosphorylation.

[1038] Release of Pro-apoptotic Factors: The loss of AM^m causes the mitochondria to swell and the outer mitochondrial membrane to become permeable. This permeability allows the release of pro-apoptotic factors such as cytochrome c, apoptosis-inducing factor (AIF), and Smac / DIABLO into the cytosol.

[1039] Activation of Caspases Leading to Apoptosis: Once in the cytosol, cytochrome c binds to Apaf-1 (apoptotic protease activating factor-1) and dATP, forming the apoptosome. This complex then activates caspase-9, which in turn activates executioner caspases like caspase-3, leading to the proteolytic cleavage of cellular components. The activation of executioner caspases results in the systematic dismantling of the cell, in the process of apoptosis.

[1040] In summary, in senescent cells, senolytic CPPs such as those described herein may selectively trigger apoptosis via a reduction in the Mitochondrial Membrane Potential (MMP) (AMJm), exposing them to prolonged mitochondrial transition pore opening and permeabilization of these mitochondria, leading to apoptosis and selective elimination of these cells. ATTORNEY DOCKET: 05336.0007WO01

[1041] Alternatively or additionally, cancer cells may also have a decreased capacity to maintain MMP compared with normal cells. Cancer cells may thus also be exposed to prolonged mPTP opening and possibly, to minority MOMP. Accordingly, MMP may provide a selective functional target for cancer cells, for example, a functional target for senolytic CPPs such as those described herein to target cancer cells.

[1042] Further, CPPs demonstrate translocate across the cell plasma membrane by a non-endocytic, receptor-independent mechanism, and entry is not restricted to a specific cell type. CPPs may thus selectively and / or preferentially kill senescent cells while avoiding and / or minimizing effect on normal, healthy cells.

[1043] Selectively and / or preferentially killing senescent cells may help reduce harmful effects associated with cellular senescence, including conditions discussed herein. Accordingly, patients may be treated by administering a therapeutic amount of a cell penetrating peptide, for example, an amount of a cell penetrating peptide sufficient to provide a senolytic effect.

[1044] Further Exemplary Models for Assessing a Senescent Cell Population in Animal Models and for Assessing Senolytic Effect In Vitro

[1045] Further exemplary models according to embodiments are now described. These models may be used in addition to or as an alternative to those described above. One of skill in the art will understand that the models are exemplary and teachings from one model may be applied to other models. Cell penetrating peptides were assessed to identify those having increased senolytic activity and reduced effects in healthy, proliferating cells. To validate new senolytic CPPs, in vitro and primarily in vivo experiments are performed.

[1046] Diet Induced Obesity (DIO) model

[1047] In further embodiments, a diet induced obesity model may be used. For example, an animal may be provided with a high fat diet (HFD). The high fat diet may be provided to naturally aged animals (for example, animals from the naturally aged model described above) and / or may be provided to animals that have undergone accelerated aging (for example, animals from the whole body gamma irradiation model described above). The ATTORNEY DOCKET: 05336.0007WO01

[1048] high fat diet may induce metabolic syndrome and / or make the animal more susceptible to developing metabolic syndrome.

[1049] After being provided with the high fat diet, the animal may be sacrificed and / or may be treated by administration of a CPP as described herein.

[1050] Senescence may be evaluated as discussed with respect to the models above and as discussed in further detail in the examples below. Likewise, senolytic activity of a CPP may be evaluated as discussed with respect to the models above and as discussed in further detail in the examples below. Further, senolytic effect may be evaluated by phenotypic analysis as discussed in more detail below. Additionally, or alternatively, amelioration / reduction of metabolic dysfunction and / or metabolic syndrome may be evaluated.

[1051] An exemplary experimental model includes that of Example 11 below. The model may be varied as would be understood by one of skill in the art.

[1052] Models Using In Vivo Imaging Systems (IVIS)

[1053] In further embodiments, senescent cells are assayed and / or quantified in vivo using imaging, for example, in vivo imaging systems (IVIS). In embodiments, IVIS may allow for senescent cells to be assayed and / or quantified without requiring sacrifice of the animal and subsequent immunohistochemical analysis of harvested organs.

[1054] In embodiments, animals from one or more of the models discussed above and / or the Examples discussed herein are used together with IVIS. For example, a naturally aged animal is used and / or an accelerated aging model is used. In embodiments, the animal is a p16-lnk4a-LUC mouse.

[1055] The animal is imaged using IVIS at various time periods, for example, prior to receiving peptide treatment, during peptide treatment, and after receiving peptide treatment.

[1056] Senolytic effect of peptides is evaluated based on data collected from the imaging, for example, a reduction in total bioluminescent signal, as analyzed by IVIS imaging, indicates a reduction in total senescent cell burden in the animal. Further, senotherapeutic effect is evaluated by phenotypic analysis as discussed in more detail below. ATTORNEY DOCKET: 05336.0007WO01

[1057] CPP Compositions

[1058] A CPP sometimes contains about 50 or fewer amino acids, or about 45 or fewer amino acids, or about 40 or fewer amino acids, or about 35 or fewer amino acids, or about 30 or fewer amino acids, or about 25 or fewer amino acids, or about 20 or fewer amino acids, or about 15 or fewer amino acids. In an embodiment, a CPP may contain 18 amino acids. In embodiments, a CPP may be categorized by its net charge, for example, the sum or total charge of individual amino acids in the CPP may be used to categorize the CPP. Certain amino acids can have a net positive charge at pH 7.0 (positively charged amino acid) or net negative charge at pH 7.0 (negatively charged amino acid), and certain amino acids are hydrophobic or hydrophilic. Amino acids are referred to herein by representative single-letter codes. Positively-charged amino acids at pH 7.0 include arginine (R), lysine (K) and histidine (H). Negatively-charged amino acids at pH 7.0 include aspartate (D) and glutamate (E). Hydrophilic amino acids include arginine (R), asparagine (N), aspartate (D), glutamine (Q), glutamate (E), histidine (H), lysine (K), serine (S) and threonine (T).

[1059] Hydrophobic amino acids include glycine (G), alanine (A), leucine (L), isoleucine (I), valine (V), tryptophan (W), tyrosine (Y), phenylalanine (F), methionine (M), cysteine (C) and proline (P).

[1060] In embodiments, a CPP may be a cationic peptide. A cationic peptide may have an overall charge at a pH of 7.0, for example, an overall positive charge. For example, in embodiments, the cationic peptide may have a charge of greater than 3 at a pH of 7.0, a charge of greater than 4 at a pH of 7.0, a charge of greater than 5 at a pH of 7.0, a charge of greater than 6 at a pH of 7.0, a charge of greater than 7 at a pH of 7.0, or a charge of greater than 8 at a pH of 7.0.

[1061] Additionally or alternatively, a cationic peptide may have a percentage of charged amino acids with respect to a total number of amino acids. For example, in embodiments the percentage of charged amino acids may be within a specified range, for example, between 25% and 50%. In embodiments, the percentage of charged amino acids may be greater than 40%. In embodiments, the percentage of charged amino acids may be 44% or greater. ATTORNEY DOCKET: 05336.0007WO01

[1062] Due at least in part to the overall positive charge and / or the percentage of charged amino acids, a cationic peptide may effectively interact with a cell membrane (for example, a negatively charged cell membrane).

[1063] In embodiments, a CPP can be an amphipathic peptide. An amphipathic peptide may have both hydrophilic (water-attracting) and hydrophobic (water-repelling) regions. Amphipathic peptides may effectively insert into lipid bilayers and may be effective at disrupting and / or crossing cell membranes.

[1064] In embodiments, a CPP can be both cationic and amphipathic. Such a CPP may be referred to as a cationic-amphipathic CPP.

[1065] Other means of categorizing a CPP may also be used, for example, whether the CPP is polar or nonpolar, hydrophobic or hydrophilic, etc.

[1066] Still further, a CPP may also be categorized based on an amount of one or more specific amino acids. For example, a CPP may be categorized as arginine rich, cysteine rich, etc. An arginine rich CPP comprises multiple arginine residues. For example, greater than 10% of total residues or greater than 20% of total residues may be arginine. Likewise, a cysteine rich CPP comprises multiple cysteine residues. For example, greater than 10% of total residues or greater than 20% of total residues may be cysteine.

[1067] In certain embodiments, a CPP contains hydrophobic amino acids, and a CPP can contain leucine (L) amino acids, or alanine amino acids (A), or a combination of L amino acids and A amino acids. In certain embodiments, a CPP contains a greater proportion of hydrophobic amino acids than hydrophilic amino acids. A CPP in certain embodiments contains a ratio of hydrophilic amino acids to hydrophobic amino acids at pH 7.0 of at least about 30:70 to about 40:60 or about 30:67 to about 40:60.

[1068] In certain embodiments, a CPP contains one or more negatively-charged amino acids at pH 7.0, and a CPP can contain one or more glutamate (E) amino acids. In certain embodiments, a CPP contains at least two but no more than three negatively-charged amino acids. In certain embodiments, a CPP contains a ratio of positively-charged amino acids to negatively-charged amino acids of at least about 6:2 to about 9:2 or about 6:2 to about 8:2. In certain embodiments, a ratio of R amino acids to E amino acids is at least about 6:2 to about 9:2 or about 6:2 to about 8:2. ATTORNEY DOCKET: 05336.0007WO01

[1069] In certain embodiments, a CPP contains six or more R amino acids, twelve or more A amino acids, and six or more L amino acids. In certain instances, a CPP contains two or more segments containing RALA (SEQ ID NO: 1). In certain embodiments, a CPP contains EARLARALARALAR (SEQ ID NO: 2); or LARALARALRA (SEQ ID NO: 3); or EARLARALARALAR (SEQ ID NO: 2) and LARALARALRA (SEQ ID NO: 3). In certain instances, a CPP contains X1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 4), where: X1is W or R; X2is selected from H or E; and X3is C or R. In certain instances, a CPP contains X1-EARLARALARALARLARALARALRA-X3-EA (SEQ ID NO: 7), where: X1is W or R; and X3is C or R.

[1070] In certain embodiments, a CPP contains an amino acid sequence at least about 80% or more identical to X1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 4).

[1071] In certain embodiments, a CPP may have a logP measure lower than 0.1 (with log P measurements extending into the negative range).

[1072] In certain embodiments, a CPP may have a net positive charge, a logP measure lower than 0.1, one or more positively charged amino acids, an Arg (R) or Lys(K) residue, and combinations thereof.

[1073] In certain embodiments a CPP may be selected from those in Table 1.

[1074] In certain embodiments a CPP may be a retro-inverso peptide of any of the SEQ IDs or peptides disclosed herein, for example a D-retro-inverso peptide.

[1075] Uses of Compositions

[1076] In certain embodiments, a CPP composition is used to selectively reduce a senescent cell population. In certain embodiments, provided is a method for reducing a senescent cell population, which includes administering a CPP composition to cells in an amount sufficient to selectively reduce the senescent cell population. In certain embodiments, a CPP composition is used to selectively reduce a senescent cell population in a tissue, organ or subject. In certain embodiments, provided is a method for selectively reducing a senescent cell population, which includes administering a CPP composition to a tissue, organ or subject in an amount sufficient to selectively reduce the senescent cell population in the tissue, organ or subject. In certain embodiments, a CPP composition is used to treat a ATTORNEY DOCKET: 05336.0007WO01

[1077] medical condition associated with a senescent cell population. In certain embodiments, provided is a method for treating a medical condition, which includes administering a CPP composition to a tissue, organ or subject in an amount sufficient to selectively reduce a senescent cell population in the subject.

[1078] In certain instances, the cells, tissue, organ or subject contain, and optionally have been detected to contain, a senescent cell population. For example, senescent cells may be found to accumulate in various cells, tissue, and / or organs. Representative examples of senescent cell accumulation in humans and other mammals may include within the eyes, lung, liver, pancreas, fat cells, skeletal muscle, skeletal structure including bone, brain, heart, kidneys, and skin. Representative examples of disease / conditions, for example, age-related diseases and conditions, that may be caused or exacerbated by senescent cell accumulation include cataracts, age-associated macular degeneration (both wet and dry), idiopathic pulmonary fibrosis, obesity, glucose intolerance, diabetes, sarcopenia, reduced exercise capacity, frailty, osteoporosis, bone fracture, cognitive decline, memory impairment, Alzheimer’s disease, Parkinson’s disease, chronic traumatic encephalopathy, age-related cardiomyocyte hypertrophy, loss of cardiac stress tolerance, heart failure, arrhythmias, glomerulosclerosis, renal RAAS hyperactivity, kidney failure, dermal thinning, and subdermal adipose layer thinning. In embodiments, a CPP composition as described herein may be used to treat or prevent one or more of these age-related diseases and conditions. Representative examples of the effects of a CPP composition as described herein may include delayed cataract formation, reduction of idiopathic pulmonary fibrosis, alleviation of metabolic and adipose tissue dysfunction, improved glucose tolerance, enhanced insulin sensitivity, amelioration of inflammation, increase muscle strength and exercise capacity, improved body weight and composition, higher bone mass and strength, better microarchitecture, reduction in lordokyphosis, improved cognition and memory, reduced incidence of neurodegenerative disease, improved cardiac diastolic function, reduced cardiac hypertrophy, reduced arrhythmias, improved kidney function (for example, as measured by albumin / Creatinine Ratio), increased thickness of dermis and subdermal adipose layer, reduction of cancer and cancer-related death, extension of lifespan, extension of healthspan.

[1079] In further embodiments, senescent cells may accumulate in tissue as a result of other injury, for example, senescent cells may accumulate in the brain as a result of mild ATTORNEY DOCKET: 05336.0007WO01

[1080] traumatic brain injury or other damage. Some examples of sources of such damage include contact sports, especially football, military operations, firing weapons, etc. These senescent cells may contribute to a host of symptoms, including but not limited to cognitive difficulties, low testosterone levels, headache, concussion signs and symptoms, depressive / emotional and behavioral dyscontrol symptoms, pain, suicidal thoughts, insomnia, paranoia, and the like. Representative examples of the effects of a CPP composition as described herein may include eliminating such senescent cells and preventing progression to persistent symptoms and neurodegenerative disease. As an example, post-concussive syndrome may be treated and / or prevented. Similarly, chronic traumatic encephalopathy may be treated and / or prevented.

[1081] In further embodiments, senescent cells may accumulate in tissue as a result of treatment with radiation therapy for cancer or other diseases or conditions, for example, senescent cells may accumulate in or around the treated tissue. Representative examples of the effects of a CPP composition as described herein may include eliminating such senescent cells and preventing progression to further diseases or conditions.

[1082] Methods for detecting senescent cells are known, including determining presence, absence and / or amount of (i) SA-beta-galactosidase; or (ii) p16 (p16INK4a for example); or (iii) urokinase plasminogen activator receptor (uPAR); or (iv) a p-21 positive cell population; or (v) a combination of one or more of (i), (ii), (iii), and (iv).). In certain embodiments, the senescent cell population is (i) a SA-beta-galactosidase-positive cell population; or (ii) a p16-positive cell population (a p16INK4a-positive cell population for example); or (iii) a urokinase plasminogen activator receptor (uPAR)-positivecell population; or (iv) a p-21 positive cell population; or (v) a combination of one or more of (i), (ii), (iii), and (iv).. In certain embodiments, presence, absence and / or amount of a senescent cells in a population is detected in vitro, ex vivo and / or in vivo. In certain instances, presence, absence and / or amount of a senescent cells in a population is detected in a sample containing cells, tissue and / or organ of subject, and / or sometimes in a subject. In certain embodiments, a CPP composition is administered based on the presence, absence or amount of senescent cells detected.

[1083] In embodiments, the senescent cell population includes cells throughout the body and in various organs. For example and without limitation, a senescent cell population may be located in one or more of the brain, kidneys, liver, lungs, eyes, inguinal adipose tissue, ATTORNEY DOCKET: 05336.0007WO01

[1084] gastrocnemius, and spleen. In certain embodiments, the senescent cell population contains skin cells, and the skin cells sometimes include epidermis cells, dermis cells, or epidermis cells and dermis cells. In certain implementations, a CPP composition is administered to skin tissue (for example, skin tissue of a subject) topically or by injection. In certain embodiments, the senescent cell population contains systemic cells. In certain embodiments, a CPP composition is administered topically or by injection. In certain embodiments, a device described herein is used to administer a CPP composition, which sometimes is for topical administration or administration by injection.

[1085] In one embodiment, a biopsy method is provided. An organ in an animal’s body is biopsied to obtain a cellular sample. In one embodiment, the animal is a human. The number or percentage of senescent cells in the cellular sample is determined. The number or percentage is correlated to statistical data for the animal’s species to determine a biologic age score for the animal. In this manner the biologic age score for the animal can be compared to the statistical data for the animal’s species and determine if the animal is experiencing an accelerated or diminished rate of aging. Still further, the percentage of senescent cells may be compared to a reference percentage.

[1086] By way of illustration and not limitation, an individual’s skin may be biopsied and a biologic age scored calculated based on the percentage of senescent cells in the biopsy. The individual may then be treated with one or more of the disclosed CPP compositions. After a predetermined period of time (e.g., at least 14 days, at least 30 days) the individual’s skin is biopsied again and the individual’s biologic age score is recalculated to determine the efficacy of that therapy in reducing that individual’s biologic age. In one embodiment, the percentage of senescent cells decreases over the predetermined period of time (i.e., the treatment recapitulates the cells).

[1087] In one embodiment, two skin biopsies are taken from an individual person, one from a sun-exposed area of the skin and one from an area of the skin not exposed to the sun (reduced-sun-exposed) e.g., the buttocks or inguinal region). A biologic age score is then calculated from each biopsy sample. A ratio of the two biologic age scores assesses whether the age of that individual’s skin is above or below their whole-body biologic age score, as measured from the non-exposed skin. In some embodiments, the disclosed composites are applied topically to only treat the skin. In some embodiments, punch biopsies of the skin are performed in multiple areas including both treated and untreated ATTORNEY DOCKET: 05336.0007WO01

[1088] areas of the skin to assess the efficacy of the treatment by comparing biologic age scores obtained from treated and untreated areas.

[1089] Other methods of determining a biologic age score include correlating senescent cell population to an observable medical condition, thereby indirectly measuring senescent cell population. Suitable tests include a glucose tolerance test (GTT), an insulin tolerance test (ITT), an endurance testing (e.g. treadmill testing), an agility test (e.g. balance testing), a grip strength test, maze testing (cognitive), and blood chemistry tests (e.g. fasting glucose, kidney, liver, cardiac). Still further, in embodiments additional and / or alternative data may be used as part of the method of determining a biologic age score. For example, nonbiopsy data such as physical data, blood test data, SASP data, a scan, a PET scan, and / or an optical scan of the skin or other organ may be used.

[1090] In some embodiments, the disclosed method treats the whole individual’s body, including the skin. Such embodiments may apply the conditions internally (e.g., injection such as IV injection) and also topically.

[1091] In certain embodiments, a CPP composition has a detectable senolytic activity, and sometimes does not have a detectable senomorphic activity.

[1092] In certain embodiments, a medical condition treated by a CPP composition is actinic keratosis, Bowen’s disease, in situ carcinoma, atopic dermatitis, non-segmental vitiligo, psoriasis, ultraviolet (UV) damaged skin or aged skin. The UV damaged skin sometimes is severely UV damaged skin, and sometimes the psoriasis is plaque psoriasis. In certain instances, a medical condition is treated in a human subject.

[1093] In some embodiments, the CPP composition is administered to treat a medical condition including delaying or preventing age-related disorders and maximizing healthy lifespan, infertility, lordokyphosis, sarcopenia, age-related cataracts, fat loss, age-related cardiomyocyte hypertrophy and loss of cardiac stress tolerance, heart failure, cardiac arrhythmias, glomerulosclerosis, renal RAAS hyperactivity, kidney failure, lungs -idiopathic pulmonary fibrosis, skeletal muscle - exercise capacity, frailty, skeleton - femur and spine - osteoporosis, fracture, arterial wall stiffening, impaired wound healing, dermal thinning (dermis and subdermal adipose layer thickness), physical fitness and exercise ability (e.g. time to exhaustion in a treadmill exercise test), amelioration of metabolic dysfunction and alleviation of age-related brain inflammation and cognitive impairment. ATTORNEY DOCKET: 05336.0007WO01

[1094] Examples of ameliorating metabolic disfunction include decreased fasting glucose levels and improved glucose tolerance when on a high-fat diet. This induces metabolic syndrome in even young animals fed a high fat diet. Metabolic syndrome is effectively reduced by elimination of senescent cells as measured by lower body weight, lower fasting blood glucose levels and improvements in both glucose and insulin tolerance. Also lower basal insulin levels after fasting that is followed by a significant increase in insulin levels 15 min after a glucose load in a Glucose Tolerance Test (GTT), indicative of improved pancreatic beta cell function.

[1095] In certain embodiments, a GPP in a composition is administered at a dose of about 1 mg / kg to about 10 mg / kg, or about 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg or 9 mg / kg. A GPP composition can be administered about one (1X) to about five times (5X) weekly, or three times (3X) weekly, and in certain instances is administered intraperitoneally, subcutaneously, intravenously or topically.

[1096] Certain Implementations

[1097] Following are non-limiting examples of certain implementations of the technology. These implementations may be used in connection with one or more of the models and / or examples described above.

[1098] A1. A method of eliminating senescent cells by administering a cell penetrating peptide (“GPP”).

[1099] A2. The method according to the embodiment of A1, wherein the CPP is an amphipathic GPP.

[1100] A3. The method according to the embodiment of A2, wherein the amphipathic CPP triggers apoptosis through disruption of either an external cell membrane or a mitochondrial membrane.

[1101] A4. The method according to the embodiment of A1, wherein the CPP is a cationic CPP. A5. The method according to the embodiment of A4, wherein the cationic CPP triggers apoptosis through disruption of either an external cell membrane or a mitochondrial membrane.

[1102] A6. The method according to the embodiment of A1, wherein the CPP is a cationic-amphipathic CPP. ATTORNEY DOCKET: 05336.0007WO01

[1103] A7. The method according to the embodiment of A6, wherein the cationic-amphipathic CPP triggers apoptosis through disruption of either an external cell membrane or a mitochondrial membrane.

[1104] A8. The method according to the embodiment of A1, wherein the CPP is an arginine-rich CPP.

[1105] A9. The method according to the embodiment of A8, wherein the arginine-rich CPP comprises arginine in an amount of at least 10% of a total number of residues.

[1106] A10. The method according to the embodiment of A1, wherein the CPP is a positively charged CPP.

[1107] A11. The method according to the embodiment of A10, wherein the positively charged CPP binds to phosphatidylserine.

[1108] A12. The method according to the embodiment of A10, wherein the positively charged CPP preferentially binds to phosphatidylserine.

[1109] A13. The method according to the embodiment of A10, wherein the positively charged CPP preferentially binds to phosphatidylserine in a membrane of a senescent cell.

[1110] A14. The method according to the embodiment of A10, wherein the positively charged CPP triggers apoptosis through disruption of either an external cell membrane or a mitochondrial membrane.

[1111] A15. The method according to the embodiment of A10, wherein the positively charged CPP triggers apoptosis through disruption of either the external cell membrane or the mitochondrial membrane as a result of binding phosphatidylserine in an external cell membrane or a mitochondrial membrane.

[1112] A16. The method according to the embodiment of A10, wherein the positively charged CPP preferentially binds phosphatidylserine in a senescent cell compared with a healthy cell.

[1113] A17. The method according to the embodiment of A1, wherein the CPP is selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

[1114] A18. The method according to the embodiment of A1, wherein the cell penetrating peptide has a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to at least ATTORNEY DOCKET: 05336.0007WO01

[1115] one sequence selected from the group consisting: SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20,, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

[1116] A19. The method according to the embodiment of A1, wherein the cell penetrating peptide is selected from the group consisting of: SEQ ID NO: 028 and any of SEQ ID NO: 557-SEQ ID NO: 742.

[1117] A20. The method according to the embodiment of A1, wherein the cell penetrating peptide is selected from the group consisting of: any of SEQ ID NO: 513-SEQ ID NO: 556. A21. The method according to the embodiment of A1, wherein the cell penetrating peptide is selected from the group consisting of: SEQ ID NO: 1- SEQ ID NO. 11, SEQ ID NO: 13-SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 27, and any of SEQ ID NO: 29-SEQ ID NO: 64.

[1118] A22. The method according to the embodiment of A1, wherein the cell penetrating peptide is selected from the group consisting of: SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 25, any of SEQ ID NO: 65-498, and SEQ ID NO: 504.

[1119] A23. The method according to the embodiment of A1, wherein the cell penetrating peptide is selected from the group consisting of: any of SEQ ID NO: 743-SEQ ID NO: 779. A24. The method according to the embodiment of A1, wherein the cell penetrating peptide is derived from murine vascular endothelial cadherin.

[1120] A25. The method according to the embodiment of A1, wherein the cell penetrating peptide is derived from human vascular endothelial cadherin.

[1121] A26. The method according to the embodiment of A1, wherein the cell penetrating peptide comprises SEQ ID NO: 607.

[1122] B1. A composition, comprising a senolytic cell penetrating peptide in an amount sufficient to selectively reduce a senescent cell population.

[1123] B2. The composition of embodiment B1, wherein the senescent cell population is (i) a SA- beta-galactosidase-positive cell population; or (ii) a p16-positive cell population; or (iii) a urokinase plasminogen activator receptor (uPAR)-positivecell population; or (iv) a p-21 positive cell population; or (v) a combination of one or more of (i), (ii), (iii), and (iv)..

[1124] B3. The composition of embodiment B1 or B2, wherein the cell penetrating peptide contains about 50 or fewer amino acids. ATTORNEY DOCKET: 05336.0007WO01

[1125] B4. The composition of any one of embodiments 1-B3, wherein the cell penetrating peptide is an amphipathic peptide.

[1126] B5. The composition of any one of embodiments B1-B4, wherein the cell penetrating peptide has a net positive charge at pH 7.0.

[1127] B6. The composition of any one of embodiments B1-B5, wherein the cell penetrating peptide comprises hydrophilic amino acids.

[1128] B7. The composition of any one of embodiments B1-B6, wherein the cell penetrating peptide comprises positively-charged amino acids at pH 7.0.

[1129] B8. The composition of embodiment B7, wherein the positively-charged amino acids comprise arginine (R) amino acids.

[1130] B9. The composition of embodiment B7 or B8, wherein the positively-charged amino acids are evenly distributed along the length of the peptide.

[1131] B10. The composition of any one of embodiments B1-B9, wherein the cell penetrating peptide comprises hydrophobic amino acids.

[1132] B11. The composition of embodiment B10, wherein the hydrophobic amino acids comprise leucine (L) amino acids, or alanine amino acids (A), or a combination of L amino acids and A amino acids.

[1133] B12. The composition of embodiment B10 or B11, wherein the cell penetrating peptide comprises a greater proportion of hydrophobic amino acids than hydrophilic amino acids. B13. The composition of any one of embodiments B10-B12, wherein the cell penetrating peptide comprises a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues at pH 7.0 of at least about 30:70 to about 40:60 or about 30:67 to about 40:60. B14. The composition of any one of embodiments B1-B13, wherein the cell penetrating peptide comprises one or more negatively-charged amino acids at pH 7.0.

[1134] B15. The composition of embodiment B14, wherein the negatively-charged amino acids comprise a glutamate (E) amino acid.

[1135] B16. The composition of embodiment B14 or B15, wherein the cell penetrating peptide comprises at least two but no more than three negatively-charged amino acids. ATTORNEY DOCKET: 05336.0007WO01

[1136] B17. The composition of any one of embodiments B7-B16 the ratio of positively-charged amino acids to negatively-charged amino acids is at least about 6:2 to about 9:2 or about 6:2 to about 8:2.

[1137] B18. The composition of embodiment B17, wherein the ratio of R amino acids to E amino acids is at least about 6:2 to about 9:2 or about 6:2 to about 8:2.

[1138] B19. The composition of any one of embodiments B15-B18, wherein the cell penetrating peptide comprises six or more R amino acids, twelve or more A amino acids, and six or more L amino acids.

[1139] B20. The composition of any one of embodiments B8-B19, wherein the cell penetrating peptide comprises two or more segments comprising RALA (SEQ ID NO: 1).

[1140] B21. The composition of embodiment B20, wherein the cell penetrating peptide comprises EARLARALARALAR (SEQ ID NO: 2); or LARALARALRA (SEQ ID NO: 3); or EARLARALARALAR and LARALARALRA.

[1141] B22-1. The composition of embodiment B21, wherein the cell penetrating peptide comprises X1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 4), wherein: X1is W or R; X2is selected from H or E; and X3is C or R, or an amino acid sequence at least about 80% or more identical to X1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 4).

[1142] B22-2. The composition of embodiment B21, wherein the cell penetrating peptide comprises X1-EARLARALARALARLARALARALRA-X3-EA (SEQ ID NO: 7), where: X1is W or R; and X3is C or R. or an amino acid sequence at least 80% or more identical to X1-EARLARALARALARLARALARALRA-X3-EA (SEQ ID NO: 7).

[1143] B23. The composition of any one of embodiments B1-B22, wherein the cell penetrating peptide comprises WEARLARALARALARHLARALARALRACEA (SEQ ID NO: 5).

[1144] B24. The composition of any one of embodiments B1-B22, wherein the cell penetrating peptide comprises:

[1145] WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6);

[1146] WEARLARALARALARELARALARALRACEA (SEQ ID NO: 8);

[1147] WEAHLAHALARALARHLARALARALRACEA (SEQ ID NO: 17);

[1148] WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 18); ATTORNEY DOCKET: 05336.0007WO01

[1149] WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO: 19);

[1150] WEARLARALARALARHLAHALAHALHACEA (SEQ ID NO: 20);

[1151] REARLARALARALARLARALARALRACEA (SEQ ID NO: 9);

[1152] REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); or REARLARALARALARELARALARALRAREA (SEQ ID NO: 11).

[1153] B24.1. The composition of any one of embodiments B1-B8, B10, B11 and B14-B16, wherein the cell penetrating peptide comprises:

[1154] LLIILRRRIRKQAHAHSK (SEQ ID NO: 13), or

[1155] LLIFLRRRLRKQARAHGK (SEQ ID NO: 14).

[1156] B25. The composition of any one of embodiments B1-B24.1, wherein the cell penetrating peptide comprises D-amino acids, L-amino acids, or a combination of D-amino acids and L-amino acids.

[1157] B25.1. The composition of any one of embodiments B1 -B25, wherein the cell penetrating peptide comprises a peptidomimetic portion or is a peptidomimetic.

[1158] B26. The composition of any one of embodiments B1-B25.1, wherein the cell penetrating peptide is in an amount sufficient to selectively reduce the cell population in vitro.

[1159] B27. The composition of any one of embodiments B1-B26, wherein the cell penetrating peptide is in an amount sufficient to selectively reduce the cell population in a tissue or organ.

[1160] B28. The composition of any one of embodiments B1-B27, wherein the cell penetrating peptide is in an amount sufficient to selectively reduce the cell population in cells, tissue and / or organ of subject.

[1161] B29. The composition of any one of embodiments B1-B22, wherein the cell penetrating peptide has at least 80% sequence identify to a sequence selected from the group consisting of:

[1162] WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6);

[1163] WEARLARALARALARELARALARALRACEA (SEQ ID NO 8);

[1164] WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO 17);

[1165] WEARLARALARALARHLARALAHALHACEA (SEQ ID NO 18);

[1166] WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO 19);

[1167] WEARLARALARALARHLAHALAHALHACEA (SEQ ID NO 20);

[1168] in ATTORNEY DOCKET: 05336.0007WO01

[1169] REARLARALARALARLARALARALRACEA (SEQ ID NO: 9);

[1170] REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); and REARLARALARALARELARALARALRAREA (SEQ ID NO: 11).

[1171] B30. The composition of any one of embodiments B1-B22, wherein the cell penetrating peptide has at least 85% sequence identify to a sequence selected from the group consisting of:

[1172] WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6);

[1173] WEARLARALARALARELARALARALRACEA (SEQ ID NO: 8);

[1174] WEAHLAHALARALARHLARALARALRACEA (SEQ ID NO: 17);

[1175] WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 18);

[1176] WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO: 19);

[1177] WEARLARALARALARHLAHALAHALHACEA (SEQ ID NO: 20);

[1178] REARLARALARALARLARALARALRACEA (SEQ ID NO: 9);

[1179] REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); and REARLARALARALARELARALARALRAREA (SEQ ID NO: 11).

[1180] B31. The composition of any one of embodiments B1-B22, wherein the cell penetrating peptide has at least 90% sequence identify to a sequence selected from the group consisting of:

[1181] WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6);

[1182] WEARLARALARALARELARALARALRACEA (SEQ ID NO: 8);

[1183] WEAHLAHALARALARHLARALARALRACEA (SEQ ID NO: 17);

[1184] WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 18);

[1185] WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO: 19);

[1186] WEARLARALARALARHLAHALAHALHACEA (SEQ ID NO: 20);

[1187] REARLARALARALARLARALARALRACEA (SEQ ID NO: 9);

[1188] REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); and REARLARALARALARELARALARALRAREA (SEQ ID NO: 11).

[1189] B32. The composition of any one of embodiments B1-B22, wherein the cell penetrating peptide has at least 95% sequence identify to a sequence selected from the group consisting of:

[1190] WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6);

[1191] WEARLARALARALARELARALARALRACEA (SEQ ID NO: 8); ATTORNEY DOCKET: 05336.0007WO01

[1192] WEAHLAHALARALARHLARALARALRACEA (SEQ ID NO: 17);

[1193] WEARLARALARALARHLARALAHALHACEA (SEQ ID NO: 18);

[1194] WEAHLAHALAHALARHLARALARALRACEA (SEQ ID NO: 19);

[1195] WEARLARALARALARHLAHALAHALHACEA (SEQ ID NO: 20);

[1196] REARLARALARALARLARALARALRACEA (SEQ ID NO: 9);

[1197] REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); and REARLARALARALARELARALARALRAREA (SEQ ID NO: 11).

[1198] B33. The composition according to the embodiment of B1, wherein the cell penetrating peptide comprises SEQ ID NO: 607.

[1199] C1. The composition of any one of embodiments B1-B33, comprising no cargo nucleic acid.

[1200] C2. The composition of any one of embodiments B1-B33, comprising no nucleic acid. C3. The composition of any one of embodiments B1-B33, comprising no cargo agent that selectively reduces the cell population.

[1201] C4. The composition of any one of embodiments B1-B33, comprising no cargo agent. C5. The composition of any one of embodiments B1-B33, comprising no additive that selectively reduces the cell population.

[1202] C6. The composition of any one of embodiments B1-B33, wherein the composition comprises an active ingredient, and the active ingredient consists essentially of or consists of the cell penetrating peptide.

[1203] D1. A method for selectively reducing a senescent cell population, comprising administering a composition comprising an active ingredient comprising a cell penetrating peptide to cells in an amount sufficient to selectively reduce the senescent cell population. D2. A method for selectively reducing a senescent cell population, comprising administering a composition comprising an active ingredient comprising a cell penetrating peptide to a tissue, organ or subject in an amount sufficient to selectively reduce a senescent cell population.

[1204] D3. A method for treating a medical condition, comprising administering a composition comprising an active ingredient comprising a cell penetrating peptide to a tissue, organ or subject in an amount sufficient to selectively reduce a senescent cell population. ATTORNEY DOCKET: 05336.0007WO01

[1205] D4. The method of any one of embodiments D1-D3, wherein the cells, tissue, organ or subject contain a senescent cell population.

[1206] D5. The method of any one of embodiments D1-D4, wherein the senescent cell population is (i) a SA-beta-galactosidase-positive cell population; or (ii) a p16-positive cell population; or (iii) a urokinase plasminogen activator receptor (uPAR)-positivecell population; or (iv) a p-21 positive cell population; or (v) a combination of one or more of (i), (ii), (iii), and (iv).. D6. The method of any one of embodiments D1-D5, wherein the senescent cell population comprises skin cells.

[1207] D7. The method of embodiment D6, wherein the skin cells comprise epidermis cells, dermis cells, or epidermis cells and dermis cells.

[1208] D8. The method of any one of embodiments D1-D7, wherein the senescent cell population comprises systemic cells.

[1209] D9. The method of embodiment D8, wherein the systemic cells comprise kidney cells, liver cells, spleen cells, or a combination thereof.

[1210] D10. The method of any one of embodiments D1-D9, wherein the composition is of any one of embodiments A1 -A26 and B1 -B33.

[1211] D11. The method of any one of embodiments D3-D10, wherein the medical condition is actinic keratosis, Bowen’s disease, in situ carcinoma, atopic dermatitis, non-segmental vitiligo, psoriasis, ultraviolet (UV) damaged skin or aged skin.

[1212] D12. The method of embodiment D11, wherein the UV damaged skin is severely UV damaged skin.

[1213] D13. The method of embodiment D12, wherein the psoriasis is plaque psoriasis.

[1214] D14. The method of any one of embodiments D1 -D13, wherein the composition comprises about 1 mg / kg to about 10 mg / kg of the cell penetrating peptide.

[1215] D15. The method of embodiment D14, wherein the composition comprises about 5 mg / kg of the cell penetrating peptide.

[1216] D16. The method of any one of embodiments D1 -D1, wherein the composition is administered about one (1X) to about five times (5X) per week. ATTORNEY DOCKET: 05336.0007WO01

[1217] D17. The method of embodiment D16, wherein the composition is administered about three times per week.

[1218] D18. The method of any one of embodiments D1 -D17, wherein the composition is administered intraperitoneally, subcutaneously, intravenously or topically.

[1219] E1. A method for assessing a senescent cell population of an animal, comprising: (i) administering a treatment to an animal at an initiation age, and (ii) after a period of time has elapsed from (i), assessing a senescent cell population of the animal.

[1220] E2. The method of embodiment E1, wherein the animal is a rodent.

[1221] E3. The method of embodiment E2, wherein the rodent is a mouse.

[1222] E4. The method of any one of embodiments E1-E3, wherein the initiation age is about 50 weeks to about 90 weeks, or optionally about 60 weeks to about 80 weeks, optionally about 60 weeks to about 75 weeks, optionally about 55 weeks to about 65 weeks, optionally about 58 weeks to about 62 weeks, optionally about 60 weeks to about 70 weeks, optionally about 65 weeks to about 75 weeks, optionally about 70 weeks to about 80 weeks, optionally about 73 weeks to about in weeks, or optionally about 74 weeks to about 76 weeks.

[1223] E5. The method of any one of embodiments E1-E4, wherein the animal has naturally aged until the initiation age.

[1224] E6. The method of embodiment, E5, wherein the animal has not been administered a treatment prior to the initiation age that accelerates aging or increases a senescent cell population.

[1225] E7. The method of any one of embodiments E1-E6, wherein the animal naturally ages during and after the initiation age.

[1226] E8. The method of embodiment E7, wherein the animal is not administered a treatment during or after the initiation age that accelerates aging or increases a senescent cell population.

[1227] E9. The method of any one of embodiments E5-E8, wherein the animal is not administered radiation prior to, during and / or after the initiation age. ATTORNEY DOCKET: 05336.0007WO01

[1228] E10. The method of embodiment E9, wherein the radiation is gamma radiation or ultraviolet light.

[1229] E11. The method of any one of embodiments E1 -E10, wherein the treatment comprises administering a composition containing an active ingredient to the animal.

[1230] E12. The method of embodiment E11, wherein the active ingredient comprises a cell penetrating peptide.

[1231] E13. The method of embodiment E12, wherein the composition is of any one of embodiments A1-A26, B1-B33, and C1-C6.

[1232] E14. The method of any one of embodiments E11-E13, wherein the composition is administered by injection.

[1233] E15. The method of any one of embodiments E11-E14, wherein the composition is administered one or more times after (i) in a treatment time period.

[1234] E16. The method of embodiment E15, wherein the treatment time period is about 1 day to about 15 weeks, or optionally about 1 week to about 5 weeks, or optionally about 1 week to about 4 weeks.

[1235] E17. The method of any one of embodiments E1 -E16, wherein a naturally occurring senescent cell population of the animal is assessed before, during and / or after a treatment is administered.

[1236] E18. The method of embodiment E17, wherein no exogenous senescent cells are introduced to the animal before, during and / or after the first treatment is initiated.

[1237] E19. The method of any one of embodiments E1 -E18, wherein the senescent cell population is assessed one or more times after (i) in an assessment time period.

[1238] E20. The method of embodiment E19, wherein the assessment time period each independently is about 1 day to about 15 weeks, or optionally about 1 week to about 5 weeks, or optionally about 1 week to about 4 weeks.

[1239] E21. The method of any one of embodiments E1 -E20, wherein the senescent cell population is assessed for a sample from the animal. ATTORNEY DOCKET: 05336.0007WO01

[1240] E22. The method of embodiment E21, wherein the sample contains cells from the animal, optionally contains a tissue from the animal or optionally contains an organ from the animal.

[1241] E23. The method of any one of embodiments E1-E22, wherein the senescent cell population is assessed in vitro or ex vivo.

[1242] E24. The method of any one of embodiments E1-E23, wherein the senescent cell population is assessed in vivo.

[1243] E25. The method of any one of embodiments E1-E24, wherein the senescent cell population is assessed before and / or after the animal has been sacrificed.

[1244] E26. The method of any one of embodiments E1-E25, wherein the senescent cell population is assessed by detecting presence, absence and / or amount of (i) SA-beta-galactosidase; or (ii) p16 (p16INK4a for example); or (iii) urokinase plasminogen activator receptor (uPAR); or (iv) a p-21 positive cell population; or (v) a combination of one or more of (i), (ii), (iii), and (iv).

[1245] E27. The method of any one of embodiments E1-E26, wherein a senescent cell population is in or from one or more of the following tissues of the animal: brain, kidney, lung, liver and spleen.

[1246] E28. The method of embodiment E27, wherein the senescent cell population is in or from brain of an animal, and optionally is in or from one of the following tissues of an animal: hippocampus, cerebral cortex, substantia nigra and pallidum.

[1247] E29. The method of embodiment E28, wherein the senescent cell population is in or from the substantia nigra, and optionally is in or from a compact part of the substantia nigra, and / or is in or from the pallidum, and optionally is in or from a dorsal region of the pallidum region.

[1248] E30. The method of any one of embodiments E1-E29, wherein the initiation age of the animal is about 55 weeks to about 65 weeks, or optionally about 58 weeks to about 62 weeks, or optionally about 60 weeks, and a senescent cell population in or from one of the following tissues is assessed: kidney, lung, liver or spleen.

[1249] E31. The method of any one of embodiments E1 -E30, wherein the initiation age of the animal is about 55 weeks to about 65 weeks, or optionally about 58 weeks to about 62 ATTORNEY DOCKET: 05336.0007WO01

[1250] weeks, or optionally about 60 weeks, and a senescent cell population in or from cerebral cortex tissue of the animal is assessed.

[1251] E32. The method of any one of embodiments E1-E29, wherein the initiation age of the animal is about 70 weeks to about 80 weeks, or optionally about 73 weeks to about in weeks, or optionally about 75 weeks, and a senescent cell population in or from hippocampus tissue of the animal is assessed.

[1252] F1. A method for selectively reducing a senescent cell population in a patient, comprising administering to the patient a composition comprising an active ingredient in an amount sufficient to selectively reduce the senescent cell population, wherein the active ingredient comprises a cell penetrating peptide.

[1253] F2. The method of the embodiment of F1, wherein the active ingredient consists essentially of the cell penetrating peptide.

[1254] F3. The method of any one of embodiments F1-F2, wherein the cell penetrating peptide is a cationic cell penetrating peptide.

[1255] F4. The method of any one of embodiments F1-F3, wherein the cell penetrating peptide is an amphipathic cell penetrating peptide.

[1256] F5. The method of any one of embodiments F1-F4, wherein the cell penetrating peptide is a hydrophobic cell penetrating peptide.

[1257] F6. The method of any one of embodiments F1-F5, wherein the cell penetrating peptide is selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20.

[1258] F7. The method of any one of embodiments F1-F6, wherein the cell penetrating peptide has a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to at least one sequence selected from the group consisting: SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20,, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

[1259] F8. The method according to the embodiment of F1, wherein the cell penetrating peptide comprises SEQ ID NO: 607. ATTORNEY DOCKET: 05336.0007WO01

[1260] G1. A method for treating a condition in a patient, comprising administering to the patient a composition comprising an active ingredient in an amount sufficient to selectively reduce senescent cell population, wherein the active ingredient comprises a cell penetrating peptide.

[1261] G2. The method of the embodiment of G1, wherein the active ingredient consists essentially of the cell penetrating peptide.

[1262] G3. The method of any one of embodiments G1 -G2, wherein the cell penetrating peptide is a cationic cell penetrating peptide.

[1263] G4. The method of any one of embodiments G1 -G3, wherein the cell penetrating peptide is an amphipathic cell penetrating peptide.

[1264] G5. The method of any one of embodiments G1-G4, wherein the cell penetrating peptide is a hydrophobic cell penetrating peptide.

[1265] G6. The method of any one of embodiments G1 -G5, wherein the cell penetrating peptide is selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

[1266] G7. The method of any one of embodiments G1 -G6, wherein the cell penetrating peptide has a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to at least one sequence selected from the group consisting: SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20,, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

[1267] G8. The method of any one of embodiments G1 -G7, wherein the condition is an age-related disease.

[1268] G9. The method of any one of embodiments G1 -G8, wherein the condition is selected from the group consisting of: dementia, Alzheimer’s, sarcopenia, frailty, diabetes, prediabetes, cataracts, infertility, lordokyphosis, geographic atrophy of the macula, age-associated macular degeneration, wet age-associated macular degeneration, dry age- ATTORNEY DOCKET: 05336.0007WO01

[1269] associated macular degeneration, uveitis, fat loss, age-related cardiomyocyte hypertrophy, age-related loss of cardiac stress tolerance, heart failure, cardiac arrythmias, glomerulosclerosis, renal RAAS hyperactivity, kidney failure, lung disease, idiopathic pulmonary fibrosis, skeletal muscle decline, osteoporosis, bone fracture, arterial wall stiffening, impaired wound healing, dermal thinning, subdermal adipose layer thinning, physical fitness, exercise ability, metabolic dysfunction, metabolic syndrome, age-related brain inflammation, cognitive impairment, and post-concussive syndrome.

[1270] G10. The method of any one of embodiments G1 -G8, wherein the condition is diabetes and / or pre-diabetes.

[1271] G11. The method of any one of embodiments G10, wherein the cell penetrating peptide has a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 18.

[1272] G12. The method of any one of embodiments G1 -G8, wherein the condition is sarcopenia and / or frailty.

[1273] G13. The method of the embodiment G12, wherein the cell penetrating peptide has a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 18.

[1274] G14. The method of any one of embodiments G1 -8, wherein the condition is post-concussive syndrome.

[1275] G15. The method of embodiment G14, wherein the cell penetrating peptide has a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 13.

[1276] G16. The method according to the embodiment of G1, wherein the cell penetrating peptide comprises SEQ ID NO: 607.

[1277] H1. A method of treating an animal, the method comprising:

[1278] administering to the animal the composition of any one of embodiments A1 -A26, B1 -33, and C1-6.

[1279] H2. The method of any one of embodiments H1, wherein the animal is a human. ATTORNEY DOCKET: 05336.0007WO01

[1280] H3. The method of any one of embodiments H1-H2, the method further comprising: obtaining a first biopsy sample from the animal prior to the administering;

[1281] obtaining a second biopsy sample from the animal subsequent to the administering; quantifying a first senescent cell population of the first biopsy sample; quantifying a second senescent cell population of the second biopsy sample;

[1282] comparing the second senescent cell population to the first senescent cell population. H4. The method of the embodiment H3, wherein the first biopsy sample and the second biopsy sample are a first skin sample and a second skin sample, respectively.

[1283] H5. The method of the embodiment H4, wherein the second biopsy sample is obtained at least seven days subsequent to the administering.

[1284] H6. The method of the embodiment H4, wherein the second biopsy sample is obtained at least fourteen days subsequent to the administering.

[1285] H7. The method of the embodiment H4, wherein first skin sample is obtained from a sun- exposed area of skin and the second skin sample is obtained from a reduced-sun-exposed area of skin.

[1286] H8. The method of any one of embodiments H1-7, wherein the administering occurs by injection.

[1287] H9. The method of any one of embodiments H1-H7, wherein the administering occurs by intramuscular injection (IM), intraperitoneal (IP) injection or intravenous (IV) injection. H10. The method of any one of embodiments H1 -H7, wherein the administering occurs by topical administration.

[1288] H11. The method of any one of embodiments H1 -H7, wherein the administering occurs both (1) by injection and (2) by topical administration.

[1289] 11. A method comprising:

[1290] obtaining a first biopsy sample from an animal, and

[1291] determining a first biologic age score of the animal based on the first biopsy sample. ATTORNEY DOCKET: 05336.0007WO01

[1292] 12. The method of embodiment 11, wherein determining the first biologic age score of the animal based on the first biopsy sample includes determining a percentage of senescent cells in the first biopsy sample.

[1293] 13. The method of embodiment I2, wherein determining the first biologic age score of the animal based on the first biopsy sample further includes comparing the percentage of senescent cells in the first biopsy sample to a reference percentage.

[1294] 14. The method of any one of embodiments 11-13, further comprising:

[1295] obtaining a first non-biopsy sample from the animal, wherein the first non-biopsy sample includes physical data, blood test data, SASP data, a scan, a PET scan, and / or an optical scan.

[1296] 15. The method of embodiment 14, wherein determining the first biologic age score of the animal is based on the first biopsy sample and the first non-biopsy sample.

[1297] 16. The method of any one of embodiments 11-15, further comprising administering a first dose to the animal, wherein the first dose is selected from the group consisting of: the composition of any one of embodiments A1 -A26, B1 -33, C1 -6; a cell penetrating peptide; SEQ ID NO: 5; SEQ ID NO: 13; SEQ ID NO: 14; SEQ ID NO: 17; SEQ ID NO: 18; SEQ ID NO: 19; SEQ ID NO: 20, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

[1298] 17. The method of embodiment I6, wherein the first dose includes a peptide having a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to at least one sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

[1299] 18. The method of any one of embodiments I6-I7, the method further comprising: obtaining the first biopsy sample from the animal prior to administering the first dose; and obtaining a second biopsy sample from the animal subsequent to administering the first does.

[1300] 19. The method of embodiment I8, further comprising: ATTORNEY DOCKET: 05336.0007WO01

[1301] determining a second biologic age score of the animal based on the second biopsy sample.

[1302] 110. The method of embodiment I9, further comprising:

[1303] comparing the second biologic age score of the animal to the first biologic age score to determine an efficacy of administering the first dose.

[1304] 111. The method of embodiment I8, wherein the first biopsy sample and the second biopsy sample are a first skin sample and a second skin sample, respectively.

[1305] 112. The method of embodiment I8, wherein the second biopsy sample is obtained at least seven days subsequent to administering the first dose.

[1306] 113. The method of embodiment I8, wherein the second biopsy sample is obtained at least fourteen days subsequent to administering the first dose.

[1307] 114. The method of embodiment I8, wherein first skin sample is obtained from a sun-exposed area of skin and the second skin sample is obtained from a reduced-sun-exposed area of skin.

[1308] 115. The method of any one of embodiments 16-114, wherein administering the first dose occurs by injection.

[1309] 116. The method of any one of embodiments 16-114, wherein administering the first dose occurs by intramuscular injection (IM), intraperitoneal (IP) injection or intravenous (IV) injection.

[1310] 117. The method of any one of embodiments 16-114, wherein administering the first dose occurs by topical administration.

[1311] 118. The method of any one of embodiments 16-114, wherein administering the first dose occurs both (1) by injection and (2) by topical administration.

[1312] 119. The method of any one of embodiments 16-118, wherein administering the first dose is dependent on the first biologic age score.

[1313] 120. The method of any one of embodiments 16-118, further comprising administering a second dose to the animal.

[1314] 121. The method of any one of embodiments 16-118, wherein administering the second dose is dependent on the second biologic age score. ATTORNEY DOCKET: 05336.0007WO01

[1315] I22. The method of any one of embodiments 11-121, wherein the animal is a human. J1. A method preventing and / or treating a condition in a patient, comprising: identifying a mild traumatic brain injury in the patient,

[1316] administering a senolytic cell penetrating peptide to the patient.

[1317] J2. The method of embodiment J1, wherein the senolytic cell penetrating peptide is capable of crossing the blood brain barrier.

[1318] J3. The method of any one of embodiments J1 -J2, wherein the senolytic cell penetrating peptide comprises SEQ ID NO: 13.

[1319] J4. The method of any one of embodiments J1 -J2, wherein the senolytic cell penetrating peptide has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 13.

[1320] J5. The method of any one of embodiments J1 -J4, wherein the condition is selected from the group comprising: post-concussive syndrome, chronic traumatic encephalopathy, and a neurodegenerative disease.

[1321] K1. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to selectively eliminate senescent cells.

[1322] L1. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to reduce inflammation and improve tissue and organ health by the elimination of senescent cells.

[1323] M1. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to reduce the effects of aging and improve the overall health and functioning of the patient by the elimination of senescent cells.

[1324] N1. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to reduce the effects of aging and improve the overall health and functioning of the patient by the elimination of senescent cells, wherein administering comprises topical administration and / or administration by microneedle.

[1325] 01. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to trigger apoptosis through disruption of a mitochondrial membrane. ATTORNEY DOCKET: 05336.0007WO01

[1326] 02. The method of 01, wherein the cell penetrating peptide has a net positive charge, a logP measure lower than 0.1, one or more positively charged amino acids, an Arg (R) or Lys(K) residue, or combinations thereof.

[1327] P1. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to selectively eliminate cancer cells.

[1328] P2. The method of P1, wherein the cancer cells are human leukemia cells.

[1329] Q. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to reduce late radiation-induced toxicity.

[1330] R1. A method comprising: administering a cell penetrating peptide to a patient in an amount sufficient to reduce therapy-induced senescence and / or to eliminate therapy induced senescent cells.

[1331] R2. The method of R1, wherein the patient is receiving radiotherapy and / or chemotherapy. The entirety of each patent, patent application, publication and document referenced herein is incorporated by reference. Citation of patents, patent applications, publications and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. Their citation is not an indication of a search for relevant disclosures. All statements regarding the date(s) or contents of the documents are based on available information and is not an admission as to their accuracy or correctness.

[1332] The technology has been described with reference to specific examples and implementations. The terms and expressions that have been utilized herein to describe the technology are descriptive and not necessarily limiting. Certain modifications made to the disclosed implementations can be considered within the scope of the technology. Certain aspects of the disclosed implementations suitably may be practiced in the presence or absence of certain elements not specifically disclosed herein.

[1333] Each of the terms “comprising,” “consisting essentially of,” and “consisting of” may be replaced with either of the other two terms. The term “a” or “an” can refer to one of or a plurality of the elements it modifies (e.g., “a reagent” can mean one or more reagents) unless it is contextually clear either one of the elements or more than one of the elements is described. The term “about” as used herein refers to a value within 10% of the ATTORNEY DOCKET: 05336.0007WO01

[1334] underlying parameter (i.e., plus or minus 10%; e.g., a weight of “about 100 grams” can include a weight between 90 grams and 110 grams). Use of the term “about” at the beginning of a listing of values modifies each of the values (e.g., “about 1, 2 and 3” refers to "about 1, about 2 and about 3"). When a listing of values is described, the listing includes all intermediate values and all fractional values thereof (e.g., the listing of values "80%, 85% or 90%" includes the intermediate value 86% and the fractional value 86.4%). When a listing of values is followed by the term "or more," the term "or more" applies to each of the values listed (e.g., the listing of "80%, 90%, 95%, or more" or "80%, 90%, 95% or more" or "80%, 90%, or 95% or more" refers to "80% or more, 90% or more, or 95% or more"). When a listing of values is described, the listing includes all ranges between any two of the values listed (e.g., the listing of "80%, 90% or 95%" includes ranges of "80% to 90%, " "80% to 95%" and "90% to 95%").

[1335] TABLE 1: Examples of CCPs

[1336] Ch

[1337] N- C- em Linear Peptide See SEQ

[1338] Category termi term / Cycli LogP Sequence ID NO:

[1339] nus inus Mo c

[1340] d

[1341] RRR Cationic n / a Free NA NA Linear -2.37 Acet

[1342] amid

[1343] RKC Arginine-rich n / a ylatio NA Linear

[1344] ation

[1345] n 1.64 Cationic

[1346] SEQ ID RALA and Linear

[1347] NO: 0001

[1348] amphipathic -0.53 Cationic

[1349] EARLARALARAL SEQ ID

[1350] and Linear

[1351] AR NO: 0002

[1352] amphipathic -3.38 Cationic

[1353] SEQ ID LARALARALRA and Linear

[1354] NO: 0003

[1355] amphipathic -1.32 XEARLARALARA Cationic

[1356] SEQ ID LARXLARALARA and Linear

[1357] NO: 0004

[1358] LRAXEA amphipathic

[1359] -5.97 WEARLARALAR Cationic

[1360] SEQ ID ALARHLARALAR and Free Free NA Linear

[1361] NO: 0005

[1362] ALRACEA amphipathic

[1363]

[1364] -3.99 ATTORNEY DOCKET: 05336.0007WO01

[1365] WEARLARALAR Cationic

[1366] SEQ ID ALARLARALARA and Linear NO: 0006

[1367] LRACEA amphipathic

[1368] -3.68 XEARLARALARA Cationic

[1369] SEQ ID LARLARALARAL and Linear NO: 0007

[1370] RAXEA amphipathic

[1371] -5.97 WEARLARALAR Cationic

[1372] SEQ ID ALARELARALAR and Linear NO: 0008

[1373] ALRACEA amphipathic

[1374] -4.68 REARLARALARA Cationic

[1375] SEQ ID LARLARALARAL and Linear NO: 0009

[1376] RACEA amphipathic

[1377] -5.93 REARLARALARA Cationic

[1378] SEQ ID LARLARALARAL and Linear NO: 0010

[1379] RAREA amphipathic

[1380] -7.55 REARLARALARA Cationic

[1381] SEQ ID LARELARALARA and Linear NO: 0011

[1382] LRAREA amphipathic

[1383] -8.55 Cationic

[1384] LLIILRRRIRKQA SEQ ID

[1385] and Linear HAHSK NO: 0013

[1386] amphipathic -0.27 Cationic

[1387] LLIFLRRRLRKQ SEQ ID

[1388] and Linear ARAHGK NO: 0014

[1389] amphipathic 0.04 Cationic

[1390] CRRLRHLRHHY SEQ ID

[1391] and Free Free NA Linear RRRWHRFRC NO: 0015

[1392] amphipathic -1.92 Cationic Acet Ami

[1393] RQIKIWFQNRRM SEQ ID

[1394] and ylatio datio NA Linear KWKK NO: 0016

[1395] amphipathic n n 4.72 Cationic Ami

[1396] RQIKIWFQNRRM SEQ ID

[1397] and Free datio NA Linear KWKK NO: 0016

[1398] amphipathic n 3.29 Cationic

[1399] RQIKIWFQNRRM SEQ ID

[1400] and Free Free NA Linear KWKK NO: 0016

[1401] amphipathic 2.64 Cationic Ami

[1402] RQIKIWFQNRRM SEQ ID

[1403] and NA datio NA Linear KWKK NO: 0016

[1404]

[1405] amphipathic n 3.29 ATTORNEY DOCKET: 05336.0007WO01

[1406] Cationic

[1407] RQIKIWFQNRRM SEQ ID

[1408] and NA NA NA Linear KWKK NO: 0016

[1409] amphipathic 2.64 WEAHLAHALAR Cationic

[1410] SEQ ID ALARHLARALAR and Linear NO: 0017

[1411] ALRACEA amphipathic

[1412] -3.03 WEARLARALAR Cationic

[1413] SEQ ID ALARHLARALAH and Linear NO: 0018

[1414] ALHACEA amphipathic

[1415] -3.03 WEAHLAHALAH Cationic

[1416] SEQ ID ALARHLARALAR and Linear NO: 0019

[1417] ALRACEA amphipathic

[1418] -2.55 WEARLARALAR Cationic

[1419] SEQ ID ALARHLAHALAH and Linear NO: 0020

[1420] ALHACEA amphipathic

[1421] -2.55 Acet Ami

[1422] SEQ ID RKKRRQRRR Cationic ylatio datio NA Linear NO: 0021

[1423] n n -2.66 SEQ ID RKKRRQRRR Cationic Free Free NA Linear NO: 0021 -4.74

[1424] 12- am

[1425] ino

[1426] do

[1427] de

[1428] ca

[1429] noi

[1430] c

[1431] aci

[1432] d

[1433] RGD-ADDA- Amphipathi SEQ ID

[1434] NA Free Linear RRRRRRRR c NO: 0022 (A

[1435] DD

[1436] A)

[1437] link

[1438] ed

[1439] RG

[1440] D

[1441] mo

[1442] tit

[1443] to

[1444]

[1445] P1 -4.11 ATTORNEY DOCKET: 05336.0007WO01

[1446] RG

[1447] D

[1448] mo

[1449] tif

[1450] is

[1451] link

[1452] ed

[1453] by

[1454] P2

[1455] thr

[1456] OU RGD-Ahx- Amphipathi SEQ ID

[1457] NA Free Linear RRRRRRRR c NO: 0022 gh

[1458] 6- am

[1459] ino

[1460] he

[1461] xa

[1462] noi

[1463] c

[1464] aci

[1465] d

[1466] (Ah

[1467] x). -10.3 Acet Ami

[1468] SEQ ID RRRRRRRR Cationic ylatio datio NA Linear NO: 0022

[1469] n n -4.24 Ami

[1470] SEQ ID RRRRRRRR Cationic Free datio NA Linear NO: 0022

[1471] n -5.67 SEQ ID RRRRRRRR Cationic Free Free NA Linear NO: 0022 -6.32

[1472] Stear Ami

[1473] SEQ ID RRRRRRRR Cationic ylatio datio NA Linear NO: 0022

[1474] n n 2.83 Cationic

[1475] RKKRRRESRKK SEQ ID

[1476] and Linear RRRES NO: 0023

[1477] amphipathic -8.54 Cationic

[1478] GRPRESGKKRK SEQ ID

[1479] and Linear RKRLKP NO: 0024

[1480] amphipathic -3.89 GRRRRRRRRRP SEQ ID

[1481] Cationic Free Free NA Linear

[1482] PQ NO: 0025 -7.37

[1483] Cationic

[1484] RVRVFVVHIPRL SEQ ID

[1485] and Linear

[1486] T NO: 0026

[1487]

[1488] amphipathic 1.15 ATTORNEY DOCKET: 05336.0007WO01

[1489] Cyst GALFLGFLGAAG Cationic Acet eami

[1490] SEQ ID STMGAWSQPKK and ylatio de NA Linear NO: 0027

[1491] KRKV amphipathic n grou

[1492] P 5.1 Cyst GALFLGFLGAAG Cationic Acet eami

[1493] SEQ ID STMGAWSQPKK and ylatio de NA Linear NO: 0027

[1494] KRKV amphipathic n grou

[1495] P 5.1 Acet Ami

[1496] KLALKLALKALK Amphipathi SEQ ID

[1497] ylatio datio NA Linear AALKLA c NO: 0028

[1498] n n 6.91 Ami

[1499] KLALKLALKALK Amphipathi SEQ ID

[1500] Free datio NA Linear AALKLA c NO: 0028

[1501] n 5.48 KLALKLALKALK Amphipathi SEQ ID

[1502] Free NA NA Linear AALKLA c NO: 0028 4.83 GWTLNSAGYLL Cationic Ami

[1503] SEQ ID GKINLKALAALA and Free datio NA Linear NO: 0029

[1504] KKIL amphipathic n 5.66 GWTLNSAGYLL Cationic

[1505] SEQ ID GKINLKALAALA and Free Free NA Linear NO: 0029

[1506] KKIL amphipathic 5.01 GWTLNSAGYLL Cationic

[1507] SEQ ID GKINLKALAALA and Linear NO: 0029

[1508] KKIL amphipathic 5.01

[1509] Cationic

[1510] SEQ ID VSALK and Linear NO: 0030

[1511] amphipathic 0.57 Cationic

[1512] CSIPPEVKFNPF SEQ ID

[1513] and Linear VYLI NO: 0031

[1514] amphipathic 4.73 GIGAVLKVLTTG Cationic

[1515] SEQ ID LPALISWIKRKR and Linear NO: 0032

[1516] QQ amphipathic 3.63

[1517] Cationic

[1518] HGLASTLTRWA SEQ ID

[1519] and Linear HYNALIRAF NO: 0033

[1520] amphipathic 0.82 Cationic Stear Ami AGYLLGKLLOOL SEQ ID

[1521] and ylatio datio NA Linear AAAALOOLL NO: 0034

[1522] amphipathic n n 14.48 Cationic

[1523] AYRIKPTFRRLK SEQ ID

[1524] and Free Free NA Linear WKYKGKFW NO: 0035

[1525]

[1526] amphipathic 5.72 ATTORNEY DOCKET: 05336.0007WO01

[1527] Cationic Ami CRQIKIWFQNRR SEQ ID

[1528] and Free datio NA Linear MKWKK NO: 0036

[1529] amphipathic n 4.12 Cationic Acet Ami CRQIKIWFQNRR SEQ ID

[1530] and ylatio datio NA Linear MKWKK NO: 0036

[1531] amphipathic n n 5.55 Cationic Ami

[1532] GLRKRLRKFRN SEQ ID

[1533] and Free datio NA Linear KIKEK NO: 0037

[1534] amphipathic n -0.4 Cationic Ami GRKKRRQRRRP SEQ ID

[1535] and Free datio NA Linear PQC NO: 0038

[1536] amphipathic n -3.52 Cationic

[1537] GRKKRRQRRRP SEQ ID

[1538] and Free Free NA Linear PQC NO: 0038

[1539] amphipathic -4.17 Cationic Ami GRKKRRQRRRP SEQ ID

[1540] and NA datio NA Linear PQC NO: 0038

[1541] amphipathic n -3.52 Cationic Cys

[1542] GRKKRRQRRRP SEQ ID

[1543] and additi Free NA Linear PQC NO: 0038

[1544] amphipathic on -4.17 Cationic

[1545] HARIKPTFRRLK SEQ ID

[1546] and Free Free NA Linear WKYKGKFW NO: 0039

[1547] amphipathic 4.86 Cationic

[1548] HYRIKPTARRLK SEQ ID

[1549] and Free Free NA Linear WKYKGKFW NO: 0040

[1550] amphipathic 4.25 Cationic

[1551] HYRIKPTFRRLA SEQ ID

[1552] and Free Free NA Linear WKYKGKFW NO: 0041

[1553] amphipathic 5.24 Cationic

[1554] HYRIKPTFRRLK SEQ ID

[1555] and Free Free NA Linear WKYKGKFA NO: 0042

[1556] amphipathic 3.95 Cationic Ami

[1557] KKWKMRRNQF SEQ ID

[1558] and Free datio NA Linear WIKIQR NO: 0043

[1559] amphipathic n 3.29 Cationic Acet

[1560] KKWKMRRNQF SEQ ID

[1561] and ylatio Free NA Linear WIKIQR NO: 0043

[1562] amphipathic n 4.07 Cationic

[1563] KKWKMRRNQF SEQ ID

[1564] and Free Free NA Linear WIKIQR NO: 0043

[1565] amphipathic 2.64 Cationic Ami

[1566] SEQ ID

[1567] lliilrrrirkqahahsk and Free datio NA Linear NO: 0044

[1568] amphipathic n 0.38 Cationic Ami

[1569] LLIILRRRIRKQa SEQ ID

[1570] and Free datio NA Linear HAHSK NO: 0045

[1571]

[1572] amphipathic n 0.38 ATTORNEY DOCKET: 05336.0007WO01

[1573] Cationic Ami

[1574] LLIILRRRIRKQA SEQ ID

[1575] and Free datio NA Linear HaHSK NO: 0046

[1576] amphipathic n 0.38 Cationic

[1577] RKKRRQRRRGG Ami

[1578] and SEQ ID

[1579] GKLLKLLLKLLLK Free datio NA Linear Amphipathi NO: 0047

[1580] LLK n

[1581] c 4.1 Cationic Ami

[1582] SEQ ID

[1583] rqikiwfqnrrmkwkk and Free datio NA Linear NO: 0048

[1584] amphipathic n 3.29 Cationic

[1585] SEQ ID

[1586] rqikiwfqnrrmkwkk and Free Free NA Linear NO: 0048

[1587] amphipathic 2.64 Cationic

[1588] RQIKIWFQNRRM SEQ ID

[1589] and Free Free NA Linear KWKKK NO: 0049

[1590] amphipathic 2.81 Cationic Ami

[1591] RQIRIWFQNRR SEQ ID

[1592] and Free datio NA Linear MRWRR NO: 0050

[1593] amphipathic n -0.55 Cationic

[1594] RQIRIWFQNRR SEQ ID

[1595] and NA NA NA Linear MRWRR NO: 0050

[1596] amphipathic -1.2 Cationic Cycli

[1597] SEQ ID

[1598] [RRRRWWWW] and Free zatio NA Cyclic NO: 0051

[1599] amphipathic n 2.68 WEAKLAKALAKA Cationic

[1600] SEQ ID LAKHLAKALAKA and Free Free NA Linear NO: 0052

[1601] LKACEA amphipathic

[1602] 2.73 Cationic Ami

[1603] SEQ ID YGRKKRRQRRR and Free datio NA Linear NO: 0053

[1604] amphipathic n -3.76 Cationic

[1605] SEQ ID YGRKKRRQRRR and Free Free NA Linear NO: 0053

[1606] amphipathic -4.41 ac

[1607] P,

[1608] Ep

[1609] silo

[1610] n- Cationic

[1611] YGRKKRRQRRR SEQ ID am

[1612] and Free Free Linear -acp-OH NO: 0053 ino

[1613] amphipathic

[1614] ca

[1615] pro

[1616] ic

[1617] aci

[1618]

[1619] d -7.42 ATTORNEY DOCKET: 05336.0007WO01

[1620] ac

[1621] P,

[1622] Ep

[1623] silo

[1624] SEQ ID

[1625] n- NO: 0053 Ami YGRKKRRQRRR am

[1626] Cationic and SEQ Free datio Linear -acp-DYQQD ino

[1627] ID NO: n

[1628] ca

[1629] 0509

[1630] pro

[1631] ic

[1632] aci

[1633] d -7.15 ac

[1634] P,

[1635] Ep

[1636] silo

[1637] SEQ ID

[1638] n- NO: 0053 Ami YGRKKRRQRRR am

[1639] Cationic and SEQ Free datio Linear -acp-ENAEYLR ino

[1640] ID NO: n

[1641] ca

[1642] 0510

[1643] pro

[1644] ic

[1645] aci

[1646] d -9.15 ac

[1647] P,

[1648] Ep

[1649] silo

[1650] SEQ ID

[1651] n- NO: 0053 Ami YGRKKRRQRRR am

[1652] Cationic and SEQ Free datio Linear -acp-NYQQN ino

[1653] ID NO: n

[1654] ca

[1655] 0511

[1656] pro

[1657] ic

[1658] aci

[1659] d -8.55 ac

[1660] P,

[1661] Ep

[1662] silo

[1663] SEQ ID

[1664] n- NO: 0053 Ami YGRKKRRQRRR am

[1665] Cationic and SEQ Free datio Linear -acp-QNAQYLR ino

[1666] ID NO: n

[1667] ca

[1668] 0512

[1669] pro

[1670] ic

[1671] aci

[1672]

[1673] d -7.83 ATTORNEY DOCKET: 05336.0007WO01

[1674] Cyst

[1675] Cationic

[1676] RQIKIWFQNRRM SEQ ID eine

[1677] and Free NA Linear KWKKC NO: 0054 addit

[1678] amphipathic

[1679] ion 3.47 Cationic

[1680] RQIKIWFQNRRM SEQ ID

[1681] and NA NA NA Linear KWKKC NO: 0054

[1682] amphipathic 3.47 Nbtg-Nbtg-Nbtg- Cationic Ami

[1683] SEQ ID

[1684] Nbtg-Nbtg-Nbtg- and Free datio NA Linear NO: 0055

[1685] Nbtg-Nbtg amphipathic n

[1686] 4 Nbtg-Nbtg-Nspe- Cationic Ami

[1687] Nbtg-Nbtg-Nspe- SEQ ID

[1688] and Free datio NA Linear Nbtg-Nbtg-Nspe- NO: 0056

[1689] amphipathic n

[1690] Nbtg-Nbtg-Nspe

[1691] 8.64 Nbtg-Nspe-Nspe- Cationic Ami

[1692] Nbtg-Nspe-Nspe- SEQ ID

[1693] and Free datio NA Linear Nbtg-Nspe-Nspe- NO: 0057

[1694] amphipathic n

[1695] Nbtg-Nspe-Nspe

[1696] 11.28 NLys-NLys-NLys- NLys-NLys-NLys- Cationic Ami

[1697] SEQ ID NLys-NLys-NLeu- and Free datio NA Linear NO: 0058

[1698] NLeu-NLeu- amphipathic n

[1699] NLeu-NLeu

[1700] 0 NLys-NLys-NLys- Cationic Ami

[1701] NLys-NLys-NLys- SEQ ID

[1702] and Free datio NA Linear NLys-NLys-Nspe- NO: 0059

[1703] amphipathic n

[1704] Nspe-Nspe-Nspe

[1705] 4.64 NLys-NLys-Nspe- Cationic Ami

[1706] NLys-NLys-Nspe- SEQ ID

[1707] and Free datio NA Linear NLys-NLys-Nspe- NO: 0060

[1708] amphipathic n

[1709] NLys-NLys-Nspe

[1710]

[1711] 4.64 ATTORNEY DOCKET: 05336.0007WO01

[1712] NLys-Npm-Npm- Cationic Ami

[1713] NLys-Npm-Npm- SEQ ID

[1714] and Free datio NA Linear NLys-Npm-Npm- NO: 0061

[1715] amphipathic n

[1716] NLys-Npm-Npm

[1717] 2.4 NLys-Nspe-Nspe- Cationic Ami

[1718] SEQ ID NLys-Nspe-Nspe- and Free datio NA Linear NO: 0062

[1719] NLys-Nspe-Nspe amphipathic n

[1720] 6.96 NLys-Nspe-Nspe- Cationic Ami

[1721] NLys-Nspe-Nspe- SEQ ID

[1722] and Free datio NA Linear NLys-Nspe-Nspe- NO: 0063

[1723] amphipathic n

[1724] NLys-Nspe-Nspe

[1725] 9.28 NLys-Nssb-Nssb- Cationic Ami

[1726] NLys-Nssb-Nssb- SEQ ID

[1727] and Free datio NA Linear NLys-Nssb-Nssb- NO: 0064

[1728] amphipathic n

[1729] NLys-Nssb-Nssb

[1730] 3.2 Acet

[1731] Ac-WELVVL- SEQ ID

[1732] Cationic ylatio Free NA Linear YGRKKRRQRRR NO: 0065

[1733] n 1.15 WELVVLYGRKK SEQ ID

[1734] Cationic Free Free NA Linear RRQRRR NO: 0065 -1.71

[1735] Ami

[1736] AGYLLGHINLHH SEQ ID

[1737] Cationic Free datio NA Linear LAHLHHIL NO: 0066

[1738] n 3.58 AGYLLGHINLHH SEQ ID

[1739] Cationic Free Free NA Linear LAHLHHILC NO: 0067

[1740] 3.76 Ami

[1741] AGYLLGKINLKK SEQ ID

[1742] Cationic Free datio NA Linear LAKLLLIL NO: 0068

[1743] n 7.72 B,

[1744] Bet

[1745] Ami

[1746] SEQ ID a- B-[KrrrrrrrrE] Cationic Free datio Cyclic NO: 0069 Ala

[1747] n

[1748] nin

[1749] e -9.2 Ah

[1750] Ami

[1751] Ahx- SEQ ID x,

[1752] Cationic Free datio Linear RRRRRRRRR NO: 0070 6- n

[1753]

[1754] am -9.16 ATTORNEY DOCKET: 05336.0007WO01

[1755] ino

[1756] he

[1757] xa

[1758] noi

[1759] c

[1760] aci

[1761] d

[1762] Acet Ami

[1763] SEQ ID RRRRRRRRR Cationic ylatio datio NA Linear NO: 0070

[1764] n n -5.03 Ami

[1765] SEQ ID RRRRRRRRR Cationic Free datio NA Linear NO: 0070

[1766] n -6.46 SEQ ID RRRRRRRRR Cationic Free NA NA Linear NO: 0070 -7.11 SEQ ID RRRRRRRRR Cationic Free Free NA Linear NO: 0070 -7.11 SEQ ID AKKRRQRRR Cationic Free Free NA Linear NO: 0071 -4.22 AKKRRQRRRAK SEQ ID

[1767] Cationic Free Free NA Linear KRRQRRR NO: 0072

[1768] -8.44 ALALALALALALA Ami

[1769] SEQ ID LALKIKKIKKIKKI Cationic Free datio NA Linear NO: 0073

[1770] KKLAKLAKKIK n

[1771] 11.66 Cyst

[1772] AYGRKKRRQRR SEQ ID eine

[1773] Cationic Free NA Linear

[1774] R NO: 0074 additi

[1775] on -4.68 AYGRKKRRQRR SEQ ID

[1776] Cationic Free Free NA Linear

[1777] R NO: 0074 -4.68

[1778] B,

[1779] Bet

[1780] Ami

[1781] SEQ ID a- B-[KRrRrRrE] Cationic Free datio Cyclic NO: 0075 Ala

[1782] n

[1783] nin

[1784] e -7.62 B,

[1785] Bet

[1786] Ami

[1787] SEQ ID a- B-[KRRRRRRE] Cationic Free datio Cyclic NO: 0076 Ala

[1788] n

[1789] nin

[1790] e -7.62 B,

[1791] Ami

[1792] SEQ ID Bet

[1793] B-R[KRRRRRRE] Cationic Free datio Cyclic NO: 0076 a- n

[1794]

[1795] Ala -8.41 ATTORNEY DOCKET: 05336.0007WO01

[1796] nin

[1797] e

[1798] B,

[1799] Bet

[1800] Ami

[1801] SEQ ID a- B-[KrRrRrRrE] Cationic Free datio Cyclic NO: 0077 Ala

[1802] n

[1803] nin

[1804] e -8.41 B,

[1805] Bet

[1806] Ami

[1807] SEQ ID a- B-[KRRRRRRRE] Cationic Free datio Cyclic NO: 0078 Ala

[1808] n

[1809] nin

[1810] e -8.41 B,

[1811] Bet

[1812] Ami

[1813] SEQ ID a- B-[KrrrrrrrE] Cationic Free datio Cyclic NO: 0079 Ala

[1814] n

[1815] nin

[1816] e -8.41 B,

[1817] Bet

[1818] Ami

[1819] SEQ ID a- B-[KRrRrRrRrE] Cationic Free datio Cyclic NO: 0080 Ala

[1820] n

[1821] nin

[1822] e -9.2 B,

[1823] Bet

[1824] Ami

[1825] B- SEQ ID a- Cationic Free datio Cyclic [KRRRRRRRRE] NO: 0081 Ala

[1826] n

[1827] nin

[1828] e -9.2 B,

[1829] Bet

[1830] Ami

[1831] SEQ ID a- B-[KrrrrrrrrE] Cationic Free datio Cyclic NO: 0082 Ala

[1832] n

[1833] nin

[1834] e -9.2 B,

[1835] Bet

[1836] B- Ami

[1837] SEQ ID a- [KRRRRRRRRR Cationic Free datio Cyclic NO: 0083 Ala

[1838] E] n

[1839] nin

[1840] e -9.99 Ami GGGGRRFFRRF SEQ ID

[1841] Cationic Free datio NA Linear RR NO: 0084

[1842]

[1843] n -1.49 ATTORNEY DOCKET: 05336.0007WO01

[1844] Ami

[1845] GGGGRRFFRR SEQ ID

[1846] Cationic Free datio NA Linear WRR NO: 0085

[1847] n -1.19 Ami

[1848] GGGGRRFWRR SEQ ID

[1849] Cationic Free datio NA Linear FRR NO: 0086

[1850] n -1.19 Ami

[1851] GGGGRRFWRR SEQ ID

[1852] Cationic Free datio NA Linear WRR NO: 0087

[1853] n -0.89 Ami

[1854] GGGGRRWFRR SEQ ID

[1855] Cationic Free datio NA Linear FRR NO: 0088

[1856] n -1.19 Ami

[1857] GGGGRRWFRR SEQ ID

[1858] Cationic Free datio NA Linear WRR NO: 0089

[1859] n -0.89 Ami GGGGRRWWRR SEQ ID

[1860] Cationic Free datio NA Linear FRR NO: 0090

[1861] n -0.89 Ami GGGGRRWWRR SEQ ID

[1862] Cationic Free datio NA Linear WRR NO: 0091

[1863] n -0.59 B,

[1864] Bet

[1865] Ami

[1866] SEQ ID a- BRR[KRRRRRE] Cationic Free datio Cyclic NO: 0092 Ala

[1867] n

[1868] nin

[1869] e -8.41 B,

[1870] Bet

[1871] Ami

[1872] SEQ ID a- B[KRRRRE] Cationic Free datio Cyclic NO: 0093 Ala

[1873] n

[1874] nin

[1875] e -6.04 B,

[1876] Bet

[1877] Ami

[1878] SEQ ID a- BRRRRRR Cationic Free datio Linear NO: 0094 Ala

[1879] n

[1880] nin

[1881] e -6.79 B,

[1882] Bet

[1883] Ami

[1884] SEQ ID a- BRRRRRRR Cationic Free datio Linear NO: 0095 Ala

[1885] n

[1886] nin

[1887] e -7.58 Ami B,

[1888] SEQ ID

[1889] B-RRRRRRR Cationic NA datio Bet Linear NO: 0095

[1890]

[1891] n a- -7.58 ATTORNEY DOCKET: 05336.0007WO01

[1892] Ala

[1893] nin

[1894] e

[1895] B,

[1896] Bet

[1897] Ami

[1898] SEQ ID a- BRRRRRRRR Cationic Free datio Linear NO: 0096 Ala

[1899] n

[1900] nin

[1901] e -8.37 CALNNYGRKKR SEQ ID

[1902] Cationic Free Free NA Linear RQRRR NO: 0097 -5.01

[1903] Cyst

[1904] CAYGGQQGGQ SEQ ID eine

[1905] Cationic NA NA Linear GGG NO: 0098 additi

[1906] on -1.45 CCTGRKKRRQR SEQ ID

[1907] Cationic Free Free NA Linear RR NO: 0099 -3.56 CELAGIGILTVKK SEQ ID

[1908] Cationic Free Free NA Linear KKKQKKK NO: 0100 3.2 CELAGIGILTVRK SEQ ID

[1909] Cationic Free Free NA Linear KRRQRRR NO: 0101

[1910] -2.56 CGGGARKKAAK AARKKAAKAAR SEQ ID

[1911] Cationic Free Free NA Linear KKAAKAARKKAA NO: 0102

[1912] KA

[1913] -5.27 CGGGGYGRKKR SEQ ID

[1914] Cationic Free Free NA Linear RQRRR NO: 0103 -4.46 CGGGRRRRRR SEQ ID

[1915] Cationic Free Free NA Linear RRRLLLL NO: 0104 -3.74 CGGGYGRKKRR SEQ ID

[1916] Cationic NA NA NA Linear QRRR NO: 0105 -4.24 CGGKDCERRFS Ami

[1917] SEQ ID RSDQLKRHQRR Cationic Free datio NA Linear NO: 0106

[1918] HTGVKPFQ n

[1919] -3.35 CGRKKRAARQR SEQ ID

[1920] Cationic Free Free NA Linear AARAARPPQ NO: 0107

[1921] -5.79 CGRKKRAARQR SEQ ID

[1922] Cationic Free Free NA Linear RRPPQ NO: 0108 -4.71 CGRKKRLLRQR SEQ ID

[1923] Cationic Free Free NA Linear LLRLLRPPQ NO: 0109

[1924] 0.63 CGRKKRLLRQR SEQ ID

[1925] Cationic Free Free NA Linear

[1926]

[1927] RRPPQ NO: 0110 -2.57 ATTORNEY DOCKET: 05336.0007WO01

[1928] CGRKKRRQRAA SEQ ID

[1929] Cationic Free Free NA Linear RRPPQ NO: 0111 -4.71 CGRKKRRQRLL SEQ ID

[1930] Cationic Free Free NA Linear RRPPQ NO: 0112 -2.57 CGRKKRRQRRA SEQ ID

[1931] Cationic Free Free NA Linear ARPPQ NO: 0113 -4.71 CGRKKRRQRRL SEQ ID

[1932] Cationic Free Free NA Linear LRPPQ NO: 0114 -2.57

[1933] Acet Ami CGRKKRRQRRR SEQ ID

[1934] Cationic ylatio datio NA Linear PPQ NO: 0115

[1935] n n -2.09 CGRKKRRQRRR SEQ ID

[1936] Cationic Free Free NA Linear PPQ NO: 0115 -4.17

[1937] Palm Ami CGRKKRRQRRR SEQ ID

[1938] Cationic itoyla datio NA Linear PPQ NO: 0115

[1939] tion n -3.52 CGRKKRRQRR SEQ ID

[1940] Cationic Free Free NA Linear WWRPPQ NO: 0116

[1941] -1.25 CGRKKRRQRW SEQ ID

[1942] Cationic Free Free NA Linear WRRPPQ NO: 0117

[1943] -1.25 CGRKKRWWRQ SEQ ID

[1944] Cationic Free Free NA Linear RRRPPQ NO: 0118

[1945] -1.25 CGRKKRWWRQ SEQ ID

[1946] Cationic Free Free NA Linear RWWRWWRPPQ NO: 0119

[1947] 4.59 CGYGRKKRRQR SEQ ID

[1948] Cationic Free Free NA Cyclic RRGC NO: 0120 -3.19 CHHHHHRRRRR SEQ ID

[1949] Cationic NA NA NA Linear RRRRHHHHHC NO: 0122

[1950] -8.55 CKDEPQRRSAR SEQ ID LSAKPAPPKPEP Cationic Free Free NA Linear NO: 0123

[1951] KPKKAPAKK

[1952] -3.05 SEQ ID

[1953] ckkkkkkkkk Cationic Free Free NA Linear NO: 0124 2.36

[1954] Acet

[1955] CKYGRKKRRQR SEQ ID

[1956] Cationic amid Free NA Linear RR NO: 0125

[1957] ation -3.41 CKYGRKKRRQR SEQ ID

[1958] Cationic Free Free NA Linear RR NO: 0125 -3.41

[1959] Ami CREKAKKLFKKI SEQ ID

[1960] Cationic Free datio NA Linear LKKL NO: 0126

[1961]

[1962] n 4.87 ATTORNEY DOCKET: 05336.0007WO01

[1963] SEQ ID

[1964] [CRGDKGPDC] Cationic Free Free NA Cyclic NO: 0127 0.19

[1965] Cyst

[1966] CRKARYRGRKR SEQ ID eine

[1967] Cationic NA NA Linear QR NO: 0128 additi

[1968] on -3.85 SEQ ID

[1969] crkkrrqrrr Cationic Free Free NA Linear NO: 0129 -3.91

[1970] Cyst

[1971] SEQ ID eine

[1972] CRRRRRRRR Cationic NA NA Linear NO: 0130 additi

[1973] on -5.49 SEQ ID

[1974] crrrrrrrrr Cationic Free Free NA Linear NO: 0131 -6.28

[1975] Ami

[1976] CSSLDEPGRGG SEQ ID

[1977] Cationic Free datio NA Linear FSSESKV NO: 0132

[1978] n -1.9 CVSRRRRRRGG SEQ ID

[1979] Cationic Free Free NA Linear RRRR NO: 0133 -7.64

[1980] Acet

[1981] SEQ ID CWKKK Cationic ylatio Free NA Linear NO: 0134

[1982] n 4.23 Acet

[1983] SEQ ID CWKKKKKKKK Cationic ylatio Free NA Linear NO: 0135

[1984] n 5.08 Acet

[1985] CWKKKKKKKKK SEQ ID

[1986] Cationic ylatio Free NA Linear KKKK NO: 0136

[1987] n 5.93 Acet

[1988] CWKKKKKKKKK SEQ ID

[1989] Cationic ylatio Free NA Linear KKKKKKKKK NO: 0137

[1990] n 6.78 CYGRKKRRQRR SEQ ID

[1991] Cationic Free Free NA Linear

[1992] R NO: 0138 -3.58

[1993] Ami

[1994] DRRRRGSRPSG SEQ ID

[1995] Cationic Free datio NA Linear AERRRR NO: 0139

[1996] n -9.2 Ami

[1997] DRRRRGSRPSG SEQ ID

[1998] Cationic Free datio NA Linear AERRRRRAAAA NO: 0140

[1999] n -11.1 ELVVLGKLYGRK SEQ ID

[2000] Cationic Free Free NA Linear KRRQRRR NO: 0141

[2001] -2.42 Ami

[2002] SEQ ID ERKKRRRE Cationic Free datio NA Linear NO: 0142

[2003]

[2004] n -4.17 ATTORNEY DOCKET: 05336.0007WO01

[2005] ESGGGGSPGRR SEQ ID

[2006] Cationic Free Free NA Linear RRRRRRRRR NO: 0143

[2007] -11.5 FFFAAGRKRKK SEQ ID

[2008] Cationic Free Free NA Linear

[2009] RT NO: 0144 0.6

[2010] Ami

[2011] FFFFFFGRRRRR SEQ ID

[2012] Cationic NA datio NA Linear RRRGC NO: 0145

[2013] n 1.68 Ami

[2014] SEQ ID

[2015] ffffgrrrrrrrrgc Cationic NA datio NA Linear NO: 0146

[2016] n -0.64 Ami

[2017] FFFFGRRRRRR SEQ ID

[2018] Cationic NA datio NA Linear RRGC NO: 0147

[2019] n -0.64 Ami

[2020] FFGRRRRRRRG SEQ ID

[2021] Cationic NA datio NA Linear

[2022] C NO: 0148

[2023] n -2.17 Ami

[2024] FFLIGRRRRRRR SEQ ID

[2025] Cationic NA datio NA Linear RGC NO: 0149

[2026] n -1.46 Ami

[2027] SEQ ID

[2028] fflipkgrrrrrrrr Cationic NA datio NA Linear NO: 0150

[2029] n -1.75 Ami

[2030] FFLIPKGRRRRR SEQ ID

[2031] Cationic NA datio NA Linear RRRGC NO: 0151

[2032] n -1.14 FFLIPKGRRRRR SEQ ID

[2033] Cationic NA NA NA Linear RRRR NO: 0152 -3.19 FITKALGISYGRK SEQ ID

[2034] Cationic Free Free NA Linear KRR NO: 0153 0.63 FITKALGISYGRK SEQ ID

[2035] Cationic Free Free NA Linear KRRQRRRPPQ NO: 0154

[2036] -2.12 Ami

[2037] SEQ ID FKKFRKF Cationic Free datio NA Linear NO: 0155

[2038] n 3.85 x,

[2039] eye

[2040] loh

[2041] SEQ ID FXrFXrFXr Cationic NA NA exy Linear NO: 0156

[2042] lala

[2043] nin

[2044] e 1.11 x,

[2045] eye

[2046] SEQ ID FXrFXrFXrFXr Cationic NA NA loh Linear NO: 0157

[2047] exy

[2048]

[2049] lala 1.48 ATTORNEY DOCKET: 05336.0007WO01

[2050] nin

[2051] e

[2052] x,

[2053] eye

[2054] loh

[2055] SEQ ID FXrFXrFXrFXrFXr Cationic NA NA exy Linear NO: 0158

[2056] lala

[2057] nin

[2058] e 1.85 x,

[2059] eye

[2060] loh FXrFXrFXrFXrFXr SEQ ID

[2061] Cationic NA NA exy Linear FXr NO: 0159

[2062] lala

[2063] nin

[2064] e 2.22 Cyst GALFLAFLAAAL Acet eami

[2065] SEQ ID SLMGLWSQPKK Cationic ylatio de NA Linear NO: 0160

[2066] KRKV n grou

[2067] P 8.15 GCGGGYGRKKR SEQ ID

[2068] Cationic NA NA NA Linear RQRRR NO: 0161 -4.46

[2069] Ab

[2070] u,

[2071] iso

[2072] ste

[2073] Cyst ric GD(Abu)LPHLKL SEQ ID eine 2- Cationic Free Linear

[2074] C NO: 0162 addit am

[2075] ion ino

[2076] but

[2077] yric

[2078] aci

[2079] d 2.47 Malei

[2080] GGGGRRRRRR SEQ ID mide

[2081] Cationic Free NA Linear RRRLLLL NO: 0163 additi

[2082] on -4.79 GGGRRRRRRY SEQ ID

[2083] Cationic Free Free NA Linear GRKKRRQRR NO: 0164

[2084] -9.02 [GGVCPKILKKC

[2085] RRDSDCPGACI SEQ ID

[2086] Cationic Free Free NA Cyclic CRGNGWCGSG NO: 0165

[2087] SD]

[2088]

[2089] 2.42 ATTORNEY DOCKET: 05336.0007WO01

[2090] [GGVCPKILKKC

[2091] RRDSDCPGACI SEQ ID

[2092] Cationic Free Free NA Cyclic CRGNGYCGSGS NO: 0166

[2093] D] 1.51 [GGVCPKILRRC

[2094] RRDSDCPGACI SEQ ID

[2095] Cationic Free Free NA Cyclic CRGNGWCGSG NO: 0167

[2096] SD]

[2097] 0.5 [GGVCPKILRRC

[2098] RRDSDCPGACI SEQ ID

[2099] Cationic Free Free NA Cyclic CRGNGYCGSGS NO: 0168

[2100] D] -0.41 [GGVCPKILRRC

[2101] RRDSDCPGACI SEQ ID

[2102] Cationic Free Free NA Cyclic CRGNGYCGSGS NO: 0169

[2103] R] -0.92 [GGVCPRILRRC

[2104] RRDSDCPGACI SEQ ID

[2105] Cationic Free Free NA Cyclic CRGNGYCGSGS NO: 0170

[2106] K] -0.92 GKHRHERGHHR SEQ ID

[2107] Cationic Free Free NA Linear DRRER NO: 0171 -8.53

[2108] SEQ ID GKKKKKKKKK Cationic Free Free NA Linear NO: 0172 1.31

[2109] Ami

[2110] SEQ ID GKKKKRKREKL Cationic Free datio NA Linear NO: 0173

[2111] n -0.33 GKKKRKLSNRE SEQ ID

[2112] Cationic Free Free NA Linear SAKRSR NO: 0174 -5.33 GKKTNLFSALIK SEQ ID

[2113] Cationic Free Free NA Linear KKKTA NO: 0175 1.77 GKRARNTEAAR SEQ ID

[2114] Cationic Free Free NA Linear RSRARKL NO: 0176 -7.59 GKRRRRATAKY SEQ ID

[2115] Cationic Free Free NA Linear RSAH NO: 0177 -5.11 GKRVAKRKLIEQ SEQ ID

[2116] Cationic Free Free NA Linear NRERRR NO: 0178 -6.22

[2117] Cyst

[2118] eami GLWRALWRLLR SEQ ID

[2119] Cationic Free de NA Linear SLWRLLWKA NO: 0179

[2120] grou

[2121] P 7.54 [GRCTKSIPPICF SEQ ID

[2122] Cationic Free Free NA Cyclic PA] NO: 0180 2.85 [GRCTKSIPPICW SEQ ID

[2123] Cationic Free Free NA Cyclic

[2124]

[2125] PK] NO: 0181 3.59 ATTORNEY DOCKET: 05336.0007WO01

[2126] [GRCTRSIPPKC SEQ ID

[2127] Cationic Free Free NA Cyclic WPD] NO: 0182 1.65 GRGDGPRRKKK Acet

[2128] SEQ ID KGPRRKKKKGP Cationic ylatio Free NA Linear NO: 0183

[2129] RR n -3.67

[2130] Ph

[2131] os

[2132] Acet

[2133] SEQ ID GRGDSPRR Cationic ylatio Free Ph Linear NO: 0184 ory

[2134] n

[2135] lati

[2136] on -1.96 Ph

[2137] os GRGDSPRRKKK Acet

[2138] SEQ ID KSPRRKKKKSP Cationic ylatio Free Ph Linear NO: 0185 ory

[2139] RR n

[2140] lati

[2141] on -4.36 Ph

[2142] os

[2143] Acet

[2144] GRGDSPRRSPR SEQ ID

[2145] Cationic ylatio Free ph Linear

[2146] R NO: 0186 ory

[2147] n

[2148] lati

[2149] on -3.84 GRKKRRERRRP SEQ ID

[2150] Cationic Free Free NA Linear PERKC NO: 0187 -6.11 GRKKRRQARAP SEQ ID

[2151] Cationic Free Free NA Linear PQC NO: 0188 -3.13

[2152] SEQ ID GRKKRRQPPQC Cationic Free Free NA Linear NO: 0189 -1.8 GRKKRRQRARP SEQ ID

[2153] Cationic Free Free NA Linear PQC NO: 0190 -3.65 GRKKRRQRPPQ SEQ ID

[2154] Cationic Free Free NA Linear

[2155] C NO: 0191 -2.59 GRKKRRQRRPP SEQ ID

[2156] Cationic Free Free NA Linear QC NO: 0192 -3.38

[2157] SEQ ID GRKKRRQRRR Cationic Free Free NA Linear NO: 0193 -4.96 SEQ ID GRKKRRQRRRC Cationic Free Free NA Linear NO: 0194 -4.13 GRKKRRQRRRC SEQ ID

[2158] Cationic Free Free NA Linear

[2159] G NO: 0195 -4.35

[2160] Ami

[2161] SEQ ID GRKKRRQRRRG Cationic Free datio NA Linear NO: 0196

[2162] n -4.53 GRKKRRQRRRM SEQ ID

[2163] Cationic NA NA NA Linear

[2164]

[2165] VSAL NO: 0197 -4.05 ATTORNEY DOCKET: 05336.0007WO01

[2166] GRKKRRQRRRP SEQ ID

[2167] Cationic Free Free NA Linear

[2168] P NO: 0198 -4.66

[2169] Ami GRKKRRQRRRP SEQ ID

[2170] Cationic Free datio NA Linear

[2171] PQ NO: 0199

[2172] n -4.35 GRKKRRQRRRP SEQ ID

[2173] Cationic Free Free NA Linear

[2174] PQ NO: 0199 -5 GRKKRRQRRRP SEQ ID

[2175] Cationic Free Free NA Linear PQK NO: 0200 -4.83 GRKKRRQRRRP SEQ ID

[2176] Cationic Free Free NA Linear PQRKC NO: 0201 -4.79

[2177] Ami

[2178] [GRKKRRQRRR SEQ ID

[2179] Cationic Free datio NA Cyclic PPQY] NO: 0202

[2180] n -3.8 Ami GRKKRRQRRRP SEQ ID

[2181] Cationic Free datio NA Linear WQ NO: 0203

[2182] n -3.04 GRKLKKKKNEK SEQ ID

[2183] Cationic Free Free NA Linear EDKRPRT NO: 0204 -3.97

[2184] Ami

[2185] SEQ ID GRKRKKRT Cationic Free datio NA Linear NO: 0205

[2186] n -1.69 SEQ ID GRKRKKRT Cationic Free Free NA Linear NO: 0205 -2.34

[2187] Ami GRQLRIAGKRLE SEQ ID

[2188] Cationic Free datio NA Linear GRSK NO: 0206

[2189] n -2.59 Ami GRQLRIAGKRLR SEQ ID

[2190] Cationic Free datio NA Linear GRSK NO: 0207

[2191] n -2.38 Ami GRQLRIAGRRLR SEQ ID

[2192] Cationic Free datio NA Linear GRSR NO: 0208

[2193] n -4.3 Ami GRQLRIAGRRLR SEQ ID

[2194] Cationic Free datio NA Linear RRSR NO: 0209

[2195] n -4.87 Ami GRQLRRAGRRL SEQ ID

[2196] Cationic Free datio NA Linear RGRSR NO: 0210

[2197] n -5.79 Ami GRQLRRAGRRL SEQ ID

[2198] Cationic Free datio NA Linear RRRSR NO: 0211

[2199] n -6.36 GRRERNKMAAA SEQ ID

[2200] Cationic Free Free NA Linear KORNRRR NO: 0212

[2201] -7.84 GRRRRATAKYR SEQ ID

[2202] Cationic Free Free NA Linear

[2203]

[2204] TAH NO: 0213 -5.09 ATTORNEY DOCKET: 05336.0007WO01

[2205] GRRRRKRLSHR SEQ ID

[2206] Cationic Free Free NA Linear

[2207] T NO: 0214 -5.01

[2208] SEQ ID GRRRRRERNK Cationic Free Free NA Linear NO: 0215 -6.77

[2209] Ami

[2210] SEQ ID GRRRRRRRRR Cationic Free datio NA Linear NO: 0216

[2211] n -6.68 GSVSRRRRRRG SEQ ID

[2212] Cationic Free Free NA Linear GRRRR NO: 0217 -9.14

[2213] Carri

[2214] es

[2215] GYGRKKRRQRR SEQ ID an

[2216] Cationic Free NA Linear RG NO: 0218 extra

[2217] giyci

[2218] ne -4.85 GYGYGYGYGYG

[2219] Acet Ami

[2220] YGYGYKKRKKR SEQ ID

[2221] Cationic ylatio datio NA Linear KKRKKRKQQKQ NO: 0219

[2222] n n

[2223] QKRRK

[2224] 0.66 GYGYGYGYGYG

[2225] Ami

[2226] YGYGYKKRKKR SEQ ID

[2227] Cationic Free datio NA Linear KKRKKRKQQKQ NO: 0219

[2228] n

[2229] QKRRK

[2230] -0.77 HEHEHEHEHEH EHEHEEFGGGG SEQ ID

[2231] Cationic Free Free NA Linear GYGRGRGRGR NO: 0220

[2232] GRGRG

[2233] -17.2 HEHEHEHEHEH EHEHEEFGGGG SEQ ID

[2234] Cationic Free Free NA Linear GYGRRRRRRG NO: 0221

[2235] GGGGG

[2236] -17.2 HEHEHEHEHEH EHEHEHEHEEF SEQ ID

[2237] Cationic Free Free NA Linear GGGGGYGRGR NO: 0222

[2238] GRGRGRGRG

[2239] -19.8 HEHEHEHEHEH EHEHEHEHEEF SEQ ID

[2240] Cationic Free Free NA Linear GGGGGYGRRR NO: 0223

[2241] RRRGGGGGG

[2242]

[2243] -19.8 ATTORNEY DOCKET: 05336.0007WO01

[2244] HEHEHEHEHEH EHEHEHEHEHE SEQ ID HEEFGGGGGYG Cationic Free Free NA Linear NO: 0224

[2245] RGRGRGRGRG RG

[2246] -22.4 HEHEHEHEHEH EHEHEHEHEHE SEQ ID

[2247] Cationic Free Free NA Linear HEEFGGGGGYG NO: 0225

[2248] RKKRRQRRR

[2249] -21.1 HEHEHEHEHEH EHEHEHEHEHE SEQ ID HEEFGGGGGYG Cationic Free Free NA Linear NO: 0226

[2250] RRRRRRGGGG GG

[2251] -22.4 SEQ ID HEHEHEHEHE Cationic Free Free NA Linear NO: 0227 -6.55 SEQ ID HEHEHEHEHE Cationic Free Free NA Linear NO: 0227 -6.55 HHHHHHHHHHH

[2252] Stear Ami

[2253] HHHHHHHHHRR SEQ ID

[2254] Cationic ylatio datio NA Linear RRRRRRRRRRR NO: 0228

[2255] n n

[2256] RR

[2257] -8.9 HHHHHHHHHHH Acet Ami

[2258] SEQ ID HHHHHRRRRRR Cationic ylatio datio NA Linear NO: 0229

[2259] RRRRRRRRR n n

[2260] -14.7 HHHHHHHHHHH Stear Ami

[2261] SEQ ID HHHHHRRRRRR Cationic ylatio datio NA Linear NO: 0229

[2262] RRRRRRRRR n n

[2263] -7.66 HHHHHHHHHHH Stear Ami

[2264] SEQ ID HRRRRRRRRRR Cationic ylatio datio NA Linear NO: 0230

[2265] RRRRR n n

[2266] -6.42 Stear Ami

[2267] HHHHHHHHRRR SEQ ID

[2268] Cationic ylatio datio NA Linear RRRRR NO: 0231

[2269] n n 0.35 HHHHHHHHRRR Acet Ami

[2270] SEQ ID RRRRRRRRRRR Cationic ylatio datio NA Linear NO: 0232

[2271] R n n -12.3 HHHHHHHHRRR Stear Ami

[2272] SEQ ID RRRRRRRRRRR Cationic ylatio datio NA Linear NO: 0232

[2273]

[2274] R n n -5.18 ATTORNEY DOCKET: 05336.0007WO01

[2275] SEQ ID HHHRRRRRRRR Cationic Free Free NA Linear NO: 0233 -7.25 HILPWKWPWWP SEQ ID

[2276] Cationic Free Free NA Linear WRR NO: 0234 7.53 HSDAVFTDNYTA LRKQMAVKKYL SEQ ID

[2277] Cationic Free Free NA Linear NSILNYGRKKRR NO: 0235

[2278] QRRR

[2279] -4.56 HSDGIFTDSYSR

[2280] Ami

[2281] YRKQMAVKKYL SEQ ID

[2282] Cationic Free datio NA Linear AAVLGKRYKQR NO: 0236

[2283] n

[2284] VKNK

[2285] 0.42 X,

[2286] am

[2287] ino

[2288] Ami

[2289] HXRHXRILFQYH SEQ ID he

[2290] Cationic Free datio Linear XRHXR NO: 0237 xyl

[2291] n

[2292] res

[2293] idu

[2294] e -0.88 IKIKIKIKIKIKIKIK Acet Ami

[2295] SEQ ID KLAKLAKLAKLA Cationic ylatio datio NA Linear NO: 0238

[2296] KLAKLAKKIK n n

[2297] 14.45 IKIKIKIKIKIKIKIK Ami

[2298] SEQ ID KLAKLAKLAKLA Cationic Free datio NA Linear NO: 0238

[2299] KLAKLAKKIK n

[2300] 13.02 IPLVVPLRRRRR SEQ ID

[2301] Cationic Free Free NA Linear RRRC NO: 0239 -2.25

[2302] SEQ ID IRQRRRR Cationic Free Free NA Linear NO: 0240 -3.59 IYLATALAKWAL SEQ ID KQGFGGRRRRR Cationic Free Free NA Linear NO: 0241

[2303] RR -1.26 IYLATALAKWAL SEQ ID

[2304] Cationic Free Free NA Linear KQGGRRRRRRR NO: 0242

[2305] -2.2 Ami

[2306] KCFQWQRNMR SEQ ID

[2307] Cationic Free datio NA Linear KVRGPPVSCIKR NO: 0243

[2308] n 2.1 Ami

[2309] SEQ ID KCPSRRPKR Cationic Free datio NA Linear NO: 0244

[2310]

[2311] n -0.7 ATTORNEY DOCKET: 05336.0007WO01

[2312] KDCERRFSRSD SEQ ID QLKRHQRRHTG Cationic Free NA NA Linear NO: 0245

[2313] VKPFQK

[2314] -4.22 KETWWETWWT SEQ ID EWSQPKKKRKV Cationic Free Free NA Linear NO: 0246

[2315] C 4.09

[2316] SEQ ID KFFKFFKFFK Cationic Free Free NA Linear NO: 0247 7.64 KFLNRFWHWLQ SEQ ID

[2317] Cationic Free Free NA Linear LKPGQPMY NO: 0248

[2318] 6.36 Acet Ami

[2319] KGRKKRRQRRR SEQ ID

[2320] Cationic ylatio datio NA Linear PPQ NO: 0249

[2321] n n -2.75 KGRTPIKFGKAD Ami

[2322] SEQ ID CDRPPKHSQNG Cationic Free datio NA Linear NO: 0250

[2323] MGK n

[2324] -0.48 hey

[2325] ho

[2326] mo

[2327] cys

[2328] tei

[2329] ne

[2330] in

[2331] whi

[2332] ch

[2333] the

[2334] sid

[2335] e

[2336] K-Hcy- Ami ch FQWQRNMRKV SEQ ID

[2337] Cationic Free datio ain Linear RGPPVS-Hcy- NO: 0251

[2338] n is

[2339] IKR

[2340] on

[2341] e

[2342] me

[2343] thyl

[2344] en

[2345] e

[2346] gro

[2347] up

[2348] Ion

[2349] ger

[2350] tha

[2351] n

[2352]

[2353] in 2.58 ATTORNEY DOCKET: 05336.0007WO01

[2354] cys

[2355] tei

[2356] ne

[2357] KHKHKHKHKHK SEQ ID HKHKHKHKKLFK Cationic Free Free NA Linear NO: 0252

[2358] KILKYL

[2359] 4.4 SEQ ID KKKKKKKK Cationic Free Free NA Linear NO: 0253 1.36

[2360] Ami

[2361] SEQ ID KKKKKKKKK Cationic Free datio NA Linear NO: 0254

[2362] n 2.18 KKKKKKNKKLQ SEQ ID

[2363] Cationic Free Free NA Linear QRGD NO: 0255 -0.79

[2364] Ami

[2365] SEQ ID KKLFKKILKKL Cationic Free datio NA Linear NO: 0256

[2366] n 5.93 Ami

[2367] KKPGKKTTTKPT SEQ ID

[2368] Cationic Free datio NA Linear KK NO: 0257

[2369] n 0.88 Ami

[2370] KKPGKKTTTKPT SEQ ID

[2371] Cationic Free datio NA Linear KKPTIKTTKK NO: 0258

[2372] n 1.46 Ami

[2373] SEQ ID KKPTIKTTKK Cationic Free datio NA Linear NO: 0259

[2374] n 1.57 SEQ ID KKRRQRRR Cationic Free Free NA Linear NO: 0260 -3.95

[2375] Ami

[2376] SEQ ID KKTTTKPTKK Cationic Free datio NA Linear NO: 0261

[2377] n 0.61 X,

[2378] am

[2379] ino

[2380] Ami

[2381] KKWKMRILFQY SEQ ID he

[2382] Cationic Free datio Linear RXRRXR NO: 0262 xyl

[2383] n

[2384] res

[2385] idu

[2386]

[2387] e 2.05 ATTORNEY DOCKET: 05336.0007WO01

[2388] KLAKLAKKLAKL SEQ ID

[2389] Cationic Free Free NA Linear AKGGRRRRRRR NO: 0263

[2390] -2.83 KLAKLAKKLAKL SEQ ID AKGRKKRRQRR Cationic Free Free NA Linear NO: 0264

[2391] RP -1.67 KLAKLAKKLAKL SEQ ID AKNYRWRCKNQ Cationic Free Free NA Linear NO: 0265

[2392] N 1.29

[2393] Ami

[2394] SEQ ID KLIKGRTPIKFGK Cationic Free datio NA Linear NO: 0266

[2395] n 3.35 KLIKGRTPIKFGK Ami

[2396] SEQ ID ADCDRPPKHSG Cationic Free datio NA Linear NO: 0267

[2397] K n 2.22 KLIKGRTPIKFGK Ami

[2398] SEQ ID ADCDRPPKHSQ Cationic Free datio NA Linear NO: 0268

[2399] NGK n

[2400] 0.9 KLIKGRTPIKFGK Ami

[2401] SEQ ID ADCDRPPKHSQ Cationic Free datio NA Linear NO: 0269

[2402] NGM n

[2403] 1.24 KLIKGRTPIKFGK Ami

[2404] SEQ ID ADCDRPPKHSQ Cationic Free datio NA Linear NO: 0270

[2405] NGMGK n

[2406] 1.19 KLIKGRTPIKFGK Ami

[2407] SEQ ID ARCRRPPKHSG Cationic Free datio NA Linear NO: 0271

[2408] K n 1.2

[2409] SEQ ID KLPVM Cationic Free Free NA Linear NO: 0272 1.95 KLTRAQRRAAA SEQ ID

[2410] Cationic Free Free NA Linear RKNKRNTRGC NO: 0273

[2411] -6.72 KMTRAQRRAAA SEQ ID

[2412] Cationic Free Free NA Linear RRNRWTARGC NO: 0274

[2413] -5.97 Ami

[2414] KPRSKNPPKKP SEQ ID

[2415] Cationic Free datio NA Linear

[2416] K NO: 0275

[2417] n -0.12 KRARNTEAARR SEQ ID SRARKLQRMKQ Cationic Free Free NA Linear NO: 0276

[2418] GC -7.55

[2419] Ami

[2420] SEQ ID KRIPNKKPGKK Cationic Free datio NA Linear NO: 0277

[2421]

[2422] n 0.51 ATTORNEY DOCKET: 05336.0007WO01

[2423] Ami

[2424] SEQ ID KRIPNKKPGKKT Cationic Free datio NA Linear NO: 0278

[2425] n 0.25 Ami

[2426] KRIPNKKPGKKT SEQ ID

[2427] Cationic Free datio NA Linear TTKPTKK NO: 0279

[2428] n 0.13 Ami

[2429] KRIPNKKPGKKT SEQ ID

[2430] Cationic Free datio NA Linear TTKPTKKPTIK NO: 0280

[2431] n 0.89 KRIPNKKPGKKT Ami

[2432] SEQ ID TTKPTKKPTIKTT Cationic Free datio NA Linear NO: 0281

[2433] KK n 0.71 KRIPNKKPGKKT Ami

[2434] SEQ ID TTKPTKKPTIKTT Cationic Free datio NA Linear NO: 0282

[2435] KKDLK n

[2436] 1.4 KRIPNKKPGKKT Ami

[2437] SEQ ID TTKPTKKPTIKTT Cationic Free datio NA Linear NO: 0283

[2438] KKDLKPQTTKPK n

[2439] 1.18 Ami

[2440] SEQ ID KRIPNKKPKK Cationic Free datio NA Linear NO: 0284

[2441] n 0.73 SEQ ID KRKRWHW Cationic Free Free NA Linear NO: 0285 1.37 SEQ ID KRKRWHW Cationic NA Free NA Linear NO: 0285 1.37

[2442] Ami

[2443] KRPAAIKKAGQA SEQ ID

[2444] Cationic Free datio NA Linear KKKK NO: 0286

[2445] n 0.26 KRRIRRERNKM SEQ ID AAAKSRNRRRE Cationic Free Free NA Linear NO: 0287

[2446] LTDTGC

[2447] -10 SEQ ID KRRQRRR Cationic Free Free NA Linear NO: 0288 -4.12 KRVSRNKSEKK SEQ ID

[2448] Cationic Free NA NA Linear RR NO: 0289 -5.04

[2449] Ami KSICKTIPSNKPK SEQ ID

[2450] Cationic Free datio NA Linear KK NO: 0290

[2451] n 2.06 KSTGKANKITITN SEQ ID

[2452] Cationic Free Free NA Linear DKGRLSK NO: 0291

[2453] -2.37 Ami

[2454] SEQ ID KTIPSNKPKKK Cationic Free datio NA Linear NO: 0292

[2455]

[2456] n 0.81 ATTORNEY DOCKET: 05336.0007WO01

[2457] X,

[2458] am

[2459] ino

[2460] Ami

[2461] KXRKXRILFQYK SEQ ID he

[2462] Cationic Free datio Linear XRKXR NO: 0293 xyl

[2463] n

[2464] res

[2465] idu

[2466] e 1.04 LALALALALALAL Ami

[2467] SEQ ID AKLAKLAKLAKL Cationic Free datio NA Linear NO: 0294

[2468] AKIKKIKKKIK n

[2469] 10.45 LALALALALALAL Ami

[2470] SEQ ID ALAKIKKIKKIKKI Cationic Free datio NA Linear NO: 0295

[2471] KKLAKLAKKIK n

[2472] 11.66 LALALALALALAL

[2473] Acet Ami

[2474] ALAKKLKKLKKL SEQ ID

[2475] Cationic ylatio datio NA Linear KKLKKLKKLKYA NO: 0296

[2476] n n

[2477] K 13.78 LALALALALALAL

[2478] Ami

[2479] ALAKKLKKLKKL SEQ ID

[2480] Cationic Free datio NA Linear KKLKKLKKLKYA NO: 0296

[2481] n

[2482] K 12.35 LALALALALALAL Ami

[2483] SEQ ID ALAKLAKLAKLA Cationic Free datio NA Linear NO: 0297

[2484] KLAKLAKKIK n

[2485] 9.6 B,

[2486] Bet

[2487] Laur Ami

[2488] SEQ ID a- Lauroyl-B-rrrrrrr Cationic oylati datio Linear NO: 0298 Ala

[2489] on n

[2490] nin

[2491] e -6.49 B,

[2492] Bet

[2493] Laur Ami

[2494] Lauroyl-B- SEQ ID a- Cationic oylati datio Linear RRRRRRRRR NO: 0299 Ala

[2495] on n

[2496] nin

[2497] e -8.07 B,

[2498] Bet

[2499] Laur Ami

[2500] Lauroyl-B-rrrrr- SEQ ID a- Cationic oylati datio Linear RRRR NO: 0300 Ala

[2501] on n

[2502] nin

[2503]

[2504] e -8.07 ATTORNEY DOCKET: 05336.0007WO01

[2505] B,

[2506] Bet

[2507] Laur Ami

[2508] Lauroyl-B-RRRR- SEQ ID a- Cationic oylati datio Linear rrrrr NO: 0301 Ala

[2509] on n

[2510] nin

[2511] e -8.07 LGISYGRKKRRQ SEQ ID

[2512] Cationic Free Free NA Linear RRRPPQ NO: 0302

[2513] -3.62 Ami

[2514] LILIGRRRRRRR SEQ ID

[2515] Cationic NA datio NA Linear RGC NO: 0303

[2516] n -2.28 LILILILILILILILIKR Acet Ami

[2517] SEQ ID KKRKKRKKRKK Cationic ylatio datio NA Linear NO: 0304

[2518] RAKRAKHSK n n

[2519] 10.08 LILILILILILILILIKR Ami

[2520] SEQ ID KKRKKRKKRKK Cationic Free datio NA Linear NO: 0304

[2521] RAKRAKHSK n

[2522] 8.65 Acet Ami

[2523] LKKLCKLLKKLC SEQ ID

[2524] Cationic ylatio datio NA Linear KLAG NO: 0305

[2525] n n 9.07 Acet Ami

[2526] LKKLLKLLKKLLK SEQ ID

[2527] Cationic ylatio datio NA Linear LAG NO: 0306

[2528] n n 9.01 LKRWGTIKKSKA SEQ ID INVLRGFRKEIG Cationic Free Free NA Linear NO: 0307

[2529] RMLNILNRRRR

[2530] -1.6 LLRARWRRRRS SEQ ID

[2531] Cationic Free Free NA Linear RRFR NO: 0308 -3.61 LVVLGKL- SEQ ID

[2532] Cationic Free Free NA Linear YGRKKRRQRRR NO: 0309

[2533] -1.42 MDAQTRRRERR SEQ ID AEKQAQWKAAN Cationic Free Free NA Linear NO: 0310

[2534] GO -6.92

[2535] SEQ ID MLLLTRRRST Cationic Free Free NA Linear NO: 0311 -0.43 SEQ ID RGRGRGRGRG Cationic Free Free NA Linear NO: 0312 -5.05 SEQ ID RGRGRGRGRG Cationic Free Free NA Linear

[2536]

[2537] NO: 0312 -5.05 ATTORNEY DOCKET: 05336.0007WO01

[2538] MRRIRPRPPRLP SEQ ID RPRPRPLPFPRP Cationic Free Free NA Linear NO: 0313

[2539] GGCYPG

[2540] -0.77 B,

[2541] Bet

[2542] Myrsi Ami

[2543] Myristoyl-B- SEQ ID a- Cationic toylat datio Linear rrrrrrrrrrr NO: 0314 Ala

[2544] ion n

[2545] nin

[2546] e -9.13 B,

[2547] Bet

[2548] Myrsi Ami

[2549] Myristoyl-B- SEQ ID a- Cationic toylat datio Linear RRRRRRRRRRR NO: 0315 Ala

[2550] ion n

[2551] nin

[2552] e -9.13 NAKTRRHERRR SEQ ID

[2553] Cationic Free Free NA Linear KLAIERGC NO: 0316

[2554] -6.38 NNNAAGRKRKK SEQ ID

[2555] Cationic Free Free NA Linear

[2556] RT NO: 0317 -5.82

[2557] Ami

[2558] SEQ ID NRARRNRRRVR Cationic Free datio NA Linear NO: 0318

[2559] n -6.79 SEQ ID NYQRRCKNQN Cationic Free Free NA Linear NO: 0319 -3.65 SEQ ID NYQWRCKNQN Cationic Free Free NA Linear NO: 0320 -1.4 SEQ ID NYRRRCKNQN Cationic Free Free NA Linear NO: 0321 -4.1 SEQ ID NYRWRCK Cationic Free Free NA Linear NO: 0322 0.45 SEQ ID NYRWRCKN Cationic Free Free NA Linear NO: 0323 -0.53 SEQ ID NYRWRCKNQ Cationic Free Free NA Linear NO: 0324 -0.87 SEQ ID NYRWRCKNQN Cationic Free Free NA Linear NO: 0325 -1.85

[2560] Ami

[2561] SEQ ID PKKKRKV Cationic Free datio NA Linear NO: 0326

[2562] n 1.01 PKKKRKVAGYLL GKINLKALAALA SEQ ID KKILPQMQQNVF Cationic Free Free NA Linear NO: 0327

[2563] QYPGAGMVPQG EANF

[2564]

[2565] 4.14 ATTORNEY DOCKET: 05336.0007WO01

[2566] PKKKRKVRRRR RRRPQMQQNVF SEQ ID

[2567] Cationic Free Free NA Linear QYPGAGMVPQG NO: 0328

[2568] EANF

[2569] -6.05 PKKKRKVRRRR SEQ ID RRRYSQTSHKL Cationic Free Free NA Linear NO: 0329

[2570] VQLLTTAEQQ

[2571] -6.35 Ami

[2572] PKKKRKVWKLL SEQ ID

[2573] Cationic Free datio NA Linear QQFFGLM NO: 0330

[2574] n 6.97 Stear Ami

[2575] PKKKRKVWKLL SEQ ID

[2576] Cationic ylatio datio NA Linear QQFFGLM NO: 0330

[2577] n n 15.47 Ami

[2578] QTRRRERRAEK SEQ ID

[2579] Cationic Free datio NA Linear QAQW NO: 0331

[2580] n -5.49 SEQ ID RAKRRQRRR Cationic Free Free NA Linear NO: 0332 -5.18 RGDGPRRRPRK SEQ ID

[2581] Cationic Free Free NA Linear RRGR NO: 0333 -6.79 RGPRRQPRRHR SEQ ID

[2582] Cationic Free Free NA Linear RPRR NO: 0334 -7.53 RIKAERKRMRN SEQ ID RIAASKSRKRKL Cationic Free Free NA Linear NO: 0335

[2583] ERIARGC

[2584] -7.2 SEQ ID RKARRQRRR Cationic Free Free NA Linear NO: 0336 -5.18 SEQ ID RKKAAA Cationic Free Free NA Linear NO: 0337 -1.26 SEQ ID RKKARQRRR Cationic Free Free NA Linear NO: 0338 -4.22 SEQ ID RKKNPNCRRH Cationic Free Free NA Linear NO: 0339 -3.32 SEQ ID RKKRAQRRR Cationic Free Free NA Linear NO: 0340 -4.22 SEQ ID RKKRRARRR Cationic Free Free NA Linear NO: 0341 -4.67 SEQ ID RKKRRQARR Cationic Free Free NA Linear NO: 0342 -4.22 SEQ ID RKKRRQR Cationic Free Free NA Linear NO: 0343 -3.16 SEQ ID RKKRRQRAR Cationic Free Free NA Linear

[2585]

[2586] NO: 0344 -4.22 ATTORNEY DOCKET: 05336.0007WO01

[2587] SEQ ID RKKRRQRR Cationic Free Free NA Linear NO: 0345 -3.95 SEQ ID RKKRRQRRA Cationic Free Free NA Linear NO: 0346 -4.22 SEQ ID

[2588] rkkrrqrrr Cationic Free Free NA Linear NO: 0347 -4.74

[2589] Ami

[2590] SEQ ID RKKRRQRRRGC Cationic Free datio NA Linear NO: 0348

[2591] n -3.48 Ami

[2592] RKKRRQRRRGG SEQ ID

[2593] Cationic Free datio NA Linear

[2594] G NO: 0349

[2595] n -4.75 RKKRRQRRRHR SEQ ID

[2596] Cationic NA NA NA Linear RKKR NO: 0350 -7.08 RKKRRQRRRRK SEQ ID

[2597] Cationic Free Free NA Linear KRRQRRR NO: 0351

[2598] -9.48 SEQ ID RKKWFW Cationic Free Free NA Linear NO: 0352 3.63

[2599] Ami

[2600] SEQ ID RLLRLLRLL Cationic Free datio NA Linear NO: 0353

[2601] n 3.08 X,

[2602] 1- am

[2603] ino

[2604] eye

[2605] lop

[2606] ent

[2607] an

[2608] Ami

[2609] SEQ ID e- RLLRLLRLX Cationic Free datio Linear NO: 0354 1- n

[2610] car

[2611] bo

[2612] xyli

[2613] c

[2614] aci

[2615] ds

[2616] (Ac

[2617] 5c) 2.28 X,

[2618] 1- am

[2619] Ami

[2620] SEQ ID ino RLLRLXRLX Cationic Free datio Linear NO: 0355 eye

[2621] n

[2622] lop

[2623] ent

[2624]

[2625] an 1.48 ATTORNEY DOCKET: 05336.0007WO01

[2626] e- 1- car

[2627] bo

[2628] xyli

[2629] c

[2630] aci

[2631] ds

[2632] (Ac

[2633] 5c) RLRLRLRLRLRL

[2634] Ami RLRLKLLKLLKLL SEQ ID

[2635] Cationic Free datio NA Linear KLLKKKKKKKGY NO: 0356

[2636] n

[2637] K 9.5 RLRLRLRLRLRL

[2638] Ami

[2639] RLRLKNNKNNK SEQ ID

[2640] Cationic Free datio NA Linear NNKNNKKKKKK NO: 0357

[2641] n

[2642] KGYK

[2643] -4.74 RLRLRLRLRLRL

[2644] Ami

[2645] RLRLKRLKRLKR SEQ ID

[2646] Cationic Free datio NA Linear LKRLKKKKKKKG NO: 0358

[2647] n

[2648] YK

[2649] 3.14 X,

[2650] 1- am

[2651] ino

[2652] eye

[2653] lop

[2654] ent

[2655] an

[2656] Ami

[2657] SEQ ID e- RLXRLXRLX Cationic Free datio Linear NO: 0359 1- n

[2658] car

[2659] bo

[2660] xyli

[2661] c

[2662] aci

[2663] ds

[2664] (Ac

[2665] 5c) 0.68 X,

[2666] 1- Ami

[2667] SEQ ID am RLXRLXRXX Cationic Free datio Linear NO: 0360 ino

[2668] n

[2669] eye

[2670]

[2671] lop -0.12 ATTORNEY DOCKET: 05336.0007WO01

[2672] ent

[2673] an

[2674] e- 1- car

[2675] bo

[2676] xyli

[2677] c

[2678] aci

[2679] ds

[2680] (Ac

[2681] 5c)

[2682] X,

[2683] 1- am

[2684] ino

[2685] eye

[2686] lop

[2687] ent

[2688] an

[2689] Ami

[2690] SEQ ID e- RLXRXRXX Cationic Free datio Linear NO: 0361 1- n

[2691] car

[2692] bo

[2693] xyli

[2694] c

[2695] aci

[2696] ds

[2697] (Ac

[2698] 5c) -0.92 X,

[2699] am

[2700] ino

[2701] Ami

[2702] RMKWKKILFQY SEQ ID he

[2703] Cationic Free datio Linear RXRRXR NO: 0362 xyl

[2704] n

[2705] res

[2706] idu

[2707] e 2.05 Ami

[2708] SEQ ID RNRSRHRR Cationic Free datio NA Linear NO: 0363

[2709] n -5.04 Ami

[2710] SEQ ID RQARRNRRRC Cationic Free datio NA Linear NO: 0364

[2711] n -4.85 RQGAARVTSWL Ami

[2712] SEQ ID GRQLRIAGKRLE Cationic Free datio NA Linear NO: 0365

[2713]

[2714] GRSK n -3.4 ATTORNEY DOCKET: 05336.0007WO01

[2715] Ami

[2716] RQIKIFFQNRRM SEQ ID

[2717] Cationic Free datio NA Linear KFKK NO: 0366

[2718] n 2.69 RQIKIQFQNRRK SEQ ID

[2719] Cationic Free Free NA Linear WKK NO: 0367 0.33

[2720] Ami

[2721] RQIKIWFQNRRM SEQ ID

[2722] Cationic NA datio NA Linear KWKKGC NO: 0368

[2723] n 3.9 RQIKIWFQNRRM SEQ ID

[2724] Cationic Free Free NA Linear KWKKGG NO: 0369

[2725] 2.2 Ami

[2726] RQLRIAGRRLRG SEQ ID

[2727] Cationic Free datio NA Linear RSR NO: 0370

[2728] n -4.08 RRARRPRRLRP SEQ ID

[2729] Cationic Free Free NA Linear APGR NO: 0371 -5.83

[2730] Ami

[2731] SEQ ID RRGC Cationic NA datio NA Linear NO: 0372

[2732] n -0.32 Ami

[2733] SEQ ID RRGRRG Cationic Free datio NA Linear NO: 0373

[2734] n -2.95 Ami

[2735] SEQ ID RRIPNRRPRR Cationic Free datio NA Linear NO: 0374

[2736] n -4.07 RRIRPRPPRLPR SEQ ID PRPRPLPFPRP Cationic Free Free NA Linear NO: 0375

[2737] G -2.37

[2738] Ami

[2739] SEQ ID RRLLRRLRR Cationic Free datio NA Linear NO: 0376

[2740] n -1.69 Ami

[2741] SEQ ID RRLLRRLRR Cationic NA datio NA Linear NO: 0376

[2742] n -1.69 SEQ ID RRLSYSRRRF Cationic Free Free NA Linear NO: 0377 -2.34

[2743] Ami

[2744] SEQ ID RRRERRAEK Cationic Free datio NA Linear NO: 0378

[2745] n -5.4 SEQ ID

[2746] [rRrGrKkRr] Cationic Free Free NA Cyclic NO: 0379 -4.62 RRRQKRIVVRR SEQ ID

[2747] Cationic Free Free NA Linear RLIR NO: 0380 -3.65

[2748] SEQ ID

[2749] rrrqrrkkr Cationic Free Free NA Linear NO: 0381 -4.74 SEQ ID RRRQRRKKR Cationic Free Free NA Linear

[2750]

[2751] NO: 0382 -4.74 ATTORNEY DOCKET: 05336.0007WO01

[2752] RRRQRRKKRGY SEQ ID CKCKYGRKKRR Cationic Free Free NA Linear NO: 0383

[2753] QRRR

[2754] -6.82 SEQ ID RRRR Cationic Free Free NA Linear NO: 0384 -3.16 RRRRNRTRRNR SEQ ID

[2755] Cationic Free Free NA Linear RRVRGC NO: 0385

[2756] -9.98 SEQ ID RRRRR Cationic Free Free NA Linear NO: 0386 -3.95 SEQ ID

[2757] rrrrr Cationic Free Free NA Linear NO: 0387 -3.95 SEQ ID

[2758] rrrrrr Cationic Free Free NA Linear NO: 0388 -4.74

[2759] Ami

[2760] SEQ ID RRRRRR Cationic Free datio NA Linear NO: 0389

[2761] n -4.09 SEQ ID RRRRRR Cationic Free Free NA Linear NO: 0389 -4.74 SEQ ID RRRRRRHHH Cationic Free NA NA Linear NO: 0390 -5.67 SEQ ID

[2762] rrrrrrr Cationic Free Free NA Linear NO: 0391 -5.53 SEQ ID RRRRRRR Cationic Free Free NA Linear NO: 0392 -5.53 RRRRRRRGGIY SEQ ID

[2763] Cationic Free Free NA Linear LATALAKWALKQ NO: 0393

[2764] -2.2 RRRRRRRGGIY SEQ ID LATALAKWALKQ Cationic Free Free NA Linear NO: 0394

[2765] GF -1.26 RRRRRRRGGKL SEQ ID

[2766] Cationic Free Free NA Linear AKLAKKLAKLAK NO: 0395

[2767] -2.83 SEQ ID RRRRRRRHHH Cationic Free NA NA Linear NO: 0396 -6.46 RRRRRRRQIKIL SEQ ID FQNRRMKWKK Cationic Free Free NA Linear NO: 0397

[2768] GGC -2.37

[2769] SEQ ID

[2770] rRrRRRRR Cationic NA NA NA Linear NO: 0398 -6.32 SEQ ID

[2771] rrrRrRrR Cationic NA NA NA Linear NO: 0399 -6.32 SEQ ID

[2772] rRrRrRrR Cationic NA NA NA Linear

[2773]

[2774] NO: 0400 -6.32 ATTORNEY DOCKET: 05336.0007WO01

[2775] SEQ ID RRRRRRRRC Cationic Free Free NA Linear NO: 0401 -5.49

[2776] Cy

[2777] stei

[2778] ne

[2779] mo

[2780] difi

[2781] ed

[2782] oct

[2783] a- arg

[2784] inin

[2785] e

[2786] RRRRRRRR- SEQ ID

[2787] Cationic Free Free co Linear c(RGDfK) NO: 0402

[2788] nju

[2789] gat

[2790] ed

[2791] to

[2792] the

[2793] bra

[2794] nc

[2795] h

[2796] of

[2797] lysi

[2798] ne -5.45 Ami

[2799] SEQ ID RRRRRRRRGC Cationic NA datio NA Linear NO: 0403

[2800] n -5.06 Ami

[2801] SEQ ID

[2802] rrrrrrrrGC Cationic NA datio NA Linear NO: 0404

[2803] n -5.06 SEQ ID RRRRRRRRHHH Cationic Free NA NA Linear NO: 0405 -7.25 SEQ ID RRRRRRRRK Cationic Free Free NA Linear NO: 0406 -6.15

[2804] Ami

[2805] SEQ ID

[2806] rRRRRRRRr Cationic Free datio NA Linear NO: 0407

[2807] n -6.46 Ami

[2808] SEQ ID

[2809] rRrRrRrRr Cationic Free datio NA Linear NO: 0408

[2810] n -6.46 Ami

[2811] SEQ ID

[2812] rrrrrrrrr Cationic Free datio NA Linear NO: 0409

[2813] n -6.46 SEQ ID

[2814] rrrrrrrrr Cationic Free Free NA Linear NO: 0409 -7.11 SEQ ID Cyst

[2815] RRRRRRRRRC Cationic Free NA Linear

[2816]

[2817] NO: 0410 eine -6.28 ATTORNEY DOCKET: 05336.0007WO01

[2818] addit

[2819] ion

[2820] SEQ ID

[2821] rrrrrrrrrcqcrrkn Cationic Free Free NA Linear NO: 0411 -8.18 SEQ ID RRRRRRRRRGD Cationic Free Free NA Linear NO: 0412 -7.61 RRRRRRRRRHH SEQ ID

[2822] Cationic Free NA NA Linear

[2823] H NO: 0413 -8.04

[2824] Acet

[2825] SEQ ID

[2826] rrrrrrrrrk Cationic ylatio Free NA Linear NO: 0414

[2827] n -5.51 Ami

[2828] SEQ ID RRRRRRRRRR Cationic NA datio NA Linear NO: 0415

[2829] n -7.25 Ami

[2830] SEQ ID RRRRRRRRRRR Cationic Free datio NA Linear NO: 0416

[2831] n -8.04 SEQ ID RRRRRRRRRRR Cationic Free Free NA Linear NO: 0416 -8.69

[2832] Ami

[2833] SEQ ID

[2834] rrrrrrrrrrrr Cationic NA datio NA Linear NO: 0417

[2835] n -8.83 RRRRRRRRRRR SEQ ID

[2836] Cationic Free Free NA Linear

[2837] R NO: 0418 -9.48

[2838] Ami

[2839] RRRRRRRRRRR SEQ ID

[2840] Cationic NA datio NA Linear RGC NO: 0419

[2841] n -8.22 Ami

[2842] SEQ ID

[2843] rrrrrrrrrrrrGC Cationic NA datio NA Linear NO: 0420

[2844] n -8.22 Acet Ami

[2845] RRRRRRRRRRR SEQ ID

[2846] Cationic ylatio datio NA Linear RRRR NO: 0421

[2847] n n -9.77 RRRRRRRRRRR SEQ ID

[2848] Cationic Free Free NA Linear RRRRR NO: 0422 -12.6

[2849] Ami

[2850] RRRRRRRRRRR SEQ ID

[2851] Cationic NA datio NA Linear RRRRRGC NO: 0423

[2852] n -11.4 Ami

[2853] SEQ ID RRRRRRRW Cationic Free datio NA Linear NO: 0424

[2854] n -3.42 Ami

[2855] RRRRWWWWR SEQ ID

[2856] Cationic Free datio NA Linear RRR NO: 0425

[2857] n 0.17 Ami

[2858] RRVTSWLGRQL SEQ ID

[2859] Cationic Free datio NA Linear RIAGKRLEGRSK NO: 0426

[2860]

[2861] n -2.3 ATTORNEY DOCKET: 05336.0007WO01

[2862] RRVWRRYRRQ SEQ ID

[2863] Cationic Free Free NA Linear RWCRR NO: 0427 -2.83 RRWRRWNRFN SEQ ID

[2864] Cationic Free Free NA Linear RRRCR NO: 0428 -4.16

[2865] Ami

[2866] SEQ ID

[2867] rsrgrlrrgairlqrg Cationic Free datio NA Linear NO: 0429

[2868] n -4.3 Ami

[2869] SEQ ID RTRRNRRRVR Cationic Free datio NA Linear NO: 0430

[2870] n -5.8 Ami

[2871] RVRSWLGRQLR SEQ ID

[2872] Cationic Free datio NA Linear IAGKRLEGRSK NO: 0431

[2873] n -2.04 Ami RVTSWLGRQLRI SEQ ID

[2874] Cationic Free datio NA Linear AGKRLEGRSK NO: 0432

[2875] n -1.51 SEQ ID RWRCKNQN Cationic Free Free NA Linear NO: 0433 -1.42

[2876] Ami

[2877] RWRRWRRWRR SEQ ID

[2878] Cationic Free datio NA Linear WR NO: 0434

[2879] n 0.17 SEQ ID RWRWRWRW Cationic Free Free NA Linear NO: 0435 2.68

[2880] X,

[2881] 6- am

[2882] ino

[2883] he

[2884] xa

[2885] noi

[2886] c

[2887] aci RXRRBRRXRRB SEQ ID d

[2888] Cationic NA NA Linear RXB NO: 0436 (Ah

[2889] x)

[2890] an

[2891] d

[2892] B,

[2893] Bet

[2894] a- Ala

[2895] nin

[2896] e -9.02 X,

[2897] Ami am RXRRXRAAAAA SEQ ID

[2898] Cationic Free datio ino Linear RXRRXR NO: 0437

[2899] n he

[2900]

[2901] xyl -7.02 ATTORNEY DOCKET: 05336.0007WO01

[2902] res

[2903] idu

[2904] e

[2905] X,

[2906] am

[2907] ino

[2908] Ami

[2909] RXRRXRFLQIYR SEQ ID he

[2910] Cationic Free datio Linear XRRXR NO: 0438 xyl

[2911] n

[2912] res

[2913] idu

[2914] e -2.8 X,

[2915] am

[2916] ino

[2917] Ami

[2918] RXRRXRIEFQYR SEQ ID he

[2919] Cationic Free datio Linear XRRXR NO: 0439 xyl

[2920] n

[2921] res

[2922] idu

[2923] e -4.6 X,

[2924] am

[2925] ino

[2926] Ami

[2927] RXRRXRIKFQYR SEQ ID he

[2928] Cationic Free datio Linear XRRXR NO: 0440 xyl

[2929] n

[2930] res

[2931] idu

[2932] e -3.43 X,

[2933] am

[2934] ino

[2935] Ami

[2936] RXRRXRILFQYK SEQ ID he

[2937] Cationic Free datio Linear KWKMR NO: 0441 xyl

[2938] n

[2939] res

[2940] idu

[2941] e 2.05 X,

[2942] am

[2943] ino

[2944] Ami

[2945] RXRRXRILFQYR SEQ ID he

[2946] Cationic Free datio Linear MKWKK NO: 0442 xyl

[2947] n

[2948] res

[2949] idu

[2950] e 2.05 X,

[2951] Ami am RXRRXRILFQYR SEQ ID

[2952] Cationic Free datio ino Linear XRRXR NO: 0443

[2953] n he

[2954]

[2955] xyl -2.8 ATTORNEY DOCKET: 05336.0007WO01

[2956] res

[2957] idu

[2958] e

[2959] X,

[2960] am

[2961] ino

[2962] Ami

[2963] RXRRXRIPFQYR SEQ ID he

[2964] Cationic Free datio Linear XRRXR NO: 0444 xyl

[2965] n

[2966] res

[2967] idu

[2968] e -3.45 X,

[2969] am

[2970] ino

[2971] Ami

[2972] RXRRXRIWFQY SEQ ID he

[2973] Cationic Free datio Linear RXRRXR NO: 0445 xyl

[2974] n

[2975] res

[2976] idu

[2977] e -2.14 X,

[2978] 6- am

[2979] ino

[2980] he

[2981] xa

[2982] noi

[2983] c

[2984] aci RXRRXRRXRRX SEQ ID d

[2985] Cationic NA NA Linear RXB NO: 0446 (Ah

[2986] x)

[2987] an

[2988] d

[2989] B,

[2990] Bet

[2991] a- Ala

[2992] nin

[2993] e -9.02 X,

[2994] am

[2995] ino

[2996] Ami

[2997] RXRRXRYQFLIR SEQ ID he

[2998] Cationic Free datio Linear XRRXR NO: 0447 xyl

[2999] n

[3000] res

[3001] idu

[3002]

[3003] e -2.8 ATTORNEY DOCKET: 05336.0007WO01

[3004] X,

[3005] 6- am

[3006] ino

[3007] he

[3008] xa

[3009] noi

[3010] c

[3011] aci RXRXRXRXRXR SEQ ID d

[3012] Cationic NA NA Linear XRXRXB NO: 0448 (Ah

[3013] x)

[3014] an

[3015] d

[3016] B,

[3017] Bet

[3018] a- Ala

[3019] nin

[3020] e -9.02 X,

[3021] 1- am

[3022] ino

[3023] eye

[3024] lop

[3025] ent

[3026] an

[3027] Ami

[3028] SEQ ID e- RXXRXRXX Cationic Free datio Linear NO: 0449 1- n

[3029] car

[3030] bo

[3031] xyli

[3032] c

[3033] aci

[3034] ds

[3035] (Ac

[3036] 5c) -1.72 Ami

[3037] SEQ ID SKKKKTKV Cationic Free datio NA Linear NO: 0450

[3038] n 1.11 SQMTRQARRLY SEQ ID

[3039] Cationic Free Free NA Linear BGC NO: 0451 -1.56

[3040] SEQ ID SRRRRRRRRR Cationic NA NA NA Linear NO: 0452 -7.56

[3041] Ami X, SXRSXRILFQYS SEQ ID

[3042] Cationic Free datio am Linear XRSXR NO: 0453

[3043]

[3044] n ino -1.44 ATTORNEY DOCKET: 05336.0007WO01

[3045] he

[3046] xyl

[3047] res

[3048] idu

[3049] e TAKTRYKARRAE SEQ ID

[3050] Cationic Free Free NA Linear LIAERRGC NO: 0454

[3051] -4.55 TRQARRNRRRR SEQ ID

[3052] Cationic Free Free NA Linear WRERQR NO: 0455

[3053] -9.63 TRQARRNRRRR SEQ ID

[3054] Cationic Free Free NA Linear WRERQRGC NO: 0456

[3055] -9.02 TRRQRTRRARR SEQ ID

[3056] Cationic Free Free NA Linear NRGC NO: 0457 -7.82

[3057] Ami

[3058] TRRSKRRSHRK SEQ ID

[3059] Cationic Free datio NA Linear

[3060] F NO: 0458

[3061] n -3.27 SEQ ID VQLRRRWC Cationic Free Free NA Linear NO: 0459 0.7

[3062] Ami

[3063] SEQ ID VQRKRQKLMP Cationic Free datio NA Linear NO: 0460

[3064] n 0.51 VSRRRRRRGGR SEQ ID

[3065] Cationic Free Free NA Linear RRR NO: 0461 -8.47

[3066] Sul

[3067] Sulfh fhy VSRRRRRRGGR SEQ ID

[3068] Cationic ydryl Free dry Linear RRR NO: 0461

[3069] ation lati

[3070] on -8.47 VSRRRRRRGGR SEQ ID

[3071] Cationic Free Free NA Linear RRRK NO: 0462 -8.3 VVLGKLYGRKK SEQ ID

[3072] Cationic Free Free NA Linear RRQRRR NO: 0463 -2.22 WEAVVAYGRKK SEQ ID

[3073] Cationic Free Free NA Linear RRQRRR NO: 0464 -3.85 WEAVVLYGRKK SEQ ID

[3074] Cationic Free Free NA Linear RRQRRR NO: 0465 -2.78 WELVVAYGRKK SEQ ID

[3075] Cationic Free Free NA Linear RRQRRR NO: 0466 -2.78 WELVVLGKLYG SEQ ID

[3076] Cationic Free Free NA Linear RKKRRQRRR NO: 0467

[3077] -0.96 WELVVLGKYGR SEQ ID

[3078] Cationic Free Free NA Linear KKRRQRRR NO: 0468

[3079]

[3080] -1.76 ATTORNEY DOCKET: 05336.0007WO01

[3081] WELVVLGYGRK SEQ ID

[3082] Cationic Free Free NA Linear KRRQRRR NO: 0469

[3083] -1.93 WELVVYGRKKR SEQ ID

[3084] Cationic Free Free NA Linear RQRRR NO: 0470 -2.51 WELVYGRKKRR SEQ ID

[3085] Cationic Free Free NA Linear QRRR NO: 0471 -2.83 WELYGRKKRRQ SEQ ID

[3086] Cationic Free Free NA Linear RRR NO: 0472 -3.15 WEYGRKKRRQR SEQ ID

[3087] Cationic Free Free NA Linear RR NO: 0473 -3.95

[3088] Ami

[3089] SEQ ID WRRRRRRRR Cationic Free datio NA Linear NO: 0474

[3090] n -4.21 SEQ ID

[3091] [WRWKKKKA] Cationic NA NA NA Cyclic NO: 0475 2.54

[3092] Ami

[3093] SEQ ID WWRRRRRRRR Cationic Free datio NA Linear NO: 0476

[3094] n -2.75 Ami WWWRRRRRRR SEQ ID

[3095] Cationic Free datio NA Linear

[3096] R NO: 0477

[3097] n -1.29 Ami

[3098] WWWWRRRRR SEQ ID

[3099] Cationic Free datio NA Linear RRR NO: 0478

[3100] n 0.17 SEQ ID YARVRRRGPRR Cationic Free Free NA Linear NO: 0479 -4.21 YGDCLPHLKLCK SEQ ID ENKDCCSKKCK Cationic Free Free NA Linear NO: 0480

[3101] RRGTNIEKRCR

[3102] 0.83 YGRGGRRGRR SEQ ID

[3103] Cationic Free Free NA Linear

[3104] R NO: 0481 -5.07 YGRKKKRRQRR SEQ ID

[3105] Cationic Free Free NA Linear

[3106] R NO: 0482 -4.24

[3107] SEQ ID YGRKKRPQRRR Cationic NA NA NA Linear NO: 0483 -3.47 YGRKKRRQRRR SEQ ID AYFNGCSSPTA Cationic Free Free NA Linear NO: 0484

[3108] PLSPMSP

[3109] -3.76 Cyst YGRKKRRQRRR SEQ ID eine

[3110] Cationic Free NA Linear

[3111] 0 NO: 0485 addit

[3112] ion -3.58 YGRKKRRQRRR SEQ ID

[3113] Cationic Free Free NA Linear

[3114]

[3115] 0 NO: 0485 -3.58 ATTORNEY DOCKET: 05336.0007WO01

[3116] YGRKKRRQRRR DPYHATSGALSP SEQ ID AKDCGSQKYAY Cationic Free Free NA Linear NO: 0486

[3117] FNGCSSPTLSP MSP

[3118] -4.34 Ami YGRKKRRQRRR SEQ ID

[3119] Cationic Free datio NA Linear GO NO: 0487

[3120] n -3.15 YGRKKRRQRRR SEQ ID

[3121] Cationic Free Free NA Linear PPQG NO: 0488 -4.67 YGRKKRRQRRR SEQ ID QRRRPTAPLSP Cationic Free Free NA Linear NO: 0489

[3122] MSP -6.64

[3123] SEQ ID YRWRCKNQ Cationic Free Free NA Linear NO: 0490 0.11 SEQ ID YRWRCKNQN Cationic Free Free NA Linear NO: 0491 -0.87 YYYAAGRKRKK SEQ ID

[3124] Cationic Free Free NA Linear

[3125] RT NO: 0492 -1.23

[3126] SEQ ID RRRRRHHH Cationic Free NA NA Linear NO: 0493 -4.88 SEQ ID

[3127] rrrrrrrr Cationic Free Free NA Linear NO: 0494 -6.32 SEQ ID

[3128] rRrRrRRR Cationic NA NA NA Linear NO: 0495 -6.32 SEQ ID

[3129] rRRRRRRR Cationic NA NA NA Linear NO: 0496 -6.32

[3130] Cyst

[3131] CAYGRKKRRQR SEQ ID eine

[3132] Cationic Free NA Linear RR NO: 0497 additi

[3133] on -3.85 CAYGRKKRRQR SEQ ID

[3134] Cationic Free Free NA Linear RR NO: 0497 -3.85

[3135] SEQ ID

[3136] rRrGrKkRr Cationic Free Free NA Linear NO: 0498 -4.62

[3137] B,

[3138] SEQ ID

[3139] Bet

[3140] NO: 0499 Ami

[3141] B-[ERRRK]-(B)2- a- Cationic and SEQ Free datio Cyclic [KRRRE] Ala

[3142] ID NO: n

[3143] nin

[3144] 0500

[3145] e -8.45 B,

[3146] SEQ ID

[3147] Bet

[3148] NO: 0499 Ami

[3149] B-[ERRRK]-(B)3- a- Cationic and SEQ Free datio Cyclic [KRRRE] Ala

[3150] ID NO: n

[3151] nin

[3152] 0500

[3153]

[3154] e -8.45 ATTORNEY DOCKET: 05336.0007WO01

[3155] B,

[3156] SEQ ID

[3157] Bet

[3158] NO: 0499 Ami

[3159] B-[ERRRK]- a- Cationic and SEQ Free datio Cyclic [KRRRE] Ala

[3160] ID NO: n

[3161] nin

[3162] 0500

[3163] e -8.45 B,

[3164] SEQ ID

[3165] Bet

[3166] NO: 0499 Ami

[3167] B-[ERRRK]-B- a- Cationic and SEQ Free datio Cyclic [KRRRE] Ala

[3168] ID NO: n

[3169] nin

[3170] 0500

[3171] e -11.2 B,

[3172] SEQ ID

[3173] Bet

[3174] NO: 0501 Ami

[3175] B-RRR- a- Cationic and SEQ Free datio Cyclic [KRRRRE] Ala

[3176] ID NO: n

[3177] nin

[3178] 0093

[3179] e -8.41 B,

[3180] SEQ ID

[3181] Bet

[3182] NO: 0502 Ami

[3183] B-RRRR- a- Cationic and SEQ Free datio Cyclic [KRRRE] Ala

[3184] ID NO: n

[3185] nin

[3186] 0500

[3187] e -8.41 X,

[3188] 6- am

[3189] ino

[3190] SEQ ID

[3191] he

[3192] CGRKKR-Ahx- NO: 0504

[3193] xa

[3194] RQR-Ahx-R-ahx- Cationic and SEQ Free Free Linear noi

[3195] RPPQ ID NO:

[3196] c

[3197] 0503

[3198] aci

[3199] d

[3200] (Ah

[3201] x) -12.3 X,

[3202] 6- am

[3203] ino

[3204] SEQ ID

[3205] he

[3206] NO: 0504

[3207] CGRKKR-Ahx- xa

[3208] Cationic and SEQ Free Free Linear RQRRRPPQ noi

[3209] ID NO:

[3210] c

[3211] 0505

[3212] aci

[3213] d

[3214] (Ah

[3215]

[3216] x) -6.87 ATTORNEY DOCKET: 05336.0007WO01

[3217] X,

[3218] 6- am

[3219] ino

[3220] SEQ ID

[3221] he

[3222] NO: 0506

[3223] CGRKKRRQR- xa

[3224] Cationic and SEQ Free Free Linear Ahx-RRPPQ noi

[3225] ID NO:

[3226] c

[3227] 0507

[3228] aci

[3229] d

[3230] (Ah

[3231] x) -6.87 X,

[3232] 6- am

[3233] ino

[3234] SEQ ID

[3235] he

[3236] NO: 0508

[3237] CGRKKRRQRR- xa

[3238] Cationic and SEQ Free Free Linear Ahx-RPPQ noi

[3239] ID NO:

[3240] c

[3241] 0503

[3242] aci

[3243] d

[3244] (Ah

[3245] x) -6.87 Probably Ami

[3246] ALIILRRRIRKQA SEQ ID

[3247] Amphipathi Free datio NA Linear HAHSK NO: 0513

[3248] c n -0.69 Probably Ami AQIKIWFQNRRM SEQ ID

[3249] Amphipathi Free datio NA Linear KWKK NO: 0514

[3250] c n 3.81 Probably Ami

[3251] SEQ ID FQNRRMKWKK Amphipathi Free datio NA Linear NO: 0515

[3252] c n 1.39 Probably Ami

[3253] IKIWFQNRRMK SEQ ID

[3254] Amphipathi Free datio NA Linear WKK NO: 0516

[3255] c n 4.42 Probably Ami

[3256] IWFQNRRMKWK SEQ ID

[3257] Amphipathi Free datio NA Linear

[3258] K NO: 0517

[3259] c n 3.55 Probably Ami

[3260] KIWFQNRRMKW SEQ ID

[3261] Amphipathi Free datio NA Linear KK NO: 0518

[3262] c n 3.72 Probably Ami KSHAHAQKRIRR SEQ ID

[3263] Amphipathi Free datio NA Linear RLIILL NO: 0519

[3264] c n 0.38 Probably Ami

[3265] LAIILRRRIRKQA SEQ ID

[3266] Amphipathi Free datio NA Linear HAHSK NO: 0520

[3267]

[3268] c n -0.69 ATTORNEY DOCKET: 05336.0007WO01

[3269] Probably Ami

[3270] LLAILRRRIRKQA SEQ ID

[3271] Amphipathi Free datio NA Linear HAHSK NO: 0521

[3272] c n -0.59 Probably Ami

[3273] LLIALRRRIRKQA SEQ ID

[3274] Amphipathi Free datio NA Linear HAHSK NO: 0522

[3275] c n -0.59 Probably Ami

[3276] LLIIARRRIRKQA SEQ ID

[3277] Amphipathi Free datio NA Linear HAHSK NO: 0523

[3278] c n -0.69 Probably Ami

[3279] LLIILARRIRKQA SEQ ID

[3280] Amphipathi Free datio NA Linear HAHSK NO: 0524

[3281] c n 0.9 Probably Ami

[3282] LLIILRARIRKQA SEQ ID

[3283] Amphipathi Free datio NA Linear HAHSK NO: 0525

[3284] c n 0.9 Probably Ami

[3285] LLIILRRAIRKQA SEQ ID

[3286] Amphipathi Free datio NA Linear HAHSK NO: 0526

[3287] c n 0.9 Probably Ami

[3288] LLIILRRRARKQA SEQ ID

[3289] Amphipathi Free datio NA Linear HAHSK NO: 0527

[3290] c n -0.59 Probably Ami

[3291] LLIILRRRIARKQ SEQ ID

[3292] Amphipathi Free datio NA Linear AHAHSK NO: 0528

[3293] c n 0.11 Probably Ami

[3294] LLIILRRRIRAQA SEQ ID

[3295] Amphipathi Free datio NA Linear HAHSK NO: 0529

[3296] c n -0.06 Probably Ami

[3297] LLIILRRRIRKAA SEQ ID

[3298] Amphipathi Free datio NA Linear HAHSK NO: 0530

[3299] c n 0.45 Probably Ami

[3300] LLIILRRRIRKQA SEQ ID

[3301] Amphipathi Free datio NA Linear AAHSK NO: 0531

[3302] c n 0.42 Probably Ami

[3303] LLIILRRRIRKQA SEQ ID

[3304] Amphipathi Free datio NA Linear HAASK NO: 0532

[3305] c n 0.42 Probably Ami

[3306] LLIILRRRIRKQA SEQ ID

[3307] Amphipathi Free datio NA Linear HAHAK NO: 0533

[3308] c n 0.56 Probably Ami

[3309] LLIILRRRIRKQA SEQ ID

[3310] Amphipathi Free datio NA Linear HAHSA NO: 0534

[3311] c n -0.06 Probably Ami QIKIWFQNRRMK SEQ ID

[3312] Amphipathi Free datio NA Linear WKK NO: 0535

[3313] c n 4.08 Probably Ami

[3314] RAIKIWFQNRRM SEQ ID

[3315] Amphipathi Free datio NA Linear KWKK NO: 0536

[3316]

[3317] c n 3.36 ATTORNEY DOCKET: 05336.0007WO01

[3318] Probably Ami

[3319] RQAKIWFQNRR SEQ ID

[3320] Amphipathi Free datio NA Linear MKWKK NO: 0537

[3321] c n 2.32 Probably Ami

[3322] RQIAIWFQNRRM SEQ ID

[3323] Amphipathi Free datio NA Linear KWKK NO: 0538

[3324] c n 2.85 Probably Ami

[3325] RQIKAWFQNRR SEQ ID

[3326] Amphipathi Free datio NA Linear MKWKK NO: 0539

[3327] c n 2.32 Probably Ami

[3328] RQIKIAFQNRRM SEQ ID

[3329] Amphipathi Free datio NA Linear KWKK NO: 0540

[3330] c n 1.56 Probably Ami

[3331] RQIKIWAQNRR SEQ ID

[3332] Amphipathi Free datio NA Linear MKWKK NO: 0541

[3333] c n 1.86 Probably Ami

[3334] RQIKIWFANRRM SEQ ID

[3335] Amphipathi Free datio NA Linear KWKK NO: 0542

[3336] c n 3.36 Probably Ami

[3337] RQIKIWFQARRM SEQ ID

[3338] Amphipathi Free datio NA Linear KWKK NO: 0543

[3339] c n 4 Probably Ami

[3340] RQIKIWFQNARM SEQ ID

[3341] Amphipathi Free datio NA Linear KWKK NO: 0544

[3342] c n 3.81 Probably Ami

[3343] RQIKIWFQNRAM SEQ ID

[3344] Amphipathi Free datio NA Linear KWKK NO: 0545

[3345] c n 3.81 Probably Ami

[3346] SEQ ID RQIKIWFQNRR Amphipathi Free datio NA Linear NO: 0546

[3347] c n 0.81 Probably Ami

[3348] RQIKIWFQNRRA SEQ ID

[3349] Amphipathi Free datio NA Linear KWKK NO: 0547

[3350] c n 2.51 Probably Ami

[3351] SEQ ID RQIKIWFQNRRM Amphipathi Free datio NA Linear NO: 0548

[3352] c n 1.32 Probably Ami

[3353] RQIKIWFQNRRM SEQ ID

[3354] Amphipathi Free datio NA Linear AWKK NO: 0549

[3355] c n 2.85 Probably Ami

[3356] RQIKIWFQNRRM SEQ ID

[3357] Amphipathi Free datio NA Linear

[3358] K NO: 0550

[3359] c n 1.49 Probably Ami

[3360] RQIKIWFQNRRM SEQ ID

[3361] Amphipathi Free datio NA Linear KAKK NO: 0551

[3362] c n 1.56 Probably Ami

[3363] RQIKIWFQNRRM SEQ ID

[3364] Amphipathi Free datio NA Linear

[3365] KW NO: 0552

[3366]

[3367] c n 2.95 ATTORNEY DOCKET: 05336.0007WO01

[3368] Probably Ami

[3369] RQIKIWFQNRRM SEQ ID

[3370] Amphipathi Free datio NA Linear KWAK NO: 0553

[3371] c n 2.85 Probably Ami

[3372] RQIKIWFQNRRM SEQ ID

[3373] Amphipathi Free datio NA Linear KWK NO: 0554

[3374] c n 3.12 Probably Ami

[3375] RQIKIWFQNRRM SEQ ID

[3376] Amphipathi Free datio NA Linear KWKA NO: 0555

[3377] c n 2.85 Probably Ami WFQNRRMKWK SEQ ID

[3378] Amphipathi Free datio NA Linear

[3379] K NO: 0556

[3380] c n 2.85

[3381] L- CF

[3382] 3- Bp

[3383] g,

[3384] Trif

[3385] luo

[3386] ro

[3387] me

[3388] thyl

[3389] Ami

[3390] a-CF3-Bpg- Amphipathi SEQ ID

[3391] Free datio Linear lyllgkinlkalaalakkil c NO: 0557 bic

[3392] n

[3393] ycl

[3394] op

[3395] ent

[3396] [1 - 1.1

[3397] ]-1- yigi

[3398] yci

[3399] ne 8.25 L- CF

[3400] 3- Bp

[3401] g,

[3402] Trif

[3403] A-CF3-Bpg- Ami luo Amphipathi SEQ ID

[3404] LYLLGKINLKALA Free datio ro Linear

[3405] c NO: 0558

[3406] ALAKKIL n me

[3407] thyl

[3408] bic

[3409] ycl

[3410] op

[3411]

[3412] ent 8.25 ATTORNEY DOCKET: 05336.0007WO01

[3413] [1 - 1.1

[3414] ]-1- yigi

[3415] yci

[3416] ne

[3417] Ph

[3418] os

[3419] Stear Ami AGY(PO3)LLGKI Amphipathi SEQ ID

[3420] ylatio datio Ph Linear NLKALAALAKKIL c NO: 0559 ory

[3421] n n

[3422] lati

[3423] on 13.96 Ph

[3424] os AGY(PO3)LLGKT Stear Ami

[3425] Amphipathi SEQ ID

[3426] (PO3)NLKALAAL ylatio datio Ph Linear

[3427] c NO: 0560 ory

[3428] AKKIL n n

[3429] lati

[3430] on 13.15 Ph

[3431] os

[3432] Stear Ami AGY(PO3)LLGKT Amphipathi SEQ ID

[3433] ylatio datio Ph Linear NLKALAALAKKIL c NO: 0561 ory

[3434] n n

[3435] lati

[3436] on 13 L- CF

[3437] 3- Bp

[3438] g,

[3439] Trit

[3440] luo

[3441] ro

[3442] me

[3443] thyl

[3444] Ami

[3445] agy-CF3-Bpg- Amphipathi SEQ ID

[3446] Free datio Linear Igkinlkalaalakkil c NO: 0562 bic

[3447] n

[3448] ycl

[3449] op

[3450] ent

[3451] [1 - 1.1

[3452] ]-1- yigi

[3453] yci

[3454]

[3455] ne 6.43 ATTORNEY DOCKET: 05336.0007WO01

[3456] L- CF

[3457] 3- Bp

[3458] g,

[3459] Trit

[3460] luo

[3461] ro

[3462] me

[3463] thyl

[3464] AGY-CF3-Bpg- Ami

[3465] Amphipathi SEQ ID

[3466] LGKINLKALAALA Free datio Linear

[3467] c NO: 0563 bic

[3468] KKIL n

[3469] ycl

[3470] op

[3471] ent

[3472] [1 - 1.1

[3473] ]-1- yigi

[3474] yci

[3475] ne 6.43 0,

[3476] AGYLLG)5- Stear Or Amphipathi SEQ ID

[3477] OINLKALAALAK ylatio Free nit Linear

[3478] c NO: 0564

[3479] KIL n hin

[3480] e 12.99 0,

[3481] Stear Ami Or AGYLLGOINLKA Amphipathi SEQ ID

[3482] ylatio datio nit Linear LAALAKKIL c NO: 0564

[3483] n n hin

[3484] e 13.64 0,

[3485] 6 - (Stearyl- Stear Ami Or

[3486] AGYLLG) Amphipathi SEQ ID

[3487] ylatio datio nit Linear OINLKALAALAK c NO: 0564

[3488] n n hin

[3489] KIL

[3490] e 12.22 Ort

[3491] ho

[3492] go

[3493] nail AGYLLGK(Steary Stear Ami y

[3494] Amphipathi SEQ ID ste l)INLKALAALAKK ylatio datio Linear

[3495] c NO: 0565 ary

[3496] IL n n

[3497] I at

[3498] ed

[3499] on

[3500] Lys

[3501]

[3502] 12.39 ATTORNEY DOCKET: 05336.0007WO01

[3503] sa:

[3504] sue

[3505] cini

[3506] co

[3507] aci

[3508] d,

[3509] qn:

[3510] no

[3511] vel

[3512] 2-4

[3513] rin

[3514] g

[3515] sys

[3516] te

[3517] ms AGYLLGK[KK2sa Stear Ami

[3518] Amphipathi SEQ ID sue 4qn4]INLKALAAL ylatio datio Linear

[3519] c NO: 0566 h

[3520] AKKIL n n

[3521] as

[3522] qui

[3523] noli

[3524] ne

[3525] an

[3526] d

[3527] na

[3528] pht

[3529] hal

[3530] en

[3531] e

[3532] an

[3533] alo

[3534] gu

[3535] es 12.11 Acet Ami

[3536] AGYLLGKINLKA Amphipathi SEQ ID

[3537] ylatio datio NA Linear LAALAKKIL c NO: 0567

[3538] n n 6.74 Ami

[3539] AGYLLGKINLKA Amphipathi SEQ ID

[3540] Free datio NA Linear LAALAKKIL c NO: 0567

[3541] n 5.31 AGYLLGKINLKA Amphipathi SEQ ID

[3542] Free Free NA Linear LAALAKKIL c NO: 0567

[3543] 4.66 Stear Ami

[3544] AGYLLGKINLKA Amphipathi SEQ ID

[3545] ylatio datio NA Linear LAALAKKIL c NO: 0567

[3546] n n 13.81 Stear

[3547] AGYLLGKINLKA Amphipathi SEQ ID

[3548] ylatio Free NA Linear LAALAKKIL c NO: 0567

[3549]

[3550] n 13.16 ATTORNEY DOCKET: 05336.0007WO01

[3551] £ - (Steary- Stear Ami

[3552] Amphipathi SEQ ID

[3553] AGYLLG)KINLKA ylatio datio NA Linear

[3554] c NO: 0567

[3555] LAALAKKIL n n

[3556] 11.59 AGYLLGKINLKA Amphipathi SEQ ID

[3557] Free Free NA Linear LAALAKKILGGC c NO: 0568

[3558] 5.05 AGYLLGKLKALA Amphipathi SEQ ID

[3559] Free Free NA Linear ALAKKIL c NO: 0569 4.94

[3560] Ph

[3561] os

[3562] Stear Ami AGYLLGKT(PO3) Amphipathi SEQ ID

[3563] ylatio datio Ph Linear NLKALAALAKKIL c NO: 0570 ory

[3564] n n

[3565] lati

[3566] on 13 AHALCLTERQIKI

[3567] Amphipathi SEQ ID

[3568] WFQNRRMKWK Free Free NA Linear

[3569] c NO: 0571

[3570] KEN 0.98 AHALCPPERQIKI

[3571] Amphipathi SEQ ID

[3572] WFQNRRMKWK Free Free NA Linear

[3573] c NO: 0572

[3574] KEN 0.74 ALWMRWYSPTT Amphipathi SEQ ID

[3575] Free Free NA Linear RRYG c NO: 0573 1.65 AYALCLTERQIKI

[3576] Amphipathi SEQ ID

[3577] WFANRRMKWK Free Free NA Linear

[3578] c NO: 0574

[3579] KEN 1.91

[3580] Ami AYLLGKINLKALA Amphipathi SEQ ID

[3581] Free datio NA Linear ALAKKIL c NO: 0575

[3582] n 5.53 B,

[3583] Bet

[3584] a- Ala

[3585] nin

[3586] e;

[3587] Ami X,

[3588] Amphipathi SEQ ID

[3589] BrrXrrXrrX Free datio ct- Linear

[3590] c NO: 0576

[3591] n am

[3592] ino

[3593] iso

[3594] but

[3595] yric

[3596] aci

[3597]

[3598] d -6.79 ATTORNEY DOCKET: 05336.0007WO01

[3599] B,

[3600] Bet

[3601] a- Ala

[3602] nin

[3603] e;

[3604] Ami X, Amphipathi SEQ ID

[3605] BRRXRRXRRX Free datio ct- Linear

[3606] c NO: 0577

[3607] n am

[3608] ino

[3609] iso

[3610] but

[3611] yric

[3612] aci

[3613] d -6.79 B,

[3614] Bet

[3615] a- Ala

[3616] nin

[3617] e;

[3618] Ami X, Amphipathi SEQ ID

[3619] BRrXRrXRrX Free datio a- Linear

[3620] c NO: 0578

[3621] n am

[3622] ino

[3623] iso

[3624] but

[3625] yric

[3626] aci

[3627] d -6.79 B,

[3628] Bet

[3629] a- Ala

[3630] nin

[3631] e;

[3632] Ami X, BXRXRXXRXRX Amphipathi SEQ ID

[3633] Free datio ci- Linear XRXRX c NO: 0579

[3634] n am

[3635] ino

[3636] iso

[3637] but

[3638] yric

[3639] aci

[3640] d -6.79 CIGAVLKVLTTG

[3641] Amphipathi SEQ ID

[3642] LPALISWIKRKR Free Free NA Linear

[3643] c NO: 0580

[3644]

[3645] QQ 4.68 ATTORNEY DOCKET: 05336.0007WO01

[3646] CLLYWFRRRHR Amphipathi SEQ ID

[3647] Free Free NA Linear HHRRRHRRC c NO: 0581

[3648] -1.92 Unk

[3649] CRQIKIWFPNRR Amphipathi SEQ ID

[3650] Free now NA Linear MKWKKC c NO: 0582

[3651] n 4.79 CRQIKIWFQNRR Acet Ami

[3652] Amphipathi SEQ ID

[3653] MKWKKKLAKLA ylatio datio NA Linear

[3654] c NO: 0583

[3655] KKLAKLAK n n

[3656] 8.69 Ami

[3657] Amphipathi SEQ ID

[3658] [FRRRRQ] Free datio NA Cyclic

[3659] c NO: 0584

[3660] n 1.32 DAATARGRGRS AASRPTERPRA Amphipathi SEQ ID

[3661] Free Free NA Linear PARSASRPRRP c NO: 0585

[3662] VD -13.3 DPKGDPKGVTV

[3663] Amphipathi SEQ ID

[3664] TVTVTVTGKGDP Free NA NA Linear

[3665] c NO: 0586

[3666] KPD -0.42 DSLKSYWYLQK Amphipathi SEQ ID

[3667] Free Free NA Linear FSWR c NO: 0587 4.36 EKRPRTAFSSE QLARLKREFNEN RYLTTERRRQQ Amphipathi SEQ ID

[3668] Free Free NA Linear LSSELGLNEAQI c NO: 0588

[3669] KIWFQNKRAKIK KST

[3670] -10.6 Ami

[3671] ELALELALEALE Amphipathi SEQ ID

[3672] Free datio NA Linear AALELA c NO: 0589

[3673] n -0.37 FFKKLALHALHL

[3674] Amphipathi SEQ ID

[3675] LALLWLHLAHLA Free Free NA Linear

[3676] c NO: 0590

[3677] LKK 10.67 FKKLALHALHLL

[3678] Amphipathi SEQ ID

[3679] ALLWLHLAHLAL Free Free NA Linear

[3680] c NO: 0591

[3681] KK 9.51

[3682] Stear Ami

[3683] FLKLLKKFLKLFK Amphipathi SEQ ID

[3684] ylatio datio NA Linear KLLKLF c NO: 0592

[3685] n n 21.38 Cyst GALFLAFLAAAL Acet eami

[3686] Amphipathi SEQ ID

[3687] SLMGLWSQPKK ylatio de NA Linear

[3688] c NO: 0593

[3689] KRRV n grou

[3690]

[3691] P _ 7.19 ATTORNEY DOCKET: 05336.0007WO01

[3692] Cyst GALFLGFLGAAG Acet eami

[3693] Amphipathi SEQ ID

[3694] STMGAWSQPKS ylatio de NA Linear

[3695] c NO: 0594

[3696] KRKV n grou

[3697] P 4.48 GALFLGWLGAA

[3698] Amphipathi SEQ ID

[3699] GSTMGAPKKKR Free Free NA Linear

[3700] c NO: 0595

[3701] KV 3 GKKALKLAAKLL Amphipathi SEQ ID

[3702] Free Free NA Linear KKC c NO: 0596 4.02 GLFEALLELLESL Amphipathi SEQ ID

[3703] NA NA NA Linear WELLLEA c NO: 0597

[3704] 3.61 GLFKALLKLLKSL Amphipathi SEQ ID

[3705] NA NA NA Linear WKLLLKA c NO: 0598

[3706] 9.46 GLFRALLRLLRS Amphipathi SEQ ID

[3707] Free Free NA Linear LWRLLLRA c NO: 0599

[3708] 4.66 Ami GLKKLAELAHKL Amphipathi SEQ ID

[3709] Free datio NA Linear LKLGC c NO: 0600

[3710] n 4.67 Ami

[3711] GLKKLAELFHKL Amphipathi SEQ ID

[3712] Free datio NA Linear LKLGC c NO: 0601

[3713] n 6.1 Ami GLKKLARLAHKL Amphipathi SEQ ID

[3714] Free datio NA Linear LKLGC c NO: 0602

[3715] n 4.88 Ami GLKKLARLFHKL Amphipathi SEQ ID

[3716] Free datio NA Linear LKLGC c NO: 0603

[3717] n 6.31 Cyst

[3718] Acet eami GLWRALWRLLR Amphipathi SEQ ID

[3719] ylatio de NA Linear SLWRLLWRA c NO: 0604

[3720] n grou

[3721] P 8.01 Acet

[3722] GLWRALWRLLR Amphipathi SEQ ID

[3723] ylatio Free NA Linear SLWRLLWRA c NO: 0604

[3724] n 7.71 GLWWKAWWKA

[3725] Amphipathi SEQ ID

[3726] WWKSLWWRKR NA NA NA Linear

[3727] c NO: 0605

[3728] KRKA

[3729] 10.45 Acet

[3730] GLWWRLWWRL Amphipathi SEQ ID

[3731] ylatio Free NA Linear RSWFRLWFRA c NO: 0606

[3732]

[3733] n 10.82 ATTORNEY DOCKET: 05336.0007WO01

[3734] Amphipathi SEQ ID

[3735] GRKKRRQRRRP Free Free NA Linear

[3736] c NO: 0607 -4.81 GWTLNPAGYLL

[3737] Amphipathi SEQ ID

[3738] GKINLKALAALA Free Free NA Linear

[3739] c NO: 0608

[3740] KKIL 5.61 GWTLNPPGYLL

[3741] Amphipathi SEQ ID

[3742] GKINLKALAALA Free Free NA Linear

[3743] c NO: 0609

[3744] KKIL 6.03 GWTLNSAGYLL

[3745] Amphipathi SEQ ID

[3746] GKFLPLILRKIVT Free Free NA Linear

[3747] c NO: 0610

[3748] AL 7.04 GWTLNSAGYLL

[3749] Amphipathi SEQ ID

[3750] GKINLKALAALA Free Free NA Linear

[3751] c NO: 0611

[3752] KKLL 5.11 GWTLNSAGYLL

[3753] Amphipathi SEQ ID

[3754] GKINLKAPAALA Free Free NA Linear

[3755] c NO: 0612

[3756] KKIL 4.36 GWTLNSAGYLL

[3757] Amphipathi SEQ ID

[3758] GKLKALAALAKKI Free Free NA Linear

[3759] c NO: 0613

[3760] L 5.29 GWTLNSKINLKA Amphipathi SEQ ID

[3761] Free Free NA Linear LAALAKKIL c NO: 0614

[3762] 3.57 GYGNCRHFKQK Amphipathi SEQ ID

[3763] Free Free NA Linear PRRD c NO: 0615 -1.69 HEHEHEHEHEH EHEHEHEHEGG Amphipathi SEQ ID

[3764] Free NA NA Linear GGGKLALKLALK c NO: 0616

[3765] ALKAALKLA

[3766] -9.37 IPSRWKDQFWK Amphipathi SEQ ID

[3767] Free Free NA Linear RWHY c NO: 0617 4.32

[3768] Ami

[3769] KALAALLKKLAK Amphipathi SEQ ID

[3770] Free datio NA Linear LLAALK c NO: 0618

[3771] n 5.48 Ami KALAALLKKWAK Amphipathi SEQ ID

[3772] Free datio NA Linear LLAALK c NO: 0619

[3773] n 6.14 Ami KALAKALAKLWK Amphipathi SEQ ID

[3774] Free datio NA Linear ALAKAA c NO: 0620

[3775] n 4 Ami

[3776] KALKKLLAKWLA Amphipathi SEQ ID

[3777] Free datio NA Linear AAKALL c NO: 0621

[3778] n 6.14 Acet

[3779] KETWFETWFTE Amphipathi SEQ ID

[3780] ylatio Free NA Linear WSQPKKKRKV c NO: 0622

[3781]

[3782] n 4.09 ATTORNEY DOCKET: 05336.0007WO01

[3783] Acet

[3784] KETWWETWWT Amphipathi SEQ ID

[3785] ylatio Free NA Linear EWSQPKKKRKV c NO: 0623

[3786] n 4.69 KETWWETWWT Amphipathi SEQ ID

[3787] Free Free NA Linear EWSQPKKKRKV c NO: 0623

[3788] 3.26 KHKALHALHLLA

[3789] Amphipathi SEQ ID

[3790] LLWLHLAHLAKH Free Free NA Linear

[3791] c NO: 0624

[3792] K 6.13 KHKLLHLLHLLAL Amphipathi SEQ ID

[3793] Free Free NA Linear LWLHLLHLLKHK c NO: 0625

[3794] 10.41 Ami KIAAKSIAKIWKSI Amphipathi SEQ ID

[3795] Free datio NA Linear LKIA c NO: 0626

[3796] n 5.28 Ami

[3797] KITLKLAIKAWKL Amphipathi SEQ ID

[3798] Free datio NA Linear ALKAA c NO: 0627

[3799] n 5.95 KKALLAHALHLL

[3800] Amphipathi SEQ ID

[3801] ALLALHLAHALK Free Free NA Linear

[3802] c NO: 0628

[3803] KA 5.28 KKLALHALHLLA

[3804] Amphipathi SEQ ID

[3805] LLWLHLAHLALK Free Free NA Linear

[3806] c NO: 0629

[3807] K 8.35

[3808] Ami KLAAALLKKWKK Amphipathi SEQ ID

[3809] Free datio NA Linear LAAALL c NO: 0630

[3810] n 6.14 KLAKLAKKLAKL Amphipathi SEQ ID

[3811] Free Free NA Linear AK c NO: 0631 3.14

[3812] Ami KLALKAAAKAWK Amphipathi SEQ ID

[3813] Free datio NA Linear AAAKAA c NO: 0632

[3814] n 1.86 Ami KLALKAALKAWK Amphipathi SEQ ID

[3815] Free datio NA Linear AAAKLA c NO: 0633

[3816] n 4 Ami

[3817] KLALKALKAALK Amphipathi SEQ ID

[3818] Free datio NA Linear

[3819] LA c NO: 0634

[3820] n 3.98 Ami

[3821] KLALKLALKALK Amphipathi SEQ ID

[3822] Free datio NA Linear AA c NO: 0635

[3823] n 3.98 Ami

[3824] KLALKLALKALK Amphipathi SEQ ID

[3825] Free datio NA Linear AALK c NO: 0636

[3826] n 4.95 Ami

[3827] Amphipathi SEQ ID

[3828] klalklalkalkaalkla Free datio NA Linear

[3829] c NO: 0637

[3830]

[3831] n 5.48 ATTORNEY DOCKET: 05336.0007WO01

[3832] Ami

[3833] KLALKLALKALQ Amphipathi SEQ ID

[3834] Free datio NA Linear AALQLA c NO: 0638

[3835] n 4.46 Ami

[3836] KLALKLALKAWK Amphipathi SEQ ID

[3837] Free datio NA Linear AALKLA c NO: 0639

[3838] n 6.14 Ami

[3839] KLALKLALKWAK Amphipathi SEQ ID

[3840] Free datio NA Linear LALKAA c NO: 0640

[3841] n 6.14 Ami

[3842] KLALQLALQALQ Amphipathi SEQ ID

[3843] Free datio NA Linear AALQLA c NO: 0641

[3844] n 3.44 Ami

[3845] KLGLKLGLKGLK Amphipathi SEQ ID

[3846] Free datio NA Linear GGLKLG c NO: 0642

[3847] n 5.78 Ami KLLAKAAKKWLL Amphipathi SEQ ID

[3848] Free datio NA Linear LALKAA c NO: 0643

[3849] n 6.14 Ami

[3850] KLLAKAALKWLL Amphipathi SEQ ID

[3851] Free datio NA Linear KALKAA c NO: 0644

[3852] n 6.14 u,

[3853] a- am

[3854] ino

[3855] Acet Ami iso KLULKLULKULK Amphipathi SEQ ID

[3856] ylatio datio but Linear AULKLU c NO: 0645

[3857] n n yric

[3858] aci

[3859] d

[3860] (Ai

[3861] b) 8.26 Acet

[3862] KLULKLULKULK Amphipathi SEQ ID

[3863] ylatio Free NA Linear AULKLUGC c NO: 0646

[3864] n 8.22 KLWMRWYSATT Amphipathi SEQ ID

[3865] Free Free NA Linear RRYG c NO: 0647 1.67 KLWMRWYSPTT Amphipathi SEQ ID

[3866] Free Free NA Linear RRYG c NO: 0648 2.09 KLWMRWYSPW Amphipathi SEQ ID

[3867] Free Free NA Linear TRRYG c NO: 0649 3.81 KNAWKHSSCHH Amphipathi SEQ ID

[3868] Free Free NA Linear RHQI c NO: 0650 -1.19

[3869] Acet

[3870] KWFETWFTEWP Amphipathi SEQ ID

[3871] ylatio Free NA Linear KKRK c NO: 0651

[3872]

[3873] n 5.65 ATTORNEY DOCKET: 05336.0007WO01

[3874] LGTYTQDFNKFH Amphipathi SEQ ID

[3875] Free Free NA Linear TFPQTAIGVGAP c NO: 0652

[3876] 1.83 Ami

[3877] LIRLWSHLIHIWF Amphipathi SEQ ID

[3878] NA datio NA Linear QNRRLKWKKK c NO: 0653

[3879] n 7.41 LIRLWSHLIHIWF

[3880] Amphipathi SEQ ID

[3881] QNRRLKWKKKG Free Free NA Linear

[3882] c NO: 0654

[3883] GO 7.15

[3884] Ami LKTLATALTKLAK Amphipathi SEQ ID

[3885] Free datio NA Linear TLTTL c NO: 0655

[3886] n 3.59 Ami

[3887] LKTLTETLKELTK Amphipathi SEQ ID

[3888] Free datio NA Linear TLTEL c NO: 0656

[3889] n 1.4 LLGKINLKALAAL Amphipathi SEQ ID

[3890] Free Free NA Linear AKKIL c NO: 0657 4.6 LLHILRRSIRKQA Amphipathi SEQ ID

[3891] NA NA NA Linear HAIRK c NO: 0658 -0.27 LLHILRRSIRRQA Amphipathi SEQ ID

[3892] NA NA NA Linear HAIRR c NO: 0659 -2.19 LLIILRRRIRRRA Amphipathi SEQ ID

[3893] NA NA NA Linear RARSR c NO: 0660 -3.6

[3894] Stear Ami

[3895] LLKLLKKLLKLLK Amphipathi SEQ ID

[3896] ylatio datio NA Linear KLLKLL c NO: 0661

[3897] n n 19.94

[3898] 0,

[3899] Stear Ami Or LLOOLAAAALOO Amphipathi SEQ ID

[3900] ylatio datio nit Linear

[3901] LL c NO: 0662

[3902] n n hin

[3903] e 12.87 LLRHLRRHIRRA Amphipathi SEQ ID

[3904] NA NA NA Linear RRHIRR c NO: 0663 -4.51 LLRILRRSIRRAR Amphipathi SEQ ID

[3905] NA NA NA Linear RAIRR c NO: 0664 -3.6 LLYWFRRRHRH Amphipathi SEQ ID

[3906] Free Free NA Linear HRRRHRR c NO: 0665

[3907] -3.58 LNSAGYLLGKAL Amphipathi SEQ ID

[3908] Free Free NA Linear AALAKKIL c NO: 0666

[3909] 3.34 LNSAGYLLGKIN Amphipathi SEQ ID

[3910] Free Free NA Linear LKALAALAKKIL c NO: 0667

[3911] 4.03 LNSAGYLLGKLK Amphipathi SEQ ID

[3912] Free Free NA Linear

[3913]

[3914] ALAALAK c NO: 0668 2.64 ATTORNEY DOCKET: 05336.0007WO01

[3915] LNSAGYLLGKLK Amphipathi SEQ ID

[3916] Free Free NA Linear ALAALAKIL c NO: 0669

[3917] 4.14 MANLGCWMLVL Ami

[3918] Amphipathi SEQ ID

[3919] FVATWSDLGLC Free datio NA Linear

[3920] c NO: 0670

[3921] KKRPKP n

[3922] 9.12 MANLGYWLLAL Ami

[3923] Amphipathi SEQ ID

[3924] FVTMWTDVGLC Free datio NA Linear

[3925] c NO: 0671

[3926] KKRPKP n

[3927] 9.03 Cyst

[3928] Acet eami MGLGLHLLVLAA Amphipathi SEQ ID

[3929] ylatio de NA Linear ALQGAKKKRKV c NO: 0672

[3930] n grou

[3931] P 5.18 Cyst MGLGLHLLVLAA Acet eami

[3932] Amphipathi SEQ ID

[3933] ALQGAWSQPKK ylatio de NA Linear

[3934] c NO: 0673

[3935] KRKV n grou

[3936] P 6 MVKSKIGSWILV Ami

[3937] Amphipathi SEQ ID

[3938] LFVAMWSDVGL Free datio NA Linear

[3939] c NO: 0674

[3940] CKKRPKP n

[3941] 9.68 Ami

[3942] MVTVLFRRLRIR Amphipathi SEQ ID

[3943] Free datio NA Linear RACGPPRVRV c NO: 0675

[3944] n 0.75 Amphipathi SEQ ID

[3945] PLSSIFSRIGDP Free Free NA Linear

[3946] c NO: 0676 1.02

[3947] Ami QLALQLALQALQ Amphipathi SEQ ID

[3948] Free datio NA Linear AALQLA c NO: 0677

[3949] n 2.93 QQHLLIAINGYP Amphipathi SEQ ID

[3950] Free Free NA Linear RYN c NO: 0678 0.02 RAWMRWYSPTT Amphipathi SEQ ID

[3951] Free Free NA Linear RRYG c NO: 0679 0.06

[3952] RG

[3953] D

[3954] mo

[3955] tif

[3956] Amphipathi SEQ ID

[3957] RGDRRRRRRRR NA Free is Linear

[3958] c NO: 0680

[3959] link

[3960] ed

[3961] to

[3962]

[3963] P3 -7.61 ATTORNEY DOCKET: 05336.0007WO01

[3964] RGGRLSYSRRR Amphipathi SEQ ID

[3965] Free Free NA Linear FSTSTGRA c NO: 0681

[3966] -5.48 RHIKIWFQNRRM Amphipathi SEQ ID

[3967] Free Free NA Linear KWKK c NO: 0682 2.67 RLAMRWYSPTT Amphipathi SEQ ID

[3968] Free Free NA Linear RRYG c NO: 0683 -0.6 RLFMRFYSPTTR Amphipathi SEQ ID

[3969] Free Free NA Linear RYG c NO: 0684 0.53 RLIMRIYSPTTRR Amphipathi SEQ ID

[3970] Free Free NA Linear YG c NO: 0685 -0.39 RLLMRLYSPTTR Amphipathi SEQ ID

[3971] Free Free NA Linear RYG c NO: 0686 -0.19

[3972] Acet Ami

[3973] RLLRLLLRLWRR Amphipathi SEQ ID

[3974] ylatio datio NA Linear LLRLLR c NO: 0687

[3975] n n 6.01 RLVMRVYSPTT Amphipathi SEQ ID

[3976] Free Free NA Linear RRYG c NO: 0688 -1.15 RLWARWYSPTT Amphipathi SEQ ID

[3977] Free Free NA Linear RRYG c NO: 0689 0.35 RLWMAWYSPTT Amphipathi SEQ ID

[3978] Free Free NA Linear RRYG c NO: 0690 1.65 RLWMRAYSPTT Amphipathi SEQ ID

[3979] Free Free NA Linear RRYG c NO: 0691 -0.6 RLWMRWASPTT Amphipathi SEQ ID

[3980] Free Free NA Linear RRYG c NO: 0692 0.31 RLWMRWYAPTT Amphipathi SEQ ID

[3981] Free Free NA Linear RRYG c NO: 0693 1.31 RLWMRWYSPAT Amphipathi SEQ ID

[3982] Free Free NA Linear RRYG c NO: 0694 1.12 RLWMRWYSPTA Amphipathi SEQ ID

[3983] Free Free NA Linear RRYG c NO: 0695 1.12 RLWMRWYSPTT Amphipathi SEQ ID

[3984] Free Free NA Linear ARYG c NO: 0696 1.65 RLWMRWYSPTT Amphipathi SEQ ID

[3985] Free Free NA Linear RAYG c NO: 0697 1.65 RLWMRWYSPTT Amphipathi SEQ ID

[3986] Free Free NA Linear RRAG c NO: 0698 0.31 RLWMRWYSPTT Amphipathi SEQ ID

[3987] Free Free NA Linear RRYA c NO: 0699 1.08 RLWMRWYSPTT Amphipathi SEQ ID

[3988] Free Free NA Linear RRYG c NO: 0700 1.13 RLWMRWYSPW Amphipathi SEQ ID

[3989] Free Free NA Linear TRRWG c NO: 0701 3.76 RLWMRWYSPW Amphipathi SEQ ID

[3990] Free Free NA Linear

[3991]

[3992] TRRYG c NO: 0702 2.85 ATTORNEY DOCKET: 05336.0007WO01

[3993] RLYMRYYSPTT Amphipathi SEQ ID

[3994] Free Free NA Linear RRYG c NO: 0703 -0.69

[3995] Di- Ami

[3996] Amphipathi SEQ ID palmi

[3997] RPARPAR datio NA Linear

[3998] c NO: 0704 tilysa

[3999] n

[4000] tion -1.96 Di- Amphipathi SEQ ID palmi

[4001] RPARPAR Free NA Linear

[4002] c NO: 0704 tilysa

[4003] tion -2.61 Ami

[4004] Amphipathi SEQ ID

[4005] RPARPAR Free datio NA Linear

[4006] c NO: 0704

[4007] n -1.96 Amphipathi SEQ ID

[4008] RPARPAR Free Free NA Linear

[4009] c NO: 0704 -2.61

[4010] Ami

[4011] RQIKIFFQNRRM Amphipathi SEQ ID

[4012] Free datio NA Linear KWKK c NO: 0705

[4013] n 2.99 Ami

[4014] RQIKIWFPNRRM Amphipathi SEQ ID

[4015] Free datio NA Linear KWKK c NO: 0706

[4016] n 3.78 RQIKIWFQNMRR Amphipathi SEQ ID

[4017] NA NA NA Linear KWKK c NO: 0707 2.64 RQIKIWFQNRRM

[4018] Amphipathi SEQ ID

[4019] KWKKRQIKIWFQ Free Free NA Linear

[4020] c NO: 0708

[4021] NRRMKWK

[4022] 5.11 RRLRHLRHHYR Amphipathi SEQ ID

[4023] Free Free NA Linear RRWHRFR c NO: 0709

[4024] -3.58 RRRRRRRRRGP

[4025] Amphipathi SEQ ID

[4026] GVTWTPQAWFQ NA NA NA Linear

[4027] c NO: 0710

[4028] WV -2.54 RRWRRWWRR Amphipathi SEQ ID

[4029] Free Free NA Linear WWRRWRR c NO: 0711

[4030] 0.86 RTLVNEYKNTLK Amphipathi SEQ ID

[4031] Free Free NA Linear FSK c NO: 0712 -0.58

[4032] Ami

[4033] RVIRVWFQNKR Amphipathi SEQ ID

[4034] Free datio NA Linear CKDKK c NO: 0713

[4035] n 2.15 RVREWWYTITLK Amphipathi SEQ ID

[4036] Free Free NA Linear QES c NO: 0714 0.57

[4037] Amphipathi SEQ ID

[4038] RWRRWWRRW Free Free NA Linear

[4039]

[4040] c NO: 0715 1.89 ATTORNEY DOCKET: 05336.0007WO01

[4041] SKRTRQTYTRY QTLELEKEFHFN

[4042] Amphipathi SEQ ID

[4043] RYITRRRRIDIAN Free Free NA Linear

[4044] c NO: 0716

[4045] ALSLSERQIKIWF QNRRMKSKKDR

[4046] -7.47 VELPPPVELPPP Amphipathi SEQ ID

[4047] Free Free NA Linear VELPPP c NO: 0717 1.71

[4048] Amphipathi SEQ ID

[4049] VHLPPP Free Free NA Linear

[4050] c NO: 0718 1.26 Amphipathi SEQ ID

[4051] VHLPPPVHLPPP Free Free NA Linear

[4052] c NO: 0719 2.52 VHLPPPVHLPPP Amphipathi SEQ ID

[4053] Free Free NA Linear VHLPPP c NO: 0720 3.78

[4054] Amphipathi SEQ ID

[4055] VKLPPP Free Free NA Linear

[4056] c NO: 0721 1.74 Amphipathi SEQ ID

[4057] VKLPPPVKLPPP Free Free NA Linear

[4058] c NO: 0722 3.48 VKLPPPVKLPPP Amphipathi SEQ ID

[4059] Free Free NA Linear VKLPPP c NO: 0723 5.22

[4060] Amphipathi SEQ ID

[4061] VRLPPP Free Free NA Linear

[4062] c NO: 0724 0.78 Amphipathi SEQ ID

[4063] VRLPPPVRLPPP Free Free NA Linear

[4064] c NO: 0725 1.56 vrlpppvrlpppvrlpp Amphipathi SEQ ID

[4065] Free Free NA Linear

[4066] P c NO: 0726 2.34 VRLPPPVRLPPP Amphipathi SEQ ID

[4067] Free Free NA Linear VRLPPP c NO: 0727 2.34 WEAALAEALAEA

[4068] Amphipathi SEQ ID

[4069] LAEHLAEALAEA Free NA NA Linear

[4070] c NO: 0728

[4071] LEALAA

[4072] -4.03 WEARLARALAR

[4073] Amphipathi SEQ ID

[4074] ALARHLARALAR Free Free NA Linear

[4075] c NO: 0729

[4076] A -3.29 WKCRRQCFRVL Amphipathi SEQ ID

[4077] Free Free NA Linear HHWN c NO: 0730 2.72

[4078] Stear Ami

[4079] WLKLLKKWLKL Amphipathi SEQ ID

[4080] ylatio datio NA Linear WKKLLKLW c NO: 0731

[4081] n n 22.58 Stear Ami WLKLWKKWLKL Amphipathi SEQ ID

[4082] ylatio datio NA Linear

[4083] W c NO: 0732

[4084] n n 18.87 WLKY(PO3)LLKK Stear Ami

[4085] Amphipathi SEQ ID

[4086] WLKLWKKLLKL ylatio datio NA Linear

[4087] c NO: 0733

[4088]

[4089] W n n 23.28 ATTORNEY DOCKET: 05336.0007WO01

[4090] 0,

[4091] Stear Ami Or WLOLLOOWLOL Amphipathi SEQ ID

[4092] ylatio datio nit Linear WOOLLOLW c NO: 0734

[4093] n n hin

[4094] e 21.39 0,

[4095] Stear Ami Or WLOLLROWLRL Amphipathi SEQ ID

[4096] ylatio datio nit Linear WORLLOLW c NO: 0735

[4097] n n hin

[4098] e 19.02 0,

[4099] Stear Ami Or WLRLLORWLOL Amphipathi SEQ ID

[4100] ylatio datio nit Linear WROLLRLW c NO: 0736

[4101] n n hin

[4102] e 18.23 Y(PO3)WLKLLKK Stear Ami

[4103] Amphipathi SEQ ID

[4104] WLKLWKKLLKL ylatio datio NA Linear

[4105] c NO: 0737

[4106] W n n 23.28 YGRKKRRQRRR

[4107] Amphipathi SEQ ID

[4108] YGRKKRRQRRR Free Free NA Linear

[4109] c NO: 0738

[4110] YGRKKRRQRRR

[4111] -13.2 a, E (Stearyl- Stear Ami

[4112] Amphipathi SEQ ID

[4113] AGYLLG)2KINLK ylatio datio NA Linear

[4114] c NO: 0739

[4115] ALAALAKKIL n n

[4116] 12.39 Stear Ami AGYLLGKTNLKA Amphipathi SEQ ID

[4117] ylatio datio NA Linear LAALAKKIL c NO: 0740

[4118] n n 12.85 Stear

[4119] AGYLLGKTNLKA Amphipathi SEQ ID

[4120] ylatio Free NA Linear LAALAKKIL c NO: 0740

[4121] n 12.2 Acet

[4122] KLALKLALKALK Amphipathi SEQ ID

[4123] ylatio Free NA Linear AALKLAGC c NO: 0741

[4124] n 6.87 KKALLALALHHL

[4125] Amphipathi SEQ ID

[4126] AHLALHLALALK Free Free NA Linear

[4127] c NO: 0742

[4128] KA 5.28

[4129] Ami

[4130] ACGRGRGRCG Arginine SEQ ID

[4131] Free datio NA Cyclic RGRGRCG rich NO: 0743

[4132] n -3.41 Ami

[4133] AOGRGRGROR Arginine SEQ ID

[4134] Free datio NA Cyclic GRGRGCG rich NO: 0744

[4135]

[4136] n -3.41 ATTORNEY DOCKET: 05336.0007WO01

[4137] Ami

[4138] ACHGRRWGCG Arginine SEQ ID

[4139] Free datio NA Cyclic RHRGRCG rich NO: 0745

[4140] n -1.34 Ami

[4141] ACRDRFRNCPA Arginine SEQ ID

[4142] Free datio NA Cyclic DEALCG rich NO: 0746

[4143] n -0.69 Ami

[4144] ACRDRFRNCPA Arginine SEQ ID

[4145] Free datio NA Cyclic DERLCG rich NO: 0747

[4146] n -1.21 Ami

[4147] ACRDRFRRCPA Arginine SEQ ID

[4148] Free datio NA Cyclic DERLCG rich NO: 0748

[4149] n -1.02 Ami

[4150] ACRDRFRRCPA Arginine SEQ ID

[4151] Free datio NA Cyclic DRRLCG rich NO: 0749

[4152] n -0.81 Ami

[4153] ACRGRGRGCG Arginine SEQ ID

[4154] Free datio NA Cyclic RGRGRCG rich NO: 0750

[4155] n -3.41 Ami ACRGRGRGCGS Arginine SEQ ID

[4156] Free datio NA Cyclic GSGSCG rich NO: 0751

[4157] n -2.39 Ami ACRGRGRGCGS Arginine SEQ ID

[4158] Free datio NA Cyclic GSRSCG rich NO: 0752

[4159] n -2.96 Ami

[4160] ACRGRGRGCR Arginine SEQ ID

[4161] Free datio NA Cyclic GRGRGCG rich NO: 0753

[4162] n -3.41 Ami ACRGRGRRCGS Arginine SEQ ID

[4163] Free datio NA Cyclic GRRSCG rich NO: 0754

[4164] n -3.87 All

[4165] cys

[4166] tei

[4167] ne

[4168] s

[4169] we

[4170] re

[4171] Ami ca ACRGRGRRCGS Arginine SEQ ID

[4172] Free datio Cyclic GRRSCG rich NO: 0755 PP

[4173] n ed

[4174] wit

[4175] h

[4176] iod

[4177] oa

[4178] cet

[4179] am

[4180]

[4181] ide -3.87 ATTORNEY DOCKET: 05336.0007WO01

[4182] Ami ACRGRGRRCGS Arginine SEQ ID

[4183] Free datio NA Cyclic GSRSCG rich NO: 0756

[4184] n -3.53 Ami ACRGRRRGCGR Arginine SEQ ID

[4185] Free datio NA Cyclic RRGRCG rich NO: 0757

[4186] n -4.55 Ami ACRGSGRGCGR Arginine SEQ ID

[4187] Free datio NA Cyclic GSGRCG rich NO: 0758

[4188] n -2.73 Ami ACRRSRRGCGR Arginine SEQ ID

[4189] Free datio NA Cyclic RSRRCG rich NO: 0759

[4190] n -5.01 All

[4191] cys

[4192] tei

[4193] ne

[4194] s

[4195] we

[4196] re

[4197] Ami ca ACRRSRRGCGR Arginine SEQ ID

[4198] Free datio Cyclic RSRRCG rich NO: 0760 PP

[4199] n ed

[4200] wit

[4201] h

[4202] iod

[4203] oa

[4204] cet

[4205] am

[4206] ide -5.01 Ami

[4207] ACSDRFRNCPA Arginine SEQ ID

[4208] Free datio NA Cyclic DEALCG rich NO: 0761

[4209] n -0.35 ACSDRFRNCPA Ami

[4210] Arginine SEQ ID

[4211] DEALCGRRRRR Free datio NA Cyclic

[4212] rich NO: 0762

[4213] RRR n -6.67

[4214] All

[4215] cys

[4216] tei

[4217] ne

[4218] s ACSDRFRNCPA Ami we

[4219] Arginine SEQ ID

[4220] DEALCGRRRRR Free datio re Cyclic

[4221] rich NO: 0763

[4222] RRR n ca

[4223] PP

[4224] ed

[4225] wit

[4226] h

[4227]

[4228] iod -6.67 ATTORNEY DOCKET: 05336.0007WO01

[4229] oa

[4230] cet

[4231] am

[4232] ide

[4233] Ami ACSGRGRGCGR Arginine SEQ ID

[4234] Free datio NA Cyclic GRGSCG rich NO: 0764

[4235] n -2.73 Ami ACSGRGRGCGS Arginine SEQ ID

[4236] Free datio NA Cyclic GSGSCG rich NO: 0765

[4237] n -2.05 Ami AOSGRGSGOGS Arginine SEQ ID

[4238] Free datio NA Cyclic GRGSCG rich NO: 0766

[4239] n -2.05 Ami ACSGSGSGCGS Arginine SEQ ID

[4240] Free datio NA Cyclic GSGSCG rich NO: 0767

[4241] n -1.37 ACSGSGSGCGS Ami

[4242] Arginine SEQ ID

[4243] GSGSCGRRRRR Free datio NA Cyclic

[4244] rich NO: 0768

[4245] RRR n

[4246] -7.69 All

[4247] cys

[4248] tei

[4249] ne

[4250] s

[4251] we

[4252] re ACSGSGSGCGS Ami ca

[4253] Arginine SEQ ID

[4254] GSGSCGRRRRR Free datio Cyclic

[4255] rich NO: 0769 PP

[4256] RRR n ed

[4257] wit

[4258] h

[4259] iod

[4260] oa

[4261] cet

[4262] am

[4263] ide -7.69 ACSHSGHGCGH Ami

[4264] Arginine SEQ ID

[4265] GSHSCGRRRRR Free datio NA Cyclic

[4266] rich NO: 0770

[4267] RRR n

[4268]

[4269] -7.59 ATTORNEY DOCKET: 05336.0007WO01

[4270] ACSHSGWGCG Ami

[4271] Arginine SEQ ID

[4272] HGSWSCGRRR Free datio NA Cyclic

[4273] rich NO: 0771

[4274] RRRRR n

[4275] -4.05 Ami

[4276] ARCSDRFRNCP Arginine SEQ ID

[4277] Free datio NA Cyclic ADEALCGR rich NO: 0772

[4278] n -1.93 Ami ARCSGSGSGCG Arginine SEQ ID

[4279] Free datio NA Cyclic SGSGSCGR rich NO: 0773

[4280] n -2.95 Ami

[4281] ARRCSDRFRNC Arginine SEQ ID

[4282] Free datio NA Cyclic PADEALCGRR rich NO: 0774

[4283] n -3.51 Ami ARRCSGSGSGC Arginine SEQ ID

[4284] Free datio NA Cyclic GSGSGSCGRR rich NO: 0775

[4285] n -4.53 ARRRCSDRFRN Ami

[4286] Arginine SEQ ID

[4287] CPADEALCGRR Free datio NA Cyclic

[4288] rich NO: 0776

[4289] R n -5.09 ARRRCSGSGSG Ami

[4290] Arginine SEQ ID

[4291] CGSGSGSCGRR Free datio NA Cyclic

[4292] rich NO: 0777

[4293] R n -6.11 ARRRRCSDRFR Ami

[4294] Arginine SEQ ID

[4295] NCPADEALCGR Free datio NA Cyclic

[4296] rich NO: 0778

[4297] RRR n -6.67 ARRRRCSGSGS Ami

[4298] Arginine SEQ ID

[4299] GCGSGSGSCGR Free datio NA Cyclic

[4300] rich NO: 0779

[4301] RRR n

[4302] -7.69 Re

[4303] sid

[4304] ue

[4305] 2 is

[4306] 2,6

[4307] Ami

[4308] SEQ ID

[4309] rXKF Cationic Free datio Linear NO: 0780 di

[4310] n

[4311] me

[4312] thyl

[4313] tyr

[4314] osi

[4315] ne 1.19 Malei

[4316] AAVALLPAVLLA Ami

[4317] Amphipathi SEQ ID mide

[4318] LLAPRKKRRQR datio NA Linear

[4319] c NO: 0781 additi

[4320] RRPPQ n

[4321]

[4322] on -0.01 ATTORNEY DOCKET: 05336.0007WO01

[4323] Malei

[4324] AAVALLPAVLLA Ami

[4325] Amphipathi SEQ ID mide

[4326] LLAPRKKRRQR datio NA Linear

[4327] c NO: 0781 additi

[4328] RRPPQ n

[4329] on -0.01 AAVALLPAVLLA Ami

[4330] Amphipathi SEQ ID

[4331] LLAPRKKRRQR Free datio NA Linear

[4332] c NO: 0781

[4333] RRPPQ n

[4334] -0.01 AAVACRICMRNF Ami

[4335] Amphipathi SEQ ID

[4336] STRQARRNHRR Free datio NA Linear

[4337] c NO: 0782

[4338] RHRR n

[4339] -7.61 Ami

[4340] AAVALLPAVLLA Amphipathi SEQ ID

[4341] Free datio NA Linear LLAPRRRRRR c NO: 0783

[4342] n 0.03 Amphipathi SEQ ID

[4343] ACSSSPSKHCG Free Free NA Linear

[4344] c NO: 0784 -0.62 ACSSSPSKHCG

[4345] Arginine SEQ ID

[4346] GGGRRRRRRR Free Free NA Linear rich NO: 0785

[4347] RR -8.39 AEAEAEAEAKAK

[4348] Arginine SEQ ID

[4349] AKAKAGGGHRR Free Free NA Linear rich NO: 0786

[4350] RRRRR

[4351] -12.3 AKKAKAAKKAKA SEQ ID AKKAKAAKKAKA Cationic Free Free NA Linear NO: 0787

[4352] AKKAKA

[4353] -1.5 AKKKAAKAAKKK SEQ ID

[4354] Cationic Free Free NA Linear AAKAAKKKAAKA NO: 0788

[4355] -1.2 AKKKAAKAAKKK SEQ ID AAKAAKKKAAKA Cationic Free Free NA Linear NO: 0789

[4356] AKKKAAKA

[4357] -1.6 AKVKDEPQRRS

[4358] Amphipathi SEQ ID

[4359] ARLSAKPAPPKP Free Free NA Linear

[4360] c NO: 0790

[4361] EPKPKKAPAKK

[4362] -3.66 akvkdepqrrsarlsa

[4363] Amphipathi SEQ ID

[4364] kpappkpepkpkkap Free Free NA Linear

[4365] c NO: 0791

[4366] akk -3.66 APWHLSSQYSR Amphipathi SEQ ID

[4367] Free Free NA Linear

[4368] T c NO: 0792 -0.36 APWHLSSQYSR Amphipathi SEQ ID

[4369] Free Free NA Linear

[4370]

[4371] T c NO: 0792 -0.36 ATTORNEY DOCKET: 05336.0007WO01

[4372] ARRARAARRAR

[4373] Arginine SEQ ID

[4374] AARRARAARRA Free Free NA Linear rich NO: 0793

[4375] RAARRARA

[4376] -15.9 ARRRAARAARR

[4377] Arginine SEQ ID

[4378] RAARAARRRAA Free Free NA Linear rich NO: 0794

[4379] RA -12.7 ARRRAARAARR

[4380] Arginine SEQ ID

[4381] RAARAARRRAA Free Free NA Linear rich NO: 0795

[4382] RAARRRAARA

[4383] -17 Conj

[4384] ugati

[4385] on

[4386] with

[4387] hca

[4388] Ami

[4389] ASMWERVKSIIK Amphipathi SEQ ID (4-(7- datio NA Linear SSLAAASNI c NO: 0796 hydr

[4390] n

[4391] oxyc

[4392] oum

[4393] aryl)- acety

[4394] I) 0.08 ASMWERVKSIIK Amphipathi SEQ ID

[4395] NA NA NA Linear SSLAAASNI c NO: 0796

[4396] -0.57 Amphipathi SEQ ID

[4397] AVPAKKRZKSV NA NA NA Linear

[4398] c NO: 0797 -0.48

[4399] B,

[4400] Bet

[4401] a- Ala

[4402] nin

[4403] e;

[4404] Nl

[4405] A,

[4406] B- 2- Amphipathi SEQ ID Amid

[4407] GLRK(NIA)RLRK NA Linear

[4408] c NO: 0798 ation (2- FRNKIKEK nitr

[4409] oi

[4410] mi

[4411] da

[4412] zol

[4413] -1- yi)

[4414] ac

[4415]

[4416] etic -4.3 ATTORNEY DOCKET: 05336.0007WO01

[4417] aci

[4418] d

[4419] B,

[4420] Bet

[4421] a- Ala

[4422] nin

[4423] e;

[4424] Nl

[4425] A,

[4426] 2- (2- nitr

[4427] oi

[4428] mi

[4429] da

[4430] zol

[4431] -1- yi)

[4432] ac

[4433] etic

[4434] B- aci Amphipathi SEQ ID Amid

[4435] GLRK(NIA)RLRK NA d; Linear

[4436] c NO: 0798 ation

[4437] FRNKIKEK N

[4438] ter

[4439] mi

[4440] nal

[4441] ch

[4442] ela

[4443] tor

[4444] DO TA

[4445] (1.

[4446] 4,7

[4447] ,10

[4448] tetr

[4449] aa

[4450] za- cyc

[4451] lod

[4452] od

[4453]

[4454] ec -4.3 ATTORNEY DOCKET: 05336.0007WO01

[4455] an

[4456] e- 1,4

[4457] ,7,

[4458] 10- tetr

[4459] aa

[4460] ceti

[4461] c

[4462] aci

[4463] d)

[4464] B,

[4465] Bet

[4466] a- Ala

[4467] nin

[4468] e;

[4469] N

[4470] ter

[4471] mi

[4472] nal

[4473] ch

[4474] ela

[4475] tor

[4476] DO

[4477] B- TA

[4478] Amphipathi SEQ ID Amid

[4479] GLRKRLRKFRN NA Linear

[4480] c NO: 0799 ation (1,

[4481] KIKEK 4,7

[4482] ,10

[4483] tetr

[4484] aa

[4485] za- cyc

[4486] lod

[4487] od

[4488] ec

[4489] an

[4490] e- 1,4

[4491] ,7,

[4492]

[4493] 10- -3.75 ATTORNEY DOCKET: 05336.0007WO01

[4494] tetr

[4495] aa

[4496] ceti

[4497] c

[4498] aci

[4499] d)

[4500] Amphipathi SEQ ID

[4501] CARSKNKDC Free Free NA Linear

[4502] c NO: 0800 -0.77 CGAYDLRRRER

[4503] Arginine SEQ ID

[4504] QSRLRRRERQS NA NA NA Linear rich NO: 0801

[4505] R -9.27 CGGMVTVLFRR Ami

[4506] Arginine SEQ ID

[4507] LRIRRASGPPRV Free datio NA Linear rich NO: 0802

[4508] RV n -0.14

[4509] SEQ ID CGNKRTR Cationic NA NA NA Linear NO: 0803 -2.04

[4510] Ami

[4511] SEQ ID CGNKRTRGC Cationic Free datio NA Linear NO: 0804

[4512] n -0.78 CGNVVRQGCGY SEQ ID GRKKRRQRRRG Cationic NA NA NA Linear NO: 0805

[4513] TALDWSWLQTE

[4514] -3.44 Stear

[4515] Arginine SEQ ID

[4516] CHHRRRRHHC ylatio Free NA Cyclic

[4517] rich NO: 0806

[4518] n 5.76 Succi

[4519] nimid

[4520] yl-4- (N- mal- eimid

[4521] CLLIILRRRIRKQ Ami

[4522] Amphipathi SEQ ID omet

[4523] AHAHSKNHQQQ datio NA Linear

[4524] c NO: 0807 hyl)

[4525] NPHQPPM n

[4526] cyclo

[4527] hexa

[4528] ne-1- carb

[4529] oxyla

[4530]

[4531] te -1.77 ATTORNEY DOCKET: 05336.0007WO01

[4532] (SM

[4533] CC)

[4534] Amphipathi SEQ ID

[4535] CNGRC Free Free NA Linear

[4536] c NO: 0808 -0.33 Amphipathi SEQ ID

[4537] CRGDK Free Free NA Linear

[4538] c NO: 0809 -0.29 Amphipathi SEQ ID

[4539] CRNGRGPDC Free Free NA Linear

[4540] c NO: 0810 -1.47

[4541] Addit

[4542] CTSTTAKRKKRK SEQ ID ion of

[4543] Cationic Free NA Linear

[4544] LK NO: 0811 cyste

[4545] ine -0.6 CVKRGLKLRHV SEQ ID

[4546] Cationic NA NA NA Linear RPRVTRDV NO: 0812

[4547] -0.82 DAATATRGRSA ASRPTQRPRAP Amphipathi SEQ ID

[4548] NA NA NA Linear ARSASRPRRPV c NO: 0813

[4549] E -12.6 DPATNPGPHFP Amphipathi SEQ ID

[4550] NA NA NA Linear

[4551] R c NO: 0814 -1.35 DPVDTPNPTRR Amphipathi SEQ ID

[4552] Free NA NA Linear KPGK c NO: 0815 -2.6 EEEAAGRKRKK SEQ ID

[4553] Cationic Free Free NA Linear

[4554] RT NO: 0816 -5.88

[4555] Malei

[4556] Ami

[4557] FKQQQQQQQQ Amphipathi SEQ ID mide

[4558] datio NA Linear QQ c NO: 0817 additi

[4559] n

[4560] on -1.42 FQFNFQFNGGG Arginine SEQ ID

[4561] Free Free NA Linear HRRRRRRR rich NO: 0818

[4562] -4.5 Ami

[4563] FQWQRNMRKV Amphipathi SEQ ID

[4564] Free datio NA Linear RGPPVS c NO: 0819

[4565] n 0.19 Cys

[4566] GAYDLRRRERQ Arginine SEQ ID

[4567] additi Free NA Linear SRLRRRERQSR rich NO: 0820

[4568] on -10.1 GGAYVTRSSAV Ami

[4569] Amphipathi SEQ ID

[4570] RLRSSVPGVRLL Free datio NA Linear

[4571] c NO: 0821

[4572]

[4573] Q n -1.73 ATTORNEY DOCKET: 05336.0007WO01

[4574] GGGARKKAAKA ARKKAAKAARK SEQ ID

[4575] Cationic Free Free NA Linear KAAKAARKKAAK NO: 0822

[4576] A -6.1

[4577] Arginine SEQ ID

[4578] GGRRARRRRRR Free Free NA Linear rich NO: 0823 -7.03

[4579] Cys

[4580] GKRKKKGKLGK SEQ ID

[4581] Cationic additi Free NA Linear KRDP NO: 0824

[4582] on -0.38 Cys

[4583] GKRKKKGKLGK SEQ ID

[4584] Cationic additi Free NA Linear KRPRSR NO: 0825

[4585] on -2.13 GKYVSLTTPKNP Amphipathi SEQ ID

[4586] Free Free NA Linear TKRRITPKDV c NO: 0826

[4587] -0.73 Bio

[4588] tiny

[4589] lati GLFEAIEGFIENG on

[4590] Bioti

[4591] WEGMIDGWYG Amphipathi SEQ ID at

[4592] Free nylat Linear GGGRRRRRRR c NO: 0827 lysi

[4593] ion

[4594] RRK ne

[4595] res

[4596] idu

[4597] e -5.25 GLLEALAELLEG Ami

[4598] Amphipathi SEQ ID

[4599] LRKRLRKFRNKI Free datio NA Linear

[4600] c NO: 0828

[4601] KEK n -0.16

[4602] Lipid

[4603] GLPRRRRRRRR Arginine SEQ ID Peg

[4604] Free NA Linear

[4605] R rich NO: 0829 deriv

[4606] ative -6.38 GNYAHRVGAGA Amphipathi SEQ ID

[4607] Free Free NA Linear PVWL c NO: 0830 0.05

[4608] Bioti

[4609] GRKGKHKRKKL SEQ ID

[4610] Cationic nylati Free NA Linear

[4611] P NO: 0831

[4612] on -0.53 GRKKRRQRRRP PQGRKKRRQRR Arginine SEQ ID

[4613] NA NA NA Linear RPPQGRKKRRQ rich NO: 0832

[4614] RRRPPQ

[4615] -15 GRKKRRQRRRP

[4616] Arginine SEQ ID

[4617] PQTYADFIASGR Free Free NA Linear rich NO: 0833

[4618] TGRRNAI

[4619]

[4620] -7.74 ATTORNEY DOCKET: 05336.0007WO01

[4621] GRKKRRQRRRP SEQ ID

[4622] Cationic Free Free NA Linear

[4623] Q NO: 0834 -5.15

[4624] Bioti

[4625] GRRHHCRSKAK Amphipathi SEQ ID

[4626] nylati Free NA Linear RSRHH c NO: 0835

[4627] on -5.41 GSPWGLQHHPP Amphipathi SEQ ID

[4628] Free Free NA Linear

[4629] RT c NO: 0836 -0.19

[4630] Amphipathi SEQ ID

[4631] GSRHPSLIIPRQ NA NA NA Linear

[4632] c NO: 0837 -0.85 GSRVQIRCRFR Amphipathi SEQ ID

[4633] Free Free NA Linear NSTR c NO: 0838 -3.64

[4634] Bioti

[4635] nyl- Gly- GWTLNSAGYLL

[4636] Amphipathi SEQ ID Gly- GPHAVGNHRSF Free NA Linear

[4637] c NO: 0839 N

[4638] SDKNGLTS

[4639] 25gal

[4640] anin(

[4641] 1-29) -1.58 GYGRKKRRGRR

[4642] Arginine SEQ ID

[4643] RTHRLPRRRRR Free Free NA Linear rich NO: 0840

[4644] R -9.66

[4645] Amphipathi SEQ ID

[4646] HATKSQNINF Free Free NA Linear

[4647] c NO: 0841 -1.56

[4648] Conj Lin

[4649] ugati ker

[4650] on

[4651] HHHHHHESGGG (E

[4652] Arginine SEQ ID with SG GSPGRRRRRRR NA Linear rich NO: 0842 6- GG

[4653] RRRR

[4654] histid GS

[4655] ine PG

[4656] tag ) -13.4 HHHHHHRRRRR Arginine SEQ ID

[4657] Free Free NA Linear RRRR rich NO: 0843 -8.97 HHHHHHRRRRR Arginine SEQ ID

[4658] Free Free NA Linear RRRR rich NO: 0844 -8.97 HHHHHHTKRRIT

[4659] Amphipathi SEQ ID

[4660] PKDVIDVRSVTT Free Free NA Linear

[4661] c NO: 0845

[4662] EINT -4.97 HHHRRRRRRRR Arginine SEQ ID

[4663] Free Free NA Linear RHHH rich NO: 0846 -8.97 HPGSPFPPEHR Amphipathi SEQ ID

[4664] NA NA NA Linear

[4665] P c NO: 0847 -1.17 HQHKPPPLTNN Amphipathi SEQ ID

[4666] NA NA NA Linear

[4667] W c NO: 0848 -0.3 HQHKPPPLTNN Amphipathi SEQ ID

[4668] NA NA NA Linear

[4669]

[4670] W c NO: 0848 -0.3 ATTORNEY DOCKET: 05336.0007WO01

[4671] Amphipathi SEQ ID

[4672] HRHIRRQSLIML NA NA NA Linear

[4673] c NO: 0849 -0.27 KETWWETWWT Ami

[4674] Arginine SEQ ID

[4675] EWSQPGRKKRR Free datio NA Linear rich NO: 0850

[4676] QRRRPPQ n

[4677] -1.3 KGSKKAVTKAQ

[4678] Ami

[4679] KKDGKKRKRSR SEQ ID

[4680] Cationic Free datio NA Linear KESYSVYVYKVL NO: 0851

[4681] n

[4682] KQ

[4683] -0.95 KGSKKAVTKAQ

[4684] Ami

[4685] KKDGKKRKRSR SEQ ID

[4686] Cationic Free datio NA Linear KESYSVYVYKVL NO: 0851

[4687] n

[4688] KQ

[4689] -0.95 KHHWHHVRLPP

[4690] Amphipathi SEQ ID

[4691] PVRLPPPGNHH Free Free NA Linear

[4692] c NO: 0852

[4693] HHHH -1.11

[4694] Ami KKAAQIRSQVMT Amphipathi SEQ ID

[4695] Free datio NA Linear HLRVI c NO: 0853

[4696] n 0.52 KKDGKKRKRSR Ami

[4697] SEQ ID KESYSVYVYKVL Cationic Free datio NA Linear NO: 0854

[4698] KQ n -0.14

[4699] Ami

[4700] KKKEERADLIAY SEQ ID

[4701] Cationic Free datio NA Linear LKKA NO: 0855

[4702] n 0.47 KKWKMRRGAG Arginine SEQ ID

[4703] NA Free NA Linear RRRRRRRRR rich NO: 0856

[4704] -6.92 Amphipathi SEQ ID

[4705] KRIHPRLTRSIR NA NA NA Linear

[4706] c NO: 0857 -1.66 Amphipathi SEQ ID

[4707] KRIIQRILSRNS NA NA NA Linear

[4708] c NO: 0858 -1.52 Amphipathi SEQ ID

[4709] KTIEAHPPYYAS NA NA NA Linear

[4710] c NO: 0859 -0.29

[4711] Bioti

[4712] KWSFRVSYRGIS SEQ ID

[4713] Cationic nylati Free NA Linear YRRSRGK NO: 0860

[4714] on -1.11 LAELLAELLAEL

[4715] Arginine SEQ ID

[4716] GGGGRRRRRR Free Free NA Linear rich NO: 0861

[4717] RRR -7 LAELLAELLAEL

[4718] Arginine SEQ ID

[4719] GGGGRRRRRR Free Free NA Linear rich NO: 0862

[4720]

[4721] RRR -7 ATTORNEY DOCKET: 05336.0007WO01

[4722] LAQLLAQLLAQL

[4723] Arginine SEQ ID

[4724] GGGGRRRRRR Free Free NA Linear rich NO: 0863

[4725] RRR -5.02 LLETLLKPFQCRI Ami

[4726] SEQ ID CMRNFSTRQAR Cationic Free datio NA Linear NO: 0864

[4727] RNHRRRHRR n

[4728] -4.04 LLIILRRRIRKQA Ami

[4729] Amphipathi SEQ ID

[4730] HAHSKNHQQQN Free datio NA Linear

[4731] c NO: 0865

[4732] PHQPPM n

[4733] -2.6 LRHHLRHLLRHL

[4734] Amphipathi SEQ ID

[4735] RHLLRHLRHHLR Free Free NA Linear

[4736] c NO: 0866

[4737] HLLRH

[4738] -0.62 Cys

[4739] LRRERQSRLRR Amphipathi SEQ ID

[4740] additi Free NA Linear ERQSR c NO: 0867

[4741] on -8.3 Amphipathi SEQ ID

[4742] MAARL Free Free NA Linear

[4743] c NO: 0868 -0.02 MAMPGEPRRAN

[4744] Amphipathi SEQ ID

[4745] VMAHKLEPASL Free NA NA Linear

[4746] c NO: 0869

[4747] QLRNSCA

[4748] -3.75 MAPQRDTVGGR

[4749] Amphipathi SEQ ID

[4750] TTPPSWGPAKA Free NA NA Linear

[4751] c NO: 0870

[4752] QLRNSCA

[4753] -3.04 Me MERKKRRRESW

[4754] Amphipathi SEQ ID me VHLPPPVHLPPP Free Free Linear

[4755] c NO: 0871 thyl GGHHHHHH

[4756] gro

[4757] up -3.08 MGVADLIKKFESI

[4758] Arginine SEQ ID

[4759] SKEEGGGGKGG Free Free NA Linear rich NO: 0872

[4760] RRRRRRRR

[4761] -7.44 MHKRPTTPSRK Amphipathi SEQ ID

[4762] NA NA NA Linear

[4763] M c NO: 0873 -1.2 NHQQQNPHQPP Ami

[4764] Amphipathi SEQ ID

[4765] MLLIILRRRIRKQ Free datio NA Linear

[4766] c NO: 0874

[4767] AHAHSK n

[4768] -2.6 NRHFRFFFNFTN Amphipathi SEQ ID

[4769] Free Free NA Linear

[4770]

[4771] R c NO: 0875 -0.08 ATTORNEY DOCKET: 05336.0007WO01

[4772] Bioti

[4773] nylati

[4774] on

[4775] (Lab

[4776] eled Ami

[4777] SEQ ID NRRMKWKK Cationic with datio NA Linear NO: 0876

[4778] Bioti n

[4779] nyl- beta- Alani

[4780] ne) 0.57 NSGTMQSASRA Amphipathi SEQ ID

[4781] NA NA NA Linear

[4782] T c NO: 0877 -4.23 NYTTYKSHFQD Amphipathi SEQ ID

[4783] NA NA NA Linear

[4784] R c NO: 0878 -1.24

[4785] Fusi

[4786] on

[4787] Arginine SEQ ID

[4788] PARAARRAARR Free with NA Linear rich NO: 0879

[4789] beta

[4790] -Gal -5.15 Arginine SEQ ID

[4791] PIRRRKKLRRLK NA NA NA Linear rich NO: 0880 -0.99 Amphipathi SEQ ID

[4792] PNTRVRPDVSF NA NA NA Linear

[4793] c NO: 0881 -1.45 PPHNRIQRRLN Amphipathi SEQ ID

[4794] NA NA NA Linear

[4795] M c NO: 0882 -2.67 PPRLPRPRPRPL SEQ ID

[4796] Cationic Free Free NA Linear PFPRPG NO: 0883 -0.06 PPRLRKRRQLN SEQ ID

[4797] Cationic NA NA NA Linear

[4798] M NO: 0884 -1.9

[4799] SEQ ID PQNRLQIRRHSK Cationic NA NA NA Linear NO: 0885 -2.97 PRPPRLPRPRP Amphipathi SEQ ID

[4800] Free Free NA Linear RPLPFPRPG c NO: 0886

[4801] -0.7 PRPRPRPLPFPR Amphipathi SEQ ID

[4802] Free Free NA Linear

[4803] PG c NO: 0887 -0.37

[4804] Amphipathi SEQ ID

[4805] PSKRLLHNNLRR NA NA NA Linear

[4806] c NO: 0888 -2.37 QAASRVENYMH Amphipathi SEQ ID

[4807] NA NA NA Linear

[4808] R c NO: 0889 -3.82

[4809] Bioti

[4810] nylati

[4811] Ami

[4812] SEQ ID on

[4813] QNRRMKWKK Cationic datio NA Linear NO: 0890 (Lab

[4814] n

[4815] eled

[4816]

[4817] with 0.23 ATTORNEY DOCKET: 05336.0007WO01

[4818] Bioti

[4819] nyl- beta- Alani

[4820] ne)

[4821] SEQ ID QRIRKSKISRTL Cationic NA NA NA Linear NO: 0891 -1.33

[4822] Ami

[4823] SEQ ID QWQRNMRKVR Cationic Free datio NA Linear NO: 0892

[4824] n -0.92 Ami

[4825] QWQRNMRKVR SEQ ID

[4826] Cationic Free datio NA Linear GPPVSCIKR NO: 0893

[4827] n -0.06 Bioti Ami

[4828] RAGLQFPVGRV Amphipathi SEQ ID

[4829] nylati datio NA Linear HRLLRK c NO: 0894

[4830] on n 0.65 RARARARARAR

[4831] Arginine SEQ ID

[4832] ARARARARARA Free Free NA Linear rich NO: 0895

[4833] RARARARARA

[4834] -17 RFTFHFRFEFTF

[4835] Arginine SEQ ID

[4836] HFEGGGRRRRR Free Free NA Linear rich NO: 0896

[4837] RR -2.79

[4838] Cycli Cycli

[4839] Amphipathi SEQ ID

[4840] RGDFK clizat zatio NA Cyclic

[4841] c NO: 0897

[4842] ion n 0.04 RGDRGDRRDLR SEQ ID

[4843] Cationic Free Free NA Linear LDRGDLRC NO: 0898

[4844] -4.36 RGDRLDRRDLR SEQ ID

[4845] Cationic Free Free NA Linear LDRRDLRC NO: 0899

[4846] -3.91 RGERGERRELR SEQ ID

[4847] Cationic Free Free NA Linear LERGELRC NO: 0900

[4848] -7.96 RGERLERRELRL SEQ ID

[4849] Cationic Free Free NA Linear ERRELRC NO: 0901

[4850] -7.51 Conj

[4851] ugati

[4852] on

[4853] RGGRLAYLRRR SEQ ID with

[4854] Cationic Free NA Linear WAVLGR NO: 0902 NBD

[4855] and

[4856] TAM

[4857]

[4858] RA -1.21 ATTORNEY DOCKET: 05336.0007WO01

[4859] Conj

[4860] ugati

[4861] on

[4862] RGGRLSYSRRR SEQ ID with

[4863] Cationic Free NA Linear FSTSTGR NO: 0903 NBD

[4864] and

[4865] TAM RA -5.21 RGGRLSYSRRR SEQ ID

[4866] Cationic Free Free NA Linear FSTSTGR NO: 0903 -5.21 RGGRLSYSRRR SEQ ID

[4867] Cationic Free Free NA Linear FSTSTGR NO: 0903 -5.21 RGGRLSYSRRR SEQ ID

[4868] Cationic Free Free NA Linear FSTSTGR NO: 0903 -5.21

[4869] Conj

[4870] ugati

[4871] RGGRLSYSRRR SEQ ID

[4872] Cationic on Free NA Linear FSTSTGR NO: 0904

[4873] with

[4874] NBD -5.21 RGSRRAVTRAQ

[4875] Ami

[4876] RRDGRRRRRSR SEQ ID

[4877] Cationic Free datio NA Linear RESYSVYVYRVL NO: 0905

[4878] n

[4879] RQ

[4880] -12.5 Arginine SEQ ID

[4881] RHHLRHLRRHL Free Free NA Linear rich NO: 0906 -2 RHHLRHLRRHL Arginine SEQ ID

[4882] Free Free NA Linear RHLLRHLRHHL rich NO: 0907

[4883] -2.41 RHHLRHLRRHL Arginine SEQ ID

[4884] Free Free NA Linear RHLLRHLRHHL rich NO: 0908

[4885] -2.41 RHHLRHLRRHL

[4886] Arginine SEQ ID

[4887] RHLLRHLRHHLR Free Free NA Linear rich NO: 0910

[4888] HLRRHLRHLL

[4889] -3.3 RHHRRHHRRHR Arginine SEQ ID

[4890] Free Free NA Linear RHHRRHHRHHR rich NO: 0911

[4891] -12.1 RHNFRFFFNFRT Arginine SEQ ID

[4892] Free Free NA Linear NR rich NO: 0912 -0.87 RHNHRFNFRFF Arginine SEQ ID

[4893] Free Free NA Linear FNFRFNTRTN rich NO: 0913

[4894] -1.87 RHRHRRHRHRR Arginine SEQ ID

[4895] Free Free NA Linear

[4896]

[4897] HRHR rich NO: 0914 -8.97 ATTORNEY DOCKET: 05336.0007WO01

[4898] X,

[4899] 4- am

[4900] ino

[4901] Stear Ami

[4902] RKKRKKKRXRH SEQ ID

[4903] Cationic ylatio datio Linear XRHXRHXR NO: 0915 but

[4904] n n

[4905] an

[4906] oic

[4907] aci

[4908] d 3.54 RKKRRRESRKK SEQ ID

[4909] Cationic NA NA NA Linear RRRESC NO: 0916

[4910] -7.71 Cys

[4911] RKKRRRESRRA SEQ ID

[4912] Cationic additi Free NA Linear RRSPRHL NO: 0917

[4913] on -8.3 RKKRRRESWVH SEQ ID LPPPVHLPPPGG Cationic Free Free NA Linear NO: 0918

[4914] HHHHHH

[4915] -2.59 RLALRLALRALR Amphipathi SEQ ID

[4916] Free Free NA Linear AALRLA c NO: 0919 0.03 RLHHRLHRRLH Amphipathi SEQ ID

[4917] Free Free NA Linear RLHR c NO: 0920 -3.09 RLHHRLHRRLH

[4918] Amphipathi SEQ ID

[4919] RLHRRLHRLHH Free Free NA Linear

[4920] c NO: 0921

[4921] RLHRRLH

[4922] -5.39 RLHLRLHLRHLR Amphipathi SEQ ID

[4923] Free Free NA Linear HHLRLH c NO: 0922 -0.21 RLHRRLHRRLH Amphipathi SEQ ID

[4924] Free Free NA Linear RLHR c NO: 0923 -3.57 RLHRRLHRRLH

[4925] Amphipathi SEQ ID

[4926] RLHRRLHRLHR Free Free NA Linear

[4927] c NO: 0924

[4928] RLHRRLH

[4929] -6.35 RLIMRIYAPTTRR Amphipathi SEQ ID

[4930] NA NA NA Linear YG c NO: 0925 -0.21 RLPRPRPRPLPF Amphipathi SEQ ID

[4931] Free Free NA Linear PRPG c NO: 0926 -0.36

[4932] Ami

[4933] RQARRNRRRAL SEQ ID

[4934] Cationic Free datio NA Linear WKTLLKKVLKA NO: 0927

[4935] n -0.82 RQIKIWFQNRRM

[4936] Amphipathi SEQ ID

[4937] KWKKTYADFIAS Free Free NA Linear

[4938] c NO: 0928

[4939] GRTGRRNAI

[4940]

[4941] -0.1 ATTORNEY DOCKET: 05336.0007WO01

[4942] Cy

[4943] stei

[4944] ne RQIRIWFQNRR Amphipathi SEQ ID

[4945] NA NA mo Linear MRWRRC c NO: 0929

[4946] difi

[4947] cati

[4948] on -0.37 SEQ ID RQRSRRRPLNIR Cationic NA NA NA Linear NO: 0930 -4.86

[4949] Bioti

[4950] RRHHCRSKAKR SEQ ID

[4951] Cationic nylati Free NA Linear SR NO: 0931

[4952] on -4.57 RRHLRRHLRHL Amphipathi SEQ ID

[4953] Free Free NA Linear RRHLRRHLRHL c NO: 0932

[4954] -4.96 Arginine SEQ ID

[4955] RRIRPRP Free Free NA Linear rich NO: 0933 -2.16 RRIRPRPPRLPR Arginine SEQ ID

[4956] Free Free NA Linear PRP rich NO: 0934 -3.13 RRIRPRPPRLPR Arginine SEQ ID

[4957] Free Free NA Linear PRPRP rich NO: 0935 -3.77

[4958] Ami

[4959] SEQ ID RRKLSQQKEKK Cationic Free datio NA Linear NO: 0936

[4960] n -1.58 RRQRRTSKLMK SEQ ID

[4961] Cationic NA NA NA Linear

[4962] R NO: 0937 -3.35 RRRQRRKRGGD Ami

[4963] Amphipathi SEQ ID

[4964] IMGEWGNEIFGA Free datio NA Linear

[4965] c NO: 0938

[4966] IAGFLG n

[4967] -2.41 Brom

[4968] RRRQRRKRGGD Ami

[4969] Amphipathi SEQ ID oacet

[4970] IMGEWGNEIFGA datio NA Linear

[4971] c NO: 0938 ylatio

[4972] IAGFLG n

[4973] n -2.41

[4974] Aib

[4975] , ci- am RRRRRRRRRGG ino

[4976] Arginine SEQ ID

[4977] LAA(AIB)SGWKH Free Free iso Linear rich NO: 0939

[4978] HHHHH but

[4979] yric

[4980] aci

[4981] d -7.76 RRRRRRRRRRR

[4982] Arginine SEQ ID

[4983] TYADFIASGRTG Free Free NA Linear rich NO: 0940

[4984] RRNAI

[4985]

[4986] -11.4 ATTORNEY DOCKET: 05336.0007WO01

[4987] Malei

[4988] Ami

[4989] RVIRWFQNKRS SEQ ID mide

[4990] Cationic datio NA Linear KDKK NO: 0941 additi

[4991] n

[4992] on 0.55 Conj

[4993] ugati

[4994] on Ami

[4995] RVRILARFLRTR SEQ ID

[4996] Cationic with datio NA Linear

[4997] V NO: 0942

[4998] fluor n

[4999] escei

[5000] n 0.27

[5001] B,

[5002] Bet

[5003] a- Ala

[5004] nin

[5005] e

[5006] an

[5007] d

[5008] X,

[5009] Acet

[5010] RXRRBRRXRYQ SEQ ID 6- Cationic ylatio Free Linear FLIRXRBRXRB NO: 0943 am

[5011] n

[5012] ino

[5013] he

[5014] xa

[5015] noi

[5016] c

[5017] aci

[5018] d

[5019] (Ah

[5020] x) -6.3 X,

[5021] 6- am

[5022] ino

[5023] he

[5024] Ami

[5025] RXRRXRRXRRX Arginine SEQ ID xa

[5026] Free datio Linear

[5027] R rich NO: 0944 noi

[5028] n

[5029] c

[5030] aci

[5031] d

[5032] (Ah

[5033] x) -5.67 Ah

[5034] x, RXRRXRRXRRX Arginine SEQ ID 6- NA NA Linear

[5035] R rich NO: 0944 am

[5036] ino

[5037]

[5038] he -6.32 ATTORNEY DOCKET: 05336.0007WO01

[5039] xa

[5040] noi

[5041] c

[5042] aci

[5043] d

[5044] Ah

[5045] x,

[5046] 6- am

[5047] ino RXRRXRRXRRX Arginine SEQ ID

[5048] NA NA he Linear

[5049] R rich NO: 0944

[5050] xa

[5051] noi

[5052] c

[5053] aci

[5054] d -6.32 X,

[5055] ae

[5056] LP,

[5057] Ami am RXRRXRRXRRX Arginine SEQ ID

[5058] Free datio ino Linear

[5059] R rich NO: 0945

[5060] n eth

[5061] yip

[5062] rop

[5063] yi -5.67 x,

[5064] ap

[5065] LP,

[5066] Ami am RXRRXRRXRRX Arginine SEQ ID

[5067] Free datio ino Linear

[5068] R rich NO: 0945

[5069] n pro

[5070] pyi

[5071] pro

[5072] pyi -5.67 Bioti

[5073] SARHHCRSKAK Amphipathi SEQ ID

[5074] nylati Free NA Linear RSRHH c NO: 0946

[5075] on -5.12 Amphipathi SEQ ID

[5076] SFHQFARATLAS NA NA NA Linear

[5077] c NO: 0947 -0.29 SGRGKQGGKAR Malei

[5078] Ami AKAKTRSSRAGL Amphipathi SEQ ID mide

[5079] datio NA Linear QFPVGRVHRLL c NO: 0948 aditio

[5080] n

[5081] RKG n

[5082]

[5083] -4.9 ATTORNEY DOCKET: 05336.0007WO01

[5084] SGRGKQGGKAR

[5085] Ami AKAKTRSSRAGL Amphipathi SEQ ID

[5086] Free datio NA Linear QFPVGRVHRLL c NO: 0949

[5087] n

[5088] RKGC

[5089] -4.07 SMLKRNHSTSN SEQ ID

[5090] Cationic NA NA NA Linear

[5091] R NO: 0950 -3.98

[5092] Bioti

[5093] SRAHHCRSKAK SEQ ID

[5094] Cationic nylati Free NA Linear RSRHH NO: 0951

[5095] on -5.12 Bioti

[5096] SRRAHCRSKAK SEQ ID

[5097] Cationic nylati Free NA Linear RSRHH NO: 0952

[5098] on -5.6 Cys

[5099] SRRARRSPRES SEQ ID

[5100] Cationic additi Free NA Linear GKKRKRKR NO: 0953

[5101] on -8.33 Cys

[5102] SRRARRSPRHL SEQ ID

[5103] Cationic additi Free NA Linear GSG NO: 0954

[5104] on -5.37 Bioti

[5105] SRRHACRSKAK SEQ ID

[5106] Cationic nylati Free NA Linear RSRHH NO: 0955

[5107] on -5.6 Bioti

[5108] SRRHHARSKAK SEQ ID

[5109] Cationic nylati Free NA Linear RSRHH NO: 0956

[5110] on -6.74 Bioti

[5111] SRRHHCRAKAK SEQ ID

[5112] Cationic nylati Free NA Linear RSRHH NO: 0957

[5113] on -5.46 Bioti

[5114] SRRHHCRSAAK SEQ ID

[5115] Cationic nylati Free NA Linear RSRHH NO: 0958

[5116] on -6.08 Bioti

[5117] SRRHHCRSKAA SEQ ID

[5118] Cationic nylati Free NA Linear RSRHH NO: 0959

[5119] on -6.08 Bioti

[5120] SRRHHCRSKAK SEQ ID

[5121] Cationic nylati Free NA Linear ASRHH NO: 0960

[5122] on -5.12 Bioti

[5123] SRRHHCRSKAK SEQ ID

[5124] Cationic nylati Free NA Linear RARHH NO: 0961

[5125] on -5.46 Bioti

[5126] SRRHHCRSKAK SEQ ID

[5127] Cationic nylati Free NA Linear RSAHH NO: 0962

[5128] on -5.12 SRRKRQRSNMR SEQ ID

[5129] Cationic NA NA NA Linear

[5130] I NO: 0963 -4.79

[5131] SEQ ID SYIQRTPSTTLP Cationic NA NA NA Linear

[5132]

[5133] NO: 0964 -0.46 ATTORNEY DOCKET: 05336.0007WO01

[5134] TARRITPKDVIDV Amphipathi SEQ ID

[5135] Free Free NA Linear RSVTTEINT c NO: 0965

[5136] -3.55 TKAARITPKDVID Amphipathi SEQ ID

[5137] Free Free NA Linear VRSVTTEINT c NO: 0966

[5138] -2.86 Amphipathi SEQ ID

[5139] TKRRITPKDVIDV Free Free NA Linear

[5140] c NO: 0967 -0.13 TKRRITPKDVIDV Amphipathi SEQ ID

[5141] Free Free NA Linear RSVTTEINT c NO: 0968

[5142] -3.11 TKRRITPKDVIDV Amphipathi SEQ ID

[5143] Free Free NA Linear RSVTTEINT c NO: 0968

[5144] -3.11 TKRRITPKDVIDV Amphipathi SEQ ID

[5145] Free Free NA Linear RSVTTKINT c NO: 0969

[5146] -1.94 TKRRITPKKVIDV Amphipathi SEQ ID

[5147] Free Free NA Linear RSVTTEINT c NO: 0970

[5148] -2.66 Conj

[5149] ugati TRSSRAGLQWP on

[5150] Amphipathi SEQ ID

[5151] VGRVHRLLRKG Free with NA Linear

[5152] c NO: 0971

[5153] GO Texa

[5154] s

[5155] Red -1.26 Amphipathi SEQ ID

[5156] TSHTDAPPARSP NA NA NA Linear

[5157] c NO: 0972 -2.89

[5158] Ami

[5159] Amphipathi SEQ ID

[5160] TSPLNIHNGQKL Free datio NA Linear

[5161] c NO: 0973

[5162] n -0.27 TVDNPASTTNKD Amphipathi SEQ ID

[5163] Free Free NA Linear KLFAVRK c NO: 0974

[5164] -1.82 Cys

[5165] VKRGLKLRHVR Amphipathi SEQ ID

[5166] additi Free NA Linear PRVTRMDV c NO: 0975

[5167] on -1.14 Ami

[5168] VQAILRRNWNQ Amphipathi SEQ ID

[5169] Free datio NA Linear YKIQ c NO: 0976

[5170] n 0.52 Ami

[5171] VRRFLVTLRIRR SEQ ID

[5172] Cationic Free datio NA Linear

[5173] A NO: 0977

[5174] n 0.27 SEQ ID VSGKK Catioinic Free Free NA Linear

[5175]

[5176] NO: 0978 -0.01 ATTORNEY DOCKET: 05336.0007WO01

[5177] WKQSHKKGGKK SEQ ID

[5178] Cationic Free Free NA Linear GSG NO: 0979 -0.12 WKQSHKKGGKK SEQ ID

[5179] Cationic Free Free NA Linear GSG NO: 0979 -0.12

[5180] FITC

[5181] linke

[5182] d to

[5183] a

[5184] SEQ ID YARAAARQARA Cationic beta- NA NA Linear NO: 0980

[5185] Alani

[5186] ne

[5187] resid

[5188] ue -3.78 YARAAARQARA SEQ ID

[5189] Cationic Free Free NA Linear KALARQLGVAA NO: 0981

[5190] -4.12 Fusi

[5191] on

[5192] SEQ ID YARAARRAARR Cationic Free with NA Linear NO: 0982

[5193] beta

[5194] -Gal -4.75 Fusi

[5195] on

[5196] SEQ ID YAREARRAARR Cationic Free with NA Linear NO: 0983

[5197] beta

[5198] -Gal -5.48 Fusi

[5199] on

[5200] SEQ ID YARKARRAARR Cationic Free with NA Linear NO: 0984

[5201] beta

[5202] -Gal -4.31 Fusi

[5203] on

[5204] SEQ ID YEREARRAARR Cationic Free with NA Linear NO: 0985

[5205] beta

[5206] -Gal -6.21 Fusi

[5207] on

[5208] SEQ ID YGRAARRAARR Cationic Free with NA Linear NO: 0986

[5209] beta

[5210] -Gal -4.7 YGRKKRRQRRR Ami

[5211] SEQ ID GCYGRKKRRQR Cationic Free datio NA Linear NO: 0987

[5212] RRG n

[5213]

[5214] -7.78 ATTORNEY DOCKET: 05336.0007WO01

[5215] YGRKKRRQRRR GLFGAIAGFIEN Amphipathi SEQ ID

[5216] Free Free NA Linear GWEGMIDGWY c NO: 0988

[5217] G -0.55 YGRKKRRQRRR

[5218] Amphipathi SEQ ID

[5219] GTALDWSWLQT NA NA NA Linear

[5220] c NO: 0989

[5221] E -2.97 YGRKKRRQRRR Amphipathi SEQ ID

[5222] Free Free NA Linear YGRKKRRQRRR c NO: 0990

[5223] -8.82 YGRKKRRQRRT Amphipathi SEQ ID

[5224] Free NA NA Linear ALDASALQTE c NO: 0991

[5225] -5.42 Bio YGRKKRRQRRT Amphipathi SEQ ID tiny

[5226] Free NA Linear ALDWSWLQTE c NO: 0992 lati

[5227] on -1.96 Fusi

[5228] on

[5229] Arginine SEQ ID

[5230] YGRRARRAARR Free with NA Linear rich NO: 0993

[5231] beta

[5232] -Gal -5.22 Fusi

[5233] on

[5234] Arginine SEQ ID

[5235] YGRRARRRARR Free with NA Linear rich NO: 0994

[5236] beta

[5237] -Gal -5.74 Fusi

[5238] on

[5239] Arginine SEQ ID

[5240] YGRRARRRRRR Free with NA Linear rich NO: 0995

[5241] beta

[5242] -Gal -6.26 Fusi

[5243] on

[5244] Arginine SEQ ID

[5245] YGRRRRRRRRR Free with NA Linear rich NO: 0996

[5246] beta

[5247] -Gal -6.78 Ami YIVLRRRRKRVN Arginine SEQ ID

[5248] Free datio NA Linear TKRS rich NO: 0997

[5249] n -2.75 Amphipathi SEQ ID

[5250] YKQCHKKGG

[5251] c NO: 0998 0.8

[5252] Ah

[5253] SEQ ID

[5254] x,

[5255] NO: 0998

[5256] YKQCHKKGG- Amphipathi 6- and SEQ Free Free Linear AHX-KKGSG c am

[5257] ID NO:

[5258] ino

[5259] 0999

[5260]

[5261] he -2.45 ATTORNEY DOCKET: 05336.0007WO01

[5262] xa

[5263] noi

[5264] c

[5265] aci

[5266] d

[5267] Amphipathi SEQ ID

[5268] KKGSG

[5269] c NO: 0999 -0.55 YKQSHKKGGKK SEQ ID

[5270] Cationic Free Free NA Linear GSG NO: 1000 -1.03 YKQSHKKGGKK SEQ ID

[5271] Cationic Free Free NA Linear GSG NO: 1000 -1.03

[5272] Fusi

[5273] on

[5274] SEQ ID YKRAARRAARR Cationic Free with NA Linear NO: 1001

[5275] beta

[5276] -Gal -4.31 Fusi

[5277] on

[5278] SEQ ID YKRKARRAARR Cationic Free with NA Linear NO: 1002

[5279] beta

[5280] -Gal -3.87 Fusi

[5281] on

[5282] SEQ ID YPRAARRAARR Cationic Free with NA Linear NO: 1003

[5283] beta

[5284] -Gal -4.33 YPYDANHTRSP Amphipathi SEQ ID

[5285] NA NA NA Linear

[5286] T c NO: 1004 -2.2...

Claims

ATTORNEY DOCKET: 05336.0007WO01What is claimed is:

1. A method for selectively reducing a senescent cell population, comprising administering a composition comprising an active ingredient to cells in an amount sufficient to selectively reduce the senescent cell population, wherein the active ingredient comprises a cell penetrating peptide.

2. The method as recited in claim 1, wherein the active ingredient consists essentially of SEQ ID NO: 13 or SEQ ID NO: 14.

3. The method as recited in claim 1, wherein the active ingredient consists essentially of SEQ ID NO: 13.

4. The method as recited in claim 1, wherein the composition is administered one or more times in a treatment time period of about 1 weeks to about 15 weeks.

5. The method as recited in claim 1, wherein the composition is administered two or more times in a treatment time period of about 1 weeks to about 15 weeks.

6. The method as recited in claim 1, wherein the active ingredient consists essentially of a cell penetrating peptide selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 18 and SEQ ID NO: 1079.

7. The method as recited in claim 1, wherein the active ingredient consists essentially of a cell penetrating peptide selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 1009, SEQ ID NO: 1010, SEQ ID NO: 1077, SEQ ID NO: 1078, SEQ ID NO:1079, SEQ ID NO: 1080, and SEQ ID NO: 1081.

Images