High penetration prodrug compositions of peptides and peptide-related compounds

Abstract

To provide highly penetrating compositions or highly penetrating prodrugs of peptides and peptide-related compounds.SOLUTION: Provided herein is a high penetration composition or high penetration prodrug of a peptide or peptide-related compound comprising a functional unit, a linker and a transportational unit. The functional unit is covalently linked to the transportational unit through the linker and comprises a moiety of the peptide or peptide-related compound. The transportational unit comprises a protonatable amine group. The linker comprises a chemical bond that is cleavable after the composition penetrates across a biological barrier.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS Priority Declaration This application is a continuation-in-part of and claims priority to U.S. Patent Application No. 12 / 463,374, filed May 8, 2009, which is incorporated herein by reference. This application also claims priority to Chinese Patent Application No. 200910135997.0, filed May 8, 2009.

[0002] Technical Field The present invention relates to the field of pharmaceutical compositions capable of penetrating one or more biological barriers, and to methods of using the pharmaceutical compositions to prevent, diagnose and / or treat conditions or diseases in humans and animals treatable by peptides or peptide-related compounds. The present invention also relates to methods of using the pharmaceutical compositions to screen new drug candidates and to methods of using the pharmaceutical compositions to diagnose conditions in biological subjects. Methods for the synthesis of HPPs / HPCs of peptides from the N-terminus to the C-terminus have been developed. [Background technology]

[0003] Peptides are polymers formed by linking amino acids with amide bonds. Peptides play various roles in biological systems. For example, peptide hormones are the largest group of hormones that regulate various biological processes in living subjects. One nanogram of thyrotropin-releasing hormone injected into mice increases the uptake of iodine from the blood into the thyroid gland (RL Kisliuk, Principles of Medicinal Chemistry, 4 th Ed., WO Foye, et al. Eds., Williams & Wilkins, 4 th Ed. 1995, p. 606). Tuftsin (Thr-Lys-Pro-Arg) stimulates phagocytosis and promotes antibody-dependent cellular cytotoxicity (VA Najjar, Mol. Cell. Biochem. 41, 1, 1981). Met-enkephalin (Tyr-Gly-Gly-Phe-Met), isolated from brain and small intestine, acts like morphine in that it binds to the same receptor and has analgesic activity (JR Jaffe and WR Martin, in Pharmacological Basis of Therapeutics, AG Gilman, et al., Eds., New York, Pergamon Press, 1990, p. 481). Other examples of peptide hormones include, but are not limited to, oxytocin (Pierce et al., J. Biol. Chem. 199 , 929, 1952), vasopressin (Kamm et al., J. Am. Chem. Soc. 50 , 573, 1928), angiotensin (JC Garrison and MJ Peach, in Pharmacological Basis of Therapeutics, AG Gilman, et al., Eds., New York, Pergamon Press, 1990, p. 749), gastrin (PC Emson and BEB Sandberg, Annu, Rep. Med. Chem., 18 , 31, 1983), somatostatin (AV Schally, et al., Annu. Rev. Biochem., 47 , 89, 1978), dynorphin (MG Weisskopf, et al., Nature, 362 , 423, 1993), endothelin (AM Doherty, J. Med. Chem., 35 , 1493, 1992), secretin (E. Jorper, Gastroenterology, 55 , 157, 1968), calcitonin (MVL Ray, et al., Biotechnology, 11 , 64, 1993), insulin (F. Sanger, Br. Med. Bull., 16, 183, 1960), and competence stimulating peptide (CSP).

[0004] Another group of peptides are the antimicrobial peptides that have been found to participate in innate immunity in a wide variety of organisms (Reddy et al. 2004). These peptides and others have attracted much interest due to their potential usefulness in treating infections, especially as they are often effective against bacterial strains that have become resistant to traditional antibiotics. One well-known class of antimicrobial peptides is the tachyplesins. Another class of antimicrobial peptides is the histatin peptides and their derivatives. Another class of antimicrobial peptides is hepcidin, also called LEAP-1 for liver-expressed antimicrobial peptide.

[0005] Another group of peptides are calcium-binding peptides that specifically bind to mineralized surfaces. One example of a calcium-binding peptide is a triple repeat of amino acids (XYZ): n wherein X is aspartic acid, glutamic acid, asparagine, or glutamine; Y and Z are alanine, serine, threonine, phosphoserine, or phosphothreonine; and n is a number from 1 to 40.

[0006] Unfortunately, peptides and peptide-related compounds are rapidly proteolyzed by proteolytic enzymes. When taken orally, peptides and peptide-related compounds undergo proteolysis within minutes. Other systemic administration of peptides and peptide-related compounds is painful and often requires frequent and costly hospital visits to treat chronic conditions.

[0007] Thus, there is a need in the art for new compositions that can be efficiently and effectively delivered to the site of action of a condition (e.g., disease) to prevent, alleviate or treat the condition while minimizing adverse side effects. Summary of the Invention [Problem to be solved by the invention]

[0008] One aspect of the present invention is directed to highly permeable prodrugs (HPPs) or highly permeable compositions (HPCs) that include a functional unit covalently linked to a transport unit via a linker. The terms "HPP" and "HPC" are used herein, alone or together, and are interchangeable unless otherwise specified. [Means for solving the problem]

[0009] In certain embodiments, a functional unit of an HPP or HPC comprises a moiety of an agent, where efficient and effective delivery of the agent to a biological subject and / or transport of the agent across one or more biological barriers is desired.

[0010] In certain embodiments, a functional unit may be hydrophilic, lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic). For example, the lipophilic nature of a functional unit may be inherent or may be achieved by converting a hydrophilic moiety of the functional unit into a lipophilic moiety.

[0011] In certain embodiments, functional units of an HPP or HPC comprise portions of a peptide or peptide-related compound. Peptide-related compounds are compounds that contain a peptide structure, a peptide metabolite, or an agent that can be metabolized to a peptide or peptide metabolite after the HPP or HPC has penetrated one or more biological barriers. Peptide-related compounds further include compounds that are analogs or mimetics of a peptide or peptide metabolite, or an agent that can be metabolized to an analog or mimetics of a peptide or peptide metabolite after the HPP or HPC has penetrated one or more biological barriers. Exemplary peptides include peptide hormones (e.g., thyrotropin releasing hormone, tuftsin (Thr-Lys-Pro-Arg), Met-enkephalin (Tyr-Gly-Gly-Phe-Met), oxytocin, angiotensin, gastrin, somatostatin, dynorphin, endothelin, secretin, calcitonin and insulin), enterostatin (e.g., Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg (VPGPR) and Ala-Pro-Gly-Pro-Arg (APGPR)), melanocortin II (cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH), , opioid peptides (e.g., Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL and H-Tyr-D-Ala-Gly-Phe-Leu-OH), neuropeptides, alkaloids, anti-inflammatory peptides, antimicrobial peptides (e.g., competence stimulating peptides, tachyplesins, histatin peptides and derivatives thereof), calcium binding peptides, regulatory peptides, peptide vaccines, and peptidomimetics (e.g., α-helical mimetics and β-sheet mimetics).

[0012] In certain embodiments, the transport unit of the HPP or HPC comprises a protonatable amine group that is capable of facilitating or enhancing the transport or traversal of the HPP or HPC through one or more biological barriers. In certain embodiments, the protonatable amine group is substantially protonated at the pH of the biological barrier through which the HPP or HPC permeates. In certain embodiments, the amine group can be reversibly protonated or deprotonated.

[0013] In certain embodiments, the linker comprises a bond that covalently attaches the functional unit to a transport unit of the HPP or HPC and that can be cleaved after the HPP or HPC has permeated across one or more biological barriers. Cleavable bonds include, for example, a covalent bond, an ether bond, a thioether bond, an amide bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, or an oxime bond.

[0014] Another aspect of the invention relates to a pharmaceutical composition comprising at least one HPP or HPC of a peptide or peptide-related compound and a pharma- ceutically acceptable carrier.

[0015] Another aspect of the invention relates to a method for penetrating biological barriers using the HPP or HPC of a peptide or peptide-related compound.

[0016] Another aspect of the invention relates to a method for diagnosing the onset, progression or remission of a condition in a biological subject by using an HPP or HPC of a peptide or peptide-related compound. In certain embodiments, the HPP (or HPC) or a functional unit thereof is detectable. In certain embodiments, the HPP / HPC or a functional unit of the HPP / HPC is inherently detectable or is labeled with or conjugated to a detectable marker.

[0017] Another aspect of the invention relates to a method of screening functional units, linkers or transport units for a desired property.

[0018] Another aspect of the invention relates to a method for preventing, ameliorating or treating a condition in a biological subject by administering a composition according to the invention to the subject. In certain embodiments, the method relates to treating a condition in a subject treatable by a peptide or peptide related compound by administering a therapeutically effective amount of peptide HPP / HPC or a pharmaceutical composition thereof to the subject. In certain embodiments, the conditions treatable by the method include, but are not limited to, pain, trauma, inflammation-related conditions, microbial-related conditions, neuropeptide-related conditions, hormone-related conditions, tumors, abnormal blood pressure, obesity, brain injury, allergies, male and female impotence, metastasis, and other conditions related to tuftsin, prepartum, postpartum, anti-AD activity, antidiuretic activity, calcium homeostasis, melanocytes, hormone release, platelet aggregation, CNS activity, and phagocytosis.

[0019] In certain embodiments, pharmaceutical compositions of HPP / HPC are administered to biological subjects via a variety of routes, including, but not limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, intradermal, ocular, pulmonary, subcutaneous, and / or parenteral. In particularly preferred embodiments, pharmaceutical compositions of HPP are administered orally, transdermally, topically, subcutaneously, and / or parenterally. Effect of the Invention

[0020] Advantages of the present invention, without intending to be limited to a particular mechanism, include the ability to administer therapeutically effective amounts of HPP or HPC locally to the site of a condition at high concentrations and low dosages. Advantages of the present invention include, for example, avoidance of systemic administration, reduction of adverse effects (e.g., pain on injection, gastrointestinal / rectal effects, and other side effects), and novel therapeutic possibilities due to high local concentrations of HPP, HPC, or active agent. Advantages also include, for example, systemic administration of HPP or HPC to a biological subject to achieve faster and more efficient bioavailability, penetration of difficult to cross biological barriers (e.g., blood-brain barrier), and new applications as a result of crossing biological barriers. [Brief description of the drawings]

[0021] [Figure 1]Structure 2, Structure 3, Structure 4, Structure 5, Structure 6, Structure 7, Structure 8, Structure 9, Structure 10, Structure 11, Structure 12, Structure 13, Structure 14, Structure 15, Structure 16, Structure 17, Structure 18, Structure 19, Structure 20, Structure 21, Structure 22, Structure 23, Structure 24, Structure 25, Structure 26, Structure 27, Structure 28, Structure 37, Structure 38, Structure 39, Structure 40, Structure 41, Structure 42, Structure 43, Structure 44, Structure 45, Structure 46, Structure 47, Structure 48, Structure 49, Structure 50, Structure 51, Structure 52, Structure 53, Structure 54, Structure 55, Structure 56, Structure 57, Structure 58, Structure 59, Structure 60, Structure 61, Structure 62, Structure 63, Structure 64, Structure 65, Structure 66, Structure 67, Structure 68, Structure 69, Structure 70, Structure 71, Structure 72, Structure 73, Structure 74, Structure 75, Structure 76, Structure 77, Structure 78, Structure 79, Structure 80, Structure 81, Structure 82, Structure 83, Structure 84, Structure 85, Structure 86, Structure 87, Structure 88, Structure 89, Structure 90, Structure 91, Structure 92, Structure 93, Structure 94, Structure 95, Structure 96, Structure 97, Structure 98, Structure 99, Structure 100, Structure 101, Structure 102, Structure 103, Structure 104, Structure 105, Structure 106, Structure 107, Structure 108, Structure 109, Structure 110, Structure 111, Structure 112, Structure 113, Structure 114, Structure 115, Structure 116, Structure 117, Structure 118, Structure 119, Structure 120, Structure 121, Structure 122, Structure 123, Structure 124, Structure 125, Structure 126, Structure 127, Structure 128, Structure 137, Structure 138, Structure 139, Structure 140, Structure 141, Structure 142, Structure 143, Structure 144, Structure 145, Structure 146, Structure 147, Structure 148, Structure 149, Structure 150, Structure 151, Structure 152, Structure 153, Structure 154, Structure 155, Structure 156, Structure 157, Structure 158, Structure 159, Structure 160, Structure 161, Structure 162, Structure 163, Structure 164, Structure 165, Structure 166, Structure 167, Structure 168, Structure 169, Structure 170, Structure 171, Structure 172, Structure 173, Structure 174, Structure 175, Structure 176, Structure 177, Structure 178, Structure 179, Structure 180, Structure 181, Structure 182, Structure 183, Structure 184, Structure 185, Structure 186, Structure 187, Structure 188, Structure 189, Structure 190, Structure 191, Structure 192, Structure 193, Structure 194, Structure 195, Structure 196, Structure 197, Structure 198, Structure 199, Structure 200Structure 201, Structure 202, Structure 203, Structure 204, Structure 205, Structure 206, Structure 207, Structure 208, Structure 209, Structure 210, Structure 211, Structure 212, Structure 213, Structure 214, Structure 215, Structure 216, Structure 217, structure 218, structure 219, structure 220, structure 221, structure 222, structure 223, structure 224, structure 225, structure 226, structure 227, structure 228, structure 237, structure 238, structure 239, structure 240, structure 24 1, structure 242, structure 243, structure 244, structure 245, structure 246, structure 247, structure 248, structure 249, structure 250, structure 251, structure 252, structure 253, structure 254, structure 255, structure 256, structure 257, Structure 258, Structure 259, Structure 260, Structure 261, Structure 262, Structure 263, Structure 264, Structure 265, Structure 266, Structure 267, Structure 268, Structure 269, Structure 270, Structure 271, Structure 272, Structure 273, Structure 274, structure 275, structure 276, structure 277, structure 278, structure 279, structure 280, structure 281, structure 282, structure 283, structure 284, structure 285, structure 286, structure 287, structure 288, structure 289, structure 29 0, structure 291, structure 292, structure 293, structure 294, structure 295, structure 296, structure 297, structure 298, structure 299, structure 300, structure 301, structure 302, structure 303, structure 304, structure 305, structure 306, 3 shows structures 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 337, 338, 339, 340, 341, 342, 343, 344, and 345. [Diagram 2]Ac-Tyr(Ac)-Gly-Gly-Phe-Met-OCH2CH2N(CH2CH3)2·HCl, HCl·(CH3)2NCH2CH2CH2CO-Tyr(Ac)-Gly-Gly-Phe-Met-OCH2CH2CH2CH3, cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH2CH2N(CH2CH3)2·HCl, cyclo(1,6)-H-Nle-Asp-His-D-Phe(4-I)-Arg(Ac)-Trp-Lys-NH ... Figure 1 shows the cumulative amounts of cyclo(1,6)-H-Nle-Asp-His-D-Ala(2-naphthyl)-Arg(NO2)-Trp-Lys-NH2·HCl, Ac-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·HCl, Ac-Tyr-Gly-Gly-Phe-Met-OH, cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH, cyclo(1,6)-Ac-Nle-Asp-His-D-Phe(4-I)-Arg-Trp-Lys-NH2 and H-Val-Pro-Gly-Pro-Arg-OH. In each case the vehicle was phosphate buffer (0.2 M), pH 7.4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] I. Structure of Highly Permeable Prodrugs (HPP) or Highly Permeable Compositions (HPC) of Peptides or Peptide-Related Compounds

[0023] One aspect of the present invention is directed to highly permeable prodrugs (HPPs) or highly permeable compositions (HPCs). The terms "highly permeable prodrugs" or "HPPs" or "highly permeable compositions" or "HPCs" as used herein refer to compositions that include a functional unit covalently linked to a transport unit via a linker.

[0024] A functional unit of an HPP / HPC that comprises a portion of a parent drug has the properties that: 1) delivery of the parent drug or HPP / HPC to a biological subject and / or transport of the parent drug across a biological barrier is desirable; 2) the HPP / HPC is capable of permeating or crossing a biological barrier; and 3) the HPP / HPC can be cleaved to convert the portion of the parent drug into the parent drug or a metabolite of the parent drug.

[0025] In certain embodiments, the functional unit may be hydrophilic, lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic). The lipophilic portion of the functional unit may be inherent or may be achieved by converting the hydrophilic portion of the functional unit to a lipophilic portion. For example, the lipophilic portion of the functional unit is created by converting one or more hydrophilic groups of the functional unit to a lipophilic group via organic synthesis. Examples of hydrophilic groups include, but are not limited to, carboxyl groups, hydroxyl groups, thiol groups, amine groups, phosphate / phosphonate groups, and carbonyl groups. Lipophilic portions created via modification of these hydrophilic groups include, but are not limited to, ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates, and oximes. In certain embodiments, the functional unit is lipophilized by acylation. In certain embodiments, the functional unit is lipophilized by esterification.

[0026] In certain embodiments, the parent drug of the HPP or HPC is selected from the group consisting of peptides and peptide-related compounds. The peptide and peptide-related compound moieties can be further converted to lipophilic moieties as described above. As used herein, the term "peptide HPP / HPC" refers to HPPs or HPCs of peptides and peptide-related compounds. As used herein, the term "peptide HPPs / HPCs" refers to HPPs or HPCs of peptides and peptide-related compounds.

[0027] Peptides are well known in the art and are used in a variety of contexts. As used herein, peptide refers to a sequence of amino acids, the length of the sequence being about 2 to about 50 amino acids. For example, a peptide may be composed of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more amino acids. A peptide may contain both D-amino acids and / or L-amino acids.

[0028] Amino acids are compounds that contain both amine and carboxyl functional groups. The carbon atom next to the carbonyl group of the carboxyl functional group is called the alpha carbon. Amino acids with a side chain attached to the alpha carbon are called alpha amino acids. In amino acids with an amino group and a carbon chain linked to the alpha carbon, the carbons are labeled alpha, beta, gamma, etc. from the carbonyl carbon. Amino acids with an amino group linked to a beta or gamma carbon are called beta or gamma amino acids, respectively.

[0029] Alpha amino acids are amino acids that have an amino group and a carboxyl group attached to the same carbon (the alpha carbon). The alpha carbon is one atom away from the carboxylic acid group. Alpha amino acids have the structure 1: H2NCHR'COOH (Structure 1) The structure is and phenyl, ...

[0030] In certain embodiments, the amino acid has the structure 1, including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein R′ is H—, CH3, HN═C(NH2)—NH—(CH2)3—, H2N-CO—CH2—, HOOC-CH2—, HS-CH2—, H2N-CO—(CH2)2—, HS-(CH2)2—, HOOC-(CH2)2—, CH3-CH2-CH(CH3)—, (CH3)2CH-CH2-, H2N-(CH2)4-, CH3-S—(CH2)2-, Phenyl-CH2-, HO-CH2-, CH3-CH(OH)—, 4-OH-Phenyl-CH2-, CH3-CH(CH3), [ka] [ka] [ka] and derivatives thereof.

[0031] Examples of alpha amino acids include, but are not limited to, alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamic acid (Glu), glutamine (Gln), glycine (Gly), histidine (His), homocysteine ​​(Hcy), homoserine (Hse), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), norleucine (Nle), norvaline (Nva), ornithine (Orn), penicillamine (Pen), phenylalanine (Phe), proline (Pro), serine (Ser), tyrosine (Thr), threonine (Trp), tryptophan (Tyr), valine (Val), pyroglutamic acid (pGLU), dinitrobenzenesulfonyl ester (DnB), and phenylalanine (Phe). N-methylated lysine (dnp-LYS), phosphorylated threonine (pTHR), phosphorylated serine (pSER), phosphorylated tyrosine (pTYR), citrulline (CIT), N-methylated alanine (nme-ALA), N-methylated isoleucine (nme-ILE), N-methylated leucine (nme-LEU), N-methylated phenylalanine (nme-PHE), N-methylated valine (nme-VAL), N-methylated serine (nme-SER), N-methylated threonine (nme-THR), N-methylated tyrosine (nme-TYR), alpha amino-butyric acid (alpha-ABA), isoaspartic acid (iso-ASP), acetylated lysine (Ac-LYS), 2-methylalanine (2-Me-ALA), and oxamic acid (OXA).

[0032] A beta amino acid is an amino acid that has an amino group attached to the beta carbon that is second away from the carboxylic acid group. Examples of beta amino acids include, but are not limited to, beta-alanine (β-Ala), beta-arginine (β-Arg), beta-asparagine (β-Asn), beta-aspartic acid (β-Asp), beta-cysteine ​​(β-Cys), beta-glutamic acid (β-Glu), beta-glutamine (β-Gln), beta-histidine (β-His), beta-isoleucine (β-Ile), beta-leucine (β-Leu), beta-lysine (β-Lys), beta-methionine (β-Met), beta-phenylalanine (β-Phe), beta-proline (β-Pro), beta-serine (β-Ser), beta-tyrosine (β-Thr), beta-threonine (β-Trp), beta-tryptophan (β-Tyr), and beta-valine (β-Val).

[0033] A gamma amino acid is an amino acid having an amino group attached to the gamma carbon that is the third carbon away from the carboxylic acid group. Examples of gamma amino acids include, but are not limited to, gamma-glutamic acid (γ-GLU).

[0034] Peptide-related compounds are compounds that contain a peptide structure, a peptide metabolite, or an agent that can be metabolized to a peptide or a peptide metabolite after the peptide HPP / HPC has penetrated one or more biological barriers. Peptide-related compounds further include compounds that are analogs or mimetics of a peptide or peptide metabolite, or an agent that can be metabolized to an analog or mimetics of a peptide or a peptide metabolite after the HPP or HPC has penetrated one or more biological barriers.

[0035] Examples of peptides and peptide-related compounds include, but are not limited to, peptide hormones, neuropeptides, alkaloids, antimicrobial peptides, anti-inflammatory peptides, peptide toxins, regulatory peptides, calcium-binding peptides, peptide vaccines, and peptidomimetics.

[0036] Peptide hormones are a class of peptides that have endocrine functions in living animals. Peptide hormones have also been identified in plants with important roles in cell-cell communication and plant defense. Peptide hormones are secreted in various organs and tissues, such as the heart (arterial natriuretic peptide (ANP), arterial natriuretic factor (ANF)), pancreas (e.g., insulin, enterostatin, somatostatin), gastrointestinal tract (cholecystokinin, gastrin (e.g., gastrin-34, gastrin-17, and gastrin-14), opioid peptides (e.g., Met-enkephalin, Leu-enkephalin, H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL, and H-Tyr-D-Ala-Gly-Phe-Leu-OH), cholecystokinin, secretin, motilin, vasoactive intestinal peptide, and enteroglucan. gon), adipose tissue stores (e.g., leptin), pituitary gland (e.g., luteinizing hormone, follicle-stimulating hormone, prolactin, adrenocorticotropic hormone (ACTH), growth hormone, antidiuretic hormone, oxytocin, melanocortins, (e.g., melanocortin II)), thyroid gland (e.g., calcitonin), spleen (e.g., tuftsin), brain (e.g., oxytocin, dynorphin), liver (e.g., angiotensin, angiotensin I, and angiotensin II), and endothelium (e.g., endothelin). Other examples of peptide hormones include, but are not limited to, thyroid-stimulating hormone (TRH) and bradykinin.

[0037] Neuropeptides are peptides found in nervous tissues that are involved in regulatory and signaling processes. Examples of neuropeptides include, but are not limited to, neurotransmitters (e.g., N-acetylaspartylglutamate, gastrin, cholecystokinin, neuropeptide Y, vasopressin, oxytocin, secretin, substance P, somatostatin, vasoactive intestinal peptide (VIP), opioids (e.g., enkephalins, dynorphins, endorphins), gallatin, neurotensin, TRH, and arterial natriuretic peptide.

[0038] Alkaloids are peptides that are usually derived from plants, fungi, and some animals such as shellfish. Alkaloids are involved in protecting one organism from consumption by another. Examples of alkaloids include, but are not limited to, ergotamine, pandamine, dynorphin A-(1-8)-octapeptide, and N-β-D-Leu-D-Arg-D-Arg-D-Leu-D-Phe)-naltrexamine.

[0039] Antimicrobial peptides are peptides that inhibit the growth of microorganisms such as bacterial cells, fungi, and protozoa. Examples of antimicrobial peptides include, but are not limited to, bacitracin, gramicidin, valinomycin, competence stimulating peptide, tachyplesin, histatin peptides, and derivatives thereof.

[0040] Examples of anti-inflammatory peptides are peptides having the sequences SEQ ID NO: 47, SEQ ID NO: 48, and SEQ ID NO: 49 (Table A).

[0041] Peptide toxins are peptides that are toxic. Examples of peptide toxins are partoxin, agatoxin and cartatoxin.

[0042] A regulatory peptide is a peptide that regulates one or more processes in a biological subject. Examples of regulatory peptides include, but are not limited to, anserine and carmosine.

[0043] Other examples of peptides and peptide-related compounds include calcium-binding peptides, peptide vaccines [p45 (IEIGLEGKGFEPTLE ALFGK) and p210 (KTTKQSFDLS VKAQY KKNKH)] and peptidomimetics (eg, α-helical mimetics and β-sheet mimetics).

[0044] In certain embodiments, the functional unit of the peptide HPP / HPC has the structure F-1 [ka] Structure F-1 and includes stereoisomers thereof and pharma- ceutically acceptable salts thereof, wherein each of A1 to A m are independently selected from the residues of 2-naphthylalanine, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and Structure A: [ka] Structure A selected from the group consisting of; A1~A m p is an independently selected integer; Each A1~A m , Z NT , Z CT-1 and Z CT-2 Regarding each A1~A m Z at each carbon A-1 are independently H, CH3, or C2H 5、 selected from the group consisting of C3H7, CF3, C2F5, C3F7, substituted and unsubstituted alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides; Each A1~A m , R NT and R CT R at each carbon A is selected from the group consisting of H, substituted and unsubstituted imidazolyl, substituted and unsubstituted guanidino, substituted and unsubstituted carboxyl, substituted and unsubstituted carboxamido, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups; A1~A m When p is an integer less than 2, R on each carbon Amay be the same or different, and Z on each carbon A-1 may be the same or different; The amino and carboxyl functional groups in the peptide chain may further form lactam bridges; The thiol groups may further form disulfide bridges.

[0045] In certain embodiments, the functional unit of the peptide HPP / HPC comprises a moiety having a structure selected from the group consisting of structure F-1 as defined above, including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein A1-A m R A may be rendered further lipophilic by acylation or esterification.

[0046] In certain embodiments, the functional unit of the peptide HPP / HPC comprises a moiety having a structure selected from the group consisting of structure F-1 as defined above, including stereoisomers thereof and pharma- ceutically acceptable salts thereof, wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12... and 100.

[0047] In certain embodiments, the functional unit of the peptide HPP / HPC comprises a moiety having the structure F-1 as defined above, including its stereoisomers and pharma- ceutically acceptable salts thereof, where p is 1, 2 or 3.

[0048] In certain embodiments, the functional unit of the peptide HPP / HPC comprises a moiety having the structure F-1 as defined above, including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein p is 1, 2 or 3; Each A1~A m , Z NT , Z CT-1 and Z CT-2 Regarding each A1~A m , Z A-2 Z at each carbon A-1 are independently H, CH3, or C2H 5、selected from the group consisting of C3H7, CF3, C2F5, C3F7, substituted and unsubstituted alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides; Each A1~A m , R NT and R CT R at each carbon A is selected from the group consisting of H, substituted and unsubstituted imidazolyl, substituted and unsubstituted guanidino, substituted and unsubstituted carboxyl, substituted and unsubstituted carboxamido, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups; A1~A m When p is an integer less than 2, R on each carbon A may be the same or different, and Z on each carbon A-1 may be the same or different; The amino and carboxyl functional groups in the peptide chain may further form lactam bridges; The thiol groups may further form disulfide bridges.

[0049] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of the compound of the present invention that is safe for application in a subject. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compound of the present invention. Pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, genistate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. (i.e., 1,11-methylene-bis-(3-hydroxy-3-naphthoate). Certain compounds of the present invention can form pharma- ceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. For a review of pharma- ceutical acceptable salts, see BERGE et al., 66 J. PHARM. SCI. 1-19 (1977), incorporated herein by reference.

[0050] As used herein, unless otherwise specified, the term "alkyl" means a branched or unbranched, saturated or unsaturated, monovalent or polyvalent hydrocarbon group, and includes saturated alkyl, alkenyl, and alkynyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, decynyl, undecynyl, dodecynyl, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, and dodecylene. In certain embodiments, the hydrocarbon group contains 1 to 30 carbons. In certain embodiments, the hydrocarbon group contains 1 to 20 carbons. In certain embodiments, the hydrocarbon group contains 1 to 12 carbons.

[0051] As used herein, unless otherwise specified, the term "cycloalkyl" refers to an alkyl containing at least one ring and not containing an aromatic ring. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In certain embodiments, the hydrocarbon chain contains 1-30 carbons. In certain embodiments, the hydrocarbon group contains 1-20 carbons. In certain embodiments, the hydrocarbon group contains 1-12 carbons.

[0052] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a cycloalkyl in which at least one of the ring atoms is a non-carbon atom. Examples of non-carbon ring atoms include, but are not limited to, S, O, and N.

[0053] As used herein, unless otherwise specified, the term "alkoxy" refers to an alkyl, cycloalkyl, or heterocycloalkyl containing one or more oxygen atoms. Examples of alkoxy include, but are not limited to, -CH2-OH, -OCH3, -O-alkyl, -alkyl-OH, -alkyl-O-alkyl-, where the two alkyls can be the same or different.

[0054] As used herein, unless otherwise specified, the term "alkyl halide" refers to an alkyl, cycloalkyl, or heterocycloalkyl containing one or more halogen atoms, where the halogen atoms can be the same or different. The term "halogen" refers to fluorine, chlorine, bromine, or iodine. Examples of alkyl halides include, but are not limited to, -alkyl-F, -alkyl-Cl, -alkyl-Br, -alkyl-I, -alkyl(F)-, -alkyl(Cl)-, -alkyl(Br)-, and -alkyl(I)-.

[0055] As used herein, unless otherwise specified, the term "alkylthio" refers to an alkyl, cycloalkyl, or heterocycloalkyl containing one or more sulfur atoms. Examples of alkylthio include, but are not limited to, -CH2-SH, -SCH3, -S-alkyl, -alkyl-SH, -alkyl-S-alkyl-, where the two alkyls can be the same or different.

[0056] As used herein, unless otherwise specified, the term "alkylamino" refers to an alkyl, cycloalkyl, or heterocycloalkyl containing one or more nitrogen atoms. Examples of alkylamino include, but are not limited to, -CH2-NH, -NCH3, -N(alkyl)-alkyl-, N-alkyl-, -alkyl-NH2, -alkyl-N-alkyl-, and -alkyl-N(alkyl)-alkyl-, where the alkyls can be the same or different.

[0057] As used herein, unless otherwise specified, the term "alkylcarbonyl" refers to an alkyl, cycloalkyl, or heterocycloalkyl containing one or more carbonyl groups. Examples of alkylcarbonyl groups include, but are not limited to, aldehyde groups (-RC(O)-H), ketone groups (-RC(O)-R'), carboxylic acid groups (R-COOH), ester groups (-R-COO-R'), carboxamide groups (-R-COO-N(R')R''), enone groups (-RC(O)-C(R')=C(R'')R'''), acyl halide groups (-RC(O)-X), and anhydride groups (-RC(O)-OC(O)-R'), where R, R', R'' and R''' are the same or different alkyl, cycloalkyl, or heterocycloalkyl.

[0058] As used herein, unless otherwise specified, the term "perfluoroalkyl" means an alkyl, cycloalkyl, or heterocycloalkyl containing one or more fluoro groups, including, but not limited to, perfluoromethyl, perfluoroethyl, perfluoropropyl.

[0059] As used herein, unless otherwise specified, the term "aryl" refers to a chemical structure that includes one or more aromatic rings. In certain embodiments, the ring atoms are all carbon. In certain embodiments, one or more ring atoms are non-carbon, such as oxygen, nitrogen, or sulfur ("heteroaryl"). Examples of aryl include, but are not limited to, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinolyl, isoquinolyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl, furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidide, and benzothiazolyl.

[0060] In certain embodiments, the transport unit of the HPP / HPC comprises a protonatable amine group capable of facilitating transport or crossing of the HPP / HPC through one or more biological barriers (e.g., >about 10 times, >about 50 times, >about 100 times, >about 300 times, >about 500 times, >about 1000 times faster than the parent drug). In certain embodiments, the protonatable amine group is substantially protonated at physiological pH. In certain embodiments, the amine group is reversibly protonated. In certain embodiments, the transport unit may or may not be cleaved from the functional unit after permeation of the HPP / HPC through one or more biological barriers. In certain embodiments, the transport unit may be derived from the functional unit, especially for peptides or peptide-related compounds having at least a free amino group. In certain embodiments, if the peptide or peptide-related compound has more than one protonatable group, the peptide or peptide-related compound is modified such that one or two protonatable amine groups remain and all other protonatable groups are protected.

[0061] In certain embodiments, the protonatable amine group is selected from the group consisting of pharma- ceutically acceptable substituted and unsubstituted primary amine groups, pharma-ceutically acceptable substituted and unsubstituted secondary amine groups, and pharma-ceutically acceptable substituted and unsubstituted tertiary amine groups.

[0062] In certain embodiments, the protonatable amine group is selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr: [ka] JPEG2025039570000007.jpg35160 JPEG2025039570000008.jpg39160 JPEG2025039570000009.jpg39160 JPEG2025039570000010.jpg46160 JPEG2025039570000011.jpg3657 Structure Nr This includes stereoisomers and pharma- ceutically acceptable salts thereof.

[0063] As used herein, unless otherwise specified, each R 11 ~R 16 are independent, no, H, CH2COOR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein the carbon or hydrogen is further independently selected from the group consisting of O, S, P, NR 11 Or it may be replaced by another pharma- ceutically acceptable group.

[0064] In certain embodiments, the linker covalently connecting the functional unit and the transport unit of the HPP / HPC comprises a bond that can be cleaved after penetration of the HPP / HPC across one or more BBs. Cleavable bonds include, for example, covalent bonds, ether bonds, thioether bonds, amide bonds, ester bonds, thioester bonds, carbonate bonds, carbamate bonds, phosphate bonds, or oxime bonds.

[0065] In certain embodiments, the peptide HHP / HPC has the following structure L-1: [ka] Structure L-1 having including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein: F is a functional unit of the peptide HPP / HPC. An example of F is the structure F-1 defined above; T C and TN is independently selected from the group consisting of No, H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above: L 1C and L 1N is independently selected from the group consisting of nothing, O, S, N(L3), -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -O-CH2-O-, -O-CH(L3)-O, and -S-CH(L3)-O-; L 2C and L 2N is independently selected from the group consisting of nothing, O, S, N(L3), -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -O-CH2-O-, -O-CH(L3)-O, -S-CH(L3)-O-, -O-L3-, -N-L3-, -S-L3-, -N(L3)-L5-, and L3: L 4C and L 4N are independent of each other: none, C=O, C=S, [ka] [ka] and [ka] selected from the group consisting of; Each L 1C , L 1N , L 2C , L 2N , L 4C and L 4Nwherein L3 and L5 are independently selected from the group consisting of no, H, CH2COOL6, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, wherein carbon or hydrogen may be further independently replaced by O, S, P, NL3 or other pharma- ceutically acceptable groups; L6 is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, wherein carbon or hydrogen may be further independently replaced by O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups; L7 is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein carbon or hydrogen may be further independently replaced by O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl, or cyclic groups.

[0066] In certain embodiments, the HPP or HPC of a peptide or peptide-related compound comprises the structure L-1, including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein F, L 1C , L 1N , L2C , L 2N , T C and T N is as defined above, and L 4C and / or L 4N is C=O.

[0067] In certain embodiments, the HPP or HPC of a peptide or peptide-related compound comprises the structure of Structure L-1, including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein: F, L 1C , L 1N , L 2C , L 2N , L 4C and L 4N is as defined above; T C is the transport unit of the peptide HPP / HPC. For example, T C is selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above: T N is selected from the group consisting of nothing, H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups.

[0068] In certain embodiments, the HPP or HPC of a peptide or peptide-related compound comprises the structure of Structure L-1, including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein: F, L 1C , L 1N , L 2C , L 2N , L 4C and L 4N is as defined above; T Nis the transport unit of the peptide HPP / HPC. For example, T N is selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above: T C is selected from the group consisting of nothing, H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups.

[0069] In a particular embodiment, the peptide HPP / HPC has the following structure L-2: [ka] Structure L-2 and including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein Each A1~A m are independently selected from the residues of 2-naphthylalanine, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure A and Structure B: [ka] Structure A [ka] Structure B selected from the group consisting of; A1~A m p is an independently selected integer; Each A1~A m and T N T Bis independently selected from the group consisting of no, H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr, as defined above: Each A1~A m , L 1C and L 1N L 1B is independently selected from the group consisting of nothing, O, S, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -O-CH2-O-, -O-CH(L3)-O and -S-CH(L3)-O-; Each A1~A m , L 2C and L 2N L 2B is independently selected from the group consisting of nothing, O, S, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -O-CH2-O-, -O-CH(L3)-O, -S-CH(L3)-O-, -O-L3-, -N-L3-, -S-L3- and -N(L3)-L5-; Each A1~A m L 4B , L 4C and L 4N is C=O, C=S, [ka] [ka] and [ka] Selected from the group consisting of: L3 and L5 are as defined above; Each A1-A m , Z NT、 ZCT-1 and Z CT-2 About A1-A m , Z A-2 Z at each carbon A-1 are independently H, CH3, or C2H 5、 selected from the group consisting of C3H7, CF3, C2F5, C3F7, substituted and unsubstituted alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides; Each A1~A m , R NT and R CT Each A1 to A at each carbon m , R B R on each carbon A are independently selected from the group consisting of substituted and unsubstituted imidazolyl groups, substituted and unsubstituted quianidino groups, substituted and unsubstituted carboxyl groups, substituted and unsubstituted carboxamide groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted alkylthio groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted alkylcarbonyl groups, substituted and unsubstituted perfluoroalkyl groups, substituted and unsubstituted alkyl halide groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups; A1~A m When p is an integer less than 2, R on each carbon A or R B may be the same or different, and Z on each carbon A-1 may be the same or different; The amino and carboxyl functional groups in the peptide chain may further form lactam bridges; The thiol groups may further form disulfide bridges. Examples of peptide HPPs / HPCs

[0070] In certain embodiments, the peptide HPP / HPC is selected from the group consisting of Structure 2, Structure 3, Structure 4, Structure 5, Structure 6, Structure 7, Structure 8, Structure 9, Structure 10, Structure 11, Structure 12, Structure 13, Structure 14, Structure 15, Structure 16, Structure 17, Structure 18, Structure 19, Structure 20, Structure 21, Structure 22, Structure 23, Structure 24, Structure 25, Structure 26, Structure 27, Structure 28, Structure 37, Structure 38, Structure 39, Structure 40, Structure 41, Structure 42, Structure 43, Structure 44, Structure 45, Structure 46, Structure 47, Structure 48, Structure 49, Structure 50, Structure 51, Structure 52, Structure 53, Structure 54 as shown in FIG. , structure 55, structure 56, structure 57, structure 58, structure 59, structure 60, structure 61, structure 62, structure 63, structure 64, structure 65, structure 66, structure 67, structure 68, structure 69, structure 70, structure 71, structure 72, structure 73, structure 74, structure 75, structure 76, structure 77, structure 78, structure 7 9, Structure 80, Structure 81, Structure 82, Structure 83, Structure 84, Structure 85, Structure 86, Structure 87, Structure 88, Structure 89, Structure 90, Structure 91, Structure 92, Structure 93, Structure 94, Structure 95, Structure 96, Structure 97, Structure 98, Structure 99, Structure 100, Structure 101, Structure 102, Structure 103 , structure 104, structure 105, structure 106, structure 107, structure 108, structure 109, structure 110, structure 111, structure 112, structure 113, structure 114, structure 115, structure 116, structure 117, structure 118, structure 119, structure 120, structure 121, structure 122, structure 123, structure 1 24, Structure 125, Structure 126, Structure 127, Structure 128, Structure 137, Structure 138, Structure 139, Structure 140, Structure 141, Structure 142, Structure 143, Structure 144, Structure 145, Structure 146, Structure 147, Structure 148, Structure 149, Structure 150, Structure 151, Structure 152, Structure 153, structure 154, structure 155, structure 156, structure 157, structure 158, structure 159, structure 160, structure 161, structure 162, structure 163, structure 164, structure 165, structure 166, structure 167, structure 168, structure 169, structure 170, structure 171, structure 172, structure 173, structure Structure 174, Structure 175, Structure 176, Structure 177, Structure 178, Structure 179, Structure 180, Structure 181, Structure 182, Structure 183, Structure 184, Structure 185, Structure 186, Structure 187, Structure 188, Structure 189, Structure 190, Structure 191, Structure 192, Structure 193, Structure 194,Structure 195, Structure 196, Structure 197, Structure 198, Structure 199, Structure 200, Structure 201, Structure 202, Structure 203, Structure 204, Structure 205, Structure 206, Structure 207, Structure 208, Structure 209, Structure 210, Structure 211, Structure 212 , structure 213, structure 214, structure 215, structure 216, structure 217, structure 218, structure 219, structure 220, structure 221, structure 222, structure 223, structure 224, structure 225, structure 226, structure 227, structure 228, structure 237, structure 238 , structure 239, structure 240, structure 241, structure 242, structure 243, structure 244, structure 245, structure 246, structure 247, structure 248, structure 249, structure 250, structure 251, structure 252, structure 253, structure 254, structure 255, structure 256 , structure 257, structure 258, structure 259, structure 260, structure 261, structure 262, structure 263, structure 264, structure 265, structure 266, structure 267, structure 268, structure 269, structure 270, structure 271, structure 272, structure 273, structure 274 , structure 275, structure 276, structure 277, structure 278, structure 279, structure 280, structure 281, structure 282, structure 283, structure 284, structure 285, structure 286, structure 287, structure 288, structure 289, structure 290, structure 291, structure 29 2, Structure 293, Structure 294, Structure 295, Structure 296, Structure 297, Structure 298, Structure 299, Structure 300, Structure 301, Structure 302, Structure 303, Structure 304, Structure 305, Structure 306, Structure 307, Structure 308, Structure 309, Structure 31 0, structure 311, structure 312, structure 313, structure 314, structure 315, structure 316, structure 317, structure 318, structure 319, structure 320, structure 321, structure 322, structure 323, structure 324, structure 325, structure 326, structure 327, structure 328, structure 337, structure 338, structure 339, structure 340, structure 341, structure 342, structure 343, structure 344 and structure 345, including stereoisomers thereof and pharma- ceutically acceptable salts thereof, wherein R is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues; X, X4, X5, X6, X7, X8, X9, X 10 , X 21 , X 22 , X 23 , X 24 , X 25 , X 26 and X 27 is independently selected from the group consisting of C=O, C=S, COO, CSO, CHOCO, COOCHOCO, COCHOCO, CH-O-CH(CHOR4), CH-O-CH(CHOCOR4), SO, PO(OR), NO, NO, O, S, NR, and nothing; R1, R2, R4, R5, R 6、 R7, R8, R9, R 10 , R 21 , R 22 , R 23 , R 24、 R 25 , R 26 and R 27 is independently selected from the group consisting of H, O, NO2, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues; As used herein, unless otherwise specified, the term "HA" refers to any acid, including, but not limited to, any pharma- ceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or pamoic acid; Ar is selected from the group consisting of phenyl, 2'-naphthyl, 4-iodophenyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues.

[0071] The corresponding parent peptides of peptide HPPs / HPCs having structures 2 to 343 are listed below in Tables A(I) and (II). Table A. Parent peptides of peptide HPPs / HPCs with structures 2 to 343

[0072] [Table 1]

[0073] JPEG2025039570000023.jpg216162

[0074] JPEG2025039570000024.jpg228164

[0075] JPEG2025039570000025.jpg209162

[0076] JPEG2025039570000026.jpg199162

[0077] JPEG2025039570000027.jpg202160

[0078] JPEG2025039570000028.jpg202160

[0079] JPEG2025039570000029.jpg199162

[0080] JPEG2025039570000030.jpg210162

[0081] JPEG2025039570000031.jpg220162

[0082] JPEG2025039570000032.jpg192160

[0083] JPEG2025039570000033.jpg199162

[0084] JPEG2025039570000034.jpg212162

[0085] JPEG2025039570000035.jpg190162

[0086] JPEG2025039570000036.jpg210162

[0087] JPEG2025039570000037.jpg210162

[0088] JPEG2025039570000038.jpg195162

[0089] JPEG2025039570000039.jpg206160

[0090] JPEG2025039570000040.jpg199162

[0091] JPEG2025039570000041.jpg199162

[0092] JPEG2025039570000042.jpg199162

[0093] JPEG2025039570000043.jpg71170

[0094] [Table 2]

[0095] JPEG2025039570000045.jpg211166

[0096] JPEG2025039570000046.jpg223163

[0097] JPEG2025039570000047.jpg97166

[0098] The structures of unusual amino acids appearing in SEQ ID NOs: 1 to 172 (Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa7, Xaa9, Xaa13, Xaa14, Xaa15, Xaa17, Xaa19, Xaa21, Xaa22, Xaa23, Xaa24, Xaa25, and Xaa26) are listed in Table B. Table B. Unusual Amino Acids Occurring in SEQ ID NOs: 1-172 [Table 3]

[0099] JPEG2025039570000049.jpg184162

[0100] JPEG2025039570000050.jpg166162

[0101] JPEG2025039570000051.jpg194162

[0102] JPEG2025039570000052.jpg135162

[0103] In certain embodiments, the peptide HPP / HPC comprises a compound selected from the group consisting of structures 2-345 as defined above, including stereoisomers thereof and pharma- ceutically acceptable salts thereof, wherein: HA, Ar, X, X4, X5, X6, X7, X8, X 9、 X 10 , X 21 , X 22 , X 23 , X 24 , X 25 , X 26 and X 27 is defined as above; R is selected from the group consisting of H, substituted and unsubstituted alkyl of 1 to 20 carbons, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy of 1 to 20 carbons, substituted and unsubstituted alkylthio of 1 to 20 carbons, substituted and unsubstituted alkylamino of 1 to 20 carbons, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues; R1, R2, R4, R5, R 6、 R7, R8, R9, R 10 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 is independently selected from the group consisting of H, O, substituted and unsubstituted alkyl of 1 to 20 carbons, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy of 1 to 20 carbons, substituted and unsubstituted alkylthio of 1 to 20 carbons, substituted and unsubstituted alkylamino of 1 to 20 carbons, substituted and unsubstituted alkenyl of 1 to 20 carbons, substituted and unsubstituted alkynyl of 1 to 20 carbons, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues.

[0104] In certain embodiments, the peptide HPP / HPC comprises a structure selected from the group consisting of structure 1a, structure 1b, structure 1c, structure 1d, structure 1e, structure 1f, structure 1g, and structure 1h; [ka] structure 1a [ka] structure 1b [ka] structure 1c [ka] Structure 1d [ka] structure 1e [ka] Structure 1F [ka] structure 1g [ka] structure 1h including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein: X4, X5, X6, X7, X8, X9, R4, R5, R 6、 R7, R8, R9 and HA are defined as above. Solid-phase synthesis of peptides HPP / HPC

[0105] Short peptides (<10 amino acids) can be synthesized by solution phase, but synthesis of long peptides by solution phase is very difficult. The HPPs / HPCs of the peptides of the present disclosure are modified peptides and cannot be synthesized by standard solid phase peptide synthesis methods (C-terminus to N-terminus).

[0106] In a particular embodiment, the peptide HPP / HPC is synthesized from the N-terminus to the C-terminus, wherein the synthesis method comprises the steps of:

[0107] Methods for preparing peptide HPCs using solid phase synthesis include the following. a) providing chemically modified resins (e.g., trityl chloride resins and carbonate ester resins); b) protecting the carboxyl groups of all of the natural or modified amino acid residues as desired according to the peptide HPC with protecting groups (e.g., 2-(4-nitrophenylsulfonyl)ethyl and 9-fluorenylmethyl groups) to provide COOH-protected amino acid residues; c) coupling a COOH-protected amino acid residue at the N-terminus of peptide HPC to a chemically modified resin to provide an immobilized COOH-protected peptide HPC precursor having one amino acid residue; d) deprotecting the protected carboxyl group of the immobilized COOH-protected peptide HPC precursor with a deprotection reagent (e.g., 1% DBU / 20% piperidine / 79% DMF or other reagent capable of deprotecting a protected carboxyl group) to provide an immobilized COOH-unprotected peptide HPC precursor having one amino acid residue; e) repeating steps c) and d) with COOH-protected amino acid residues of peptide HPC until an immobilized C-unprotected peptide HPC precursor is provided having all amino acids except the C-terminal amino acid residue; f) Covalently linking the C-terminal amino acid residue to R T and providing a modified C-terminal amino acid, wherein R T is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above: g) coupling a modified C-terminal amino acid to the immobilized C-unprotected peptide HPC precursor obtained from step e) to provide an immobilized peptide HPC; and h) releasing the immobilized peptide HPC from the resin to provide the peptide HPC.

[0108] In certain embodiments, the chemically modified resin can be directly coupled to the protected amino acid, or the chemically modified resin can first be further modified and then coupled to the COOH-protected amino acid.

[0109] In certain embodiments, peptides HPP / HPC comprising a transport unit at the C-terminus are prepared by linking a C-terminal amino acid to a peptide chain, in which the carboxyl group is linked to the transport unit as described above. For example, the transport unit is selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above.

[0110] In a particular embodiment, the peptide HPP / HPC containing a transport unit at the C-terminus is prepared by linking the C-terminal amino acid to a peptide chain, in which the carboxyl group is protected, the carboxyl group is deprotected, and finally linked to the transport unit. For example, the transport unit is selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above.

[0111] In certain embodiments, the release of peptide HPP / HPC is achieved in high yield. For example, in certain embodiments, the resin is a trityl chloride resin and the release step can be achieved by reacting with TFA / DCM (e.g., 5%). In certain embodiments, the resin is a carbonate resin and the release step can be achieved by reacting with Pd-C (e.g., 10% in methanol) and H2.

[0112] In certain embodiments, the coupling reaction is carried out in the presence of a coupling agent, examples of which include, but are not limited to, HBTU / DIPEA / HOBt, TBTU / DIPEA / HOBt, BOP / DIPEA / HOBt, HATU / DIPEA / HOBt, and DIC / HOB, and combinations thereof.

[0113] As used herein, unless otherwise defined "DBU" means 1,8-diazabicyclo[5,4,0]undec-7-ene; "DMF" means dimethylformamide; "DIPWA" means N,N-diisopropylethylamine; "HBTU" means O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate; "HOBt" means 1-hydroxybenzenetriazole; "TBTU" means O-benzotriazole-N,N,N',N'-tetramethyl-uronium-tetrafluoroborate; "BOP" means benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate; "HATU" means N-(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanammonium hexafluorophosphate N-oxide; "DIC" means diisopropylcarbodiimide, and "TFA" means trifluoroacetic acid. II. Pharmaceutical Compositions Comprising HPPs / HPCs

[0114] Another aspect of the invention relates to a pharmaceutical composition comprising at least one peptide HPP / HPC and a pharma- ceutically acceptable carrier.

[0115] The term "pharmaceutical acceptable carrier" as used herein means a pharma- ceutically acceptable substance, composition or vehicle, such as, for example, a liquid or solid filler, diluent, excipient, solvent or encapsulant, that is involved in carrying or transporting an HPP / HPC from one location, fluid, organ (internal or external), or part of the body to another location, fluid, organ, or part of the body.

[0116] Each carrier is "pharmacologically acceptable" in the sense of being compatible with the other ingredients of the formulation, e.g., HPP / HPC; not exhibiting excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications; suitable for use in contact with the tissues or organs of a biological system; and commensurate with a reasonable benefit / risk ratio.

[0117] Some examples of substances which can serve as pharma- ceutically acceptable carriers include: (1) sugars, such as, for example, lactose, glucose, and sucrose; (2) starches, such as, for example, corn starch and potato starch; (3) cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, for example, cocoa butter and suppository waxes; (9) oils, such as, for example, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) propylene glycol. (11) polyols, such as, for example, glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, for example, ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as, for example, magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohols, such as, for example, ethyl alcohol and propane alcohol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances used in pharmaceutical formulations, such as acetone.

[0118] The pharmaceutical compositions may contain pharma- ceutically acceptable auxiliary substances required for appropriate physiological conditions, such as, for example, pH adjusting and buffering agents, toxicity adjusting agents such as, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.

[0119] In one embodiment, the pharma- ceutically acceptable carrier is an aqueous carrier, such as, for example, buffered saline, etc. In certain embodiments, the pharma-ceutically acceptable carrier is a polar solvent, such as, for example, water, acetone, and alcohol.

[0120] The concentration of HPP / HPC in these formulations can vary widely and is primarily selected according to the particular mode of administration selected and the needs of the biological system based on fluid volume, viscosity, body weight, etc. For example, the concentration can be 0.0001% to 100% by weight, 0.001% to 50% by weight, 0.1% to 30% by weight, 0.1% to 10% by weight.

[0121] The compositions of the present invention can be administered for preventive, therapeutic and / or hygienic purposes. Such administration can be topical, mucosal, e.g., oral, intranasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, by inhalation, intraocular and other conventional routes. The pharmaceutical compositions can be administered in various unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration include powders, tablets, pills and lozenges.

[0122] Thus, a typical pharmaceutical composition for intravenous administration would contain about 10 mg of each drug per subject per day. -10 g ~ about 100g, about 10 -10 g ~ about 10 -3 g, about 10 -9 g ~ about 10 -6 g, about 10 -6 g to about 100 g, about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.1 g to about 1 g. Dosages of from about 0.01 mg to about 50 g per subject per day may be used. Actual methods of preparing parenterally administrable compositions will be known or apparent to those of skill in the art and are described in further detail in such publications as Remington's Pharmaceutical Science, 15th Edition, Mack Publishing Company, Easton, Pa. (1980). III. Application of HPPs / HPCs i) Methods for penetrating biological barriers

[0123] Another aspect of the invention relates to a method of using the compositions of the invention in permeating one or more biological barriers in a biological subject, the method comprising administering to the biological subject an HPP / HPC or a peptide or peptide-related compound, or a pharmaceutical composition thereof. In certain embodiments, the HPP / HPC exhibits about 10-fold greater, 50-fold greater, >about 100-fold greater, >about 200-fold greater, >about 300-fold greater, >about 500-fold greater, >about 1000-fold greater or greater permeability through one or more biological barriers than its parent drug.

[0124] The term "biological barrier" as used herein refers to a biological layer that separates an environment into different spatial regions or compartments that can regulate (e.g., restrict, limit, enhance, do nothing) passage therethrough and allow a substance or object to permeate or move from one compartment / region to another. The different spatial regions or compartments referred to herein may have the same or different chemical or biological environments. Biological layers referred to herein include, but are not limited to, biological membranes, cell layers, internal surfaces of biological structures, objects, organisms, or body cavities, external surfaces of objects, organisms, organs, or body cavities, or combinations or multiples thereof.

[0125] Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (e.g., the nuclear membrane or organelle membranes, such as the membranes or envelopes of the Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosomes, nuclei, chloroplasts, plastids, peroxisomes, or microbodies).

[0126] A lipid bilayer as referred to herein is a double layer of lipid molecules, including but not limited to phospholipids and cholesterol. In a particular embodiment, the lipids for the bilayer are amphipathic molecules consisting of polar head groups and non-polar fatty acid tails. The bilayer is composed of two layers of lipids arranged such that their charged heads face toward the aqueous solution on either side of the membrane, while their hydrocarbon tails face toward each other to form an oily core supported by hydrophobic effects. In another particular embodiment, the lipid bilayer may contain one or more embedded protein and / or sugar molecules.

[0127] Examples of cell layers include the inner membranes of eukaryotic cells (e.g., epithelium, lamina propria, and smooth muscle or muscularis mucosae (of the digestive tract)), the inner membranes of prokaryotic cells (e.g., the surface layer, or S-layer, which refers to a two-dimensional monolayer composed of identical proteins or glycoproteins, particularly the S-layer, which refers to a portion of the cell envelope commonly found in bacteria and archaea), biofilms (organized communities of microorganisms encapsulated in a self-produced polymeric matrix or attached to a living or inert surface), and plant cell layers (e.g., the exine). The cells may be normal or pathological (e.g., diseased cells, cancer cells).

[0128] Examples of biological structures include structures sealed by tight or occlusive junctions that provide a barrier against toxins, bacteria, and viruses, such as the blood-milk barrier and the blood-brain barrier (BBB). In particular, the BBB is composed of an impermeable endothelium, which presents both a physical barrier via tight junctions adjacent to neighboring endothelial cells, and a transport barrier composed of efflux transporters. Biological structures may also include a mixture of cells, proteins, and sugars (e.g., blood clots).

[0129] Examples of the inner surface of a subject, organism, organ or body cavity include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory bulb mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endothelium (the mucous membrane of the uterus, the inner lining of the wall of a pollen grain or the inner wall layer of a spore), or a combination or multiple thereof.

[0130] Examples of the outer surface of an object, organism, organ or cavity include capillaries (e.g., capillaries in cardiac tissue), mucous membranes continuous with the skin (e.g., nostrils, lips, ears, genitals and anus), the outer surfaces of organs (e.g., liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum, stomach, colorectum, intestines, blood vessels, respiratory system, blood vessels, anorectum and pruritus ani), skin, keratin (e.g., the dead layer of epidermal cells or keratinocytes or the superficial layer of overlapping cells covering the hair shaft of an animal, the outer multi-layered structure of the cuticle in many invertebrates, keratin or the polymer cutin and / or cutan in plants), the outer layer of the wall of a pollen grain or the outer wall layer of a spore, and combinations or multiples thereof.

[0131] In addition, the biological barrier may further include a sugar layer, a protein layer, or other biological layers, or a combination or multiple thereof. For example, skin is a biological barrier with multiple biological layers. Skin includes an epidermal layer (outer surface), an endodermal layer, and a subcutaneous layer. The epidermal layer contains a basal cell layer, a spinous cell layer, a granular cell layer, and a stratum corneum. The cells in the epidermis are called keratinocytes. The stratum corneum ("horny layer") is the outermost layer of the epidermis, and the cells therein are flat and scaly ("squamous") in shape. These cells contain a lot of keratin and are arranged in overlapping layers that give the skin surface its tough, oil-resistant, and water-resistant properties. ii) Methods for diagnosing conditions in biological systems

[0132] Another aspect of the invention relates to a method of using the compositions of the invention in diagnosing a condition in a biological system, the method comprising the steps of: 1) administering to a biological subject a composition comprising the peptide HPP / HPC; 2) detecting the presence, location or amount of HPP / HPC, functional units of HPP / HPC or their metabolites in a biological subject; and 3) Determining conditions in biological systems.

[0133] In certain embodiments, the HPP / HPC (or an agent cleaved from the HPP / HPC) aggregates at the site of action where the condition occurs. In certain embodiments, the presence, location or amount of functional units of the HPP / HPC is also detected. In certain embodiments, the onset, development, progression or remission of an associated condition (e.g., cancer) is also determined.

[0134] In certain embodiments, the HPP / HPC is labeled or conjugated with a detection agent. Alternatively, the HPP / HPC is prepared to contain a radioisotope for detection. Numerous detection agents are available, generally grouped into the following categories: (a) For example, 35 S, 14 C. 13 C. 15 N, 125 I, 3 H and 131 Radioisotopes such as I. Diagnostic agents can be labeled with radioisotopes using techniques known in the art and radioactivity can be measured using a scintillation counter. Additionally, diagnostic agents can be spin labeled for electron paramagnetic resonance for carbon and nitrogen labels. (b) Fluorescent agents such as, for example, BODIPY, BODIPY analogs, rare earth clays and (europium chelates), fluorescein and its derivatives, FITC, 5,6-carboxylfluorescein, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin, green fluorescent protein, yellow fluorescent protein, red fluorescent protein, and Texas Red. Fluorescence can be quantified using a fluorometer. (c) various enzyme-substrate agents, such as luciferases (e.g., firefly luciferase and bacterial luciferase), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidases such as horseradish peroxidase, alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (e.g., uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Examples of enzyme-substrate combinations include, for example, (i) horseradish peroxidase with hydrogen peroxide as a substrate, where hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylenediamine (OPD) or 3,3',5,5'-tetramethylbenzidine hydrochloride (TMB); (ii) paranitrophenyl phosphate with alkaline phosphatase as a chromogenic substrate; and (iii) β-D-galactosidase (β-D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl-β-D-galactosidase) or a fluorogenic substrate, 4-methylumbelliferyl-β-D-galactosidase.

[0135] In certain embodiments, the detection agent is not necessarily conjugated to the diagnostic agent, but is capable of recognizing the presence of the diagnostic agent and is capable of detecting the diagnostic agent.

[0136] In certain embodiments, peptide HPP / HPC may be provided in a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for carrying out the diagnostic assay. When HPP / HPC is labeled with an enzyme, the kit includes a substrate and cofactors required by the enzyme (e.g., a substrate precursor that provides a detectable chromophore or fluorophore). In addition, additives such as, for example, stabilizers, buffers (e.g., block buffer or lysis buffer), and the like, may be included. The relative amounts of the various reagents may vary widely to provide concentrations in solution of the reagents that substantially optimize the sensitivity of the assay. In particular, the reagents may be provided as dry powders, usually lyophilized, including excipients that, upon dissolution, provide a reagent solution having the appropriate concentration. iii) Methods for screening substances for desired properties

[0137] Another aspect of the invention relates to methods of screening HPP / HPC for desired properties.

[0138] In certain embodiments, the method includes: (1) covalently linking a test functional unit to a transport unit via a linker to form a test composition (or covalently linking a functional unit to a test transport unit via a linker, or covalently linking a functional unit to a transport unit via a test linker); (2) administering the test composition to the biological system; (3) Determining whether the test composition has a desired property or characteristic.

[0139] In one embodiment, the desired properties include, for example, (1) the ability of the test functional unit to form a highly permeable composition or revert to the parent drug, (2) the permeation capacity and / or permeation rate of the test composition, (3) the efficiency and / or effectiveness of the test composition, (4) the transport capacity of the test transport unit, and (5) the cleavage ability of the test linker. iv) Methods of Treating a Condition in a Biological Subject

[0140] Another aspect of the invention relates to a method of using the compositions of the invention in treating a condition in a biological subject, the method comprising administering to the biological system a pharmaceutical composition.

[0141] The term "treating" as used herein means to cure, alleviate, inhibit or prevent. The term "treat" as used herein means to cure, alleviate, inhibit or prevent. The term "treatment" as used herein means to cure, alleviate, inhibit or prevent.

[0142] The terms "biological system", "biological subject" or "subject" as used herein refer to an organ, a group of organs that function together to perform a particular task, an organism, or a group of organisms. The term "organism" as used herein refers to a collection of molecules that function as a more or less stable whole and that has the properties of life, e.g., an animal, a plant, a fungus, or a microorganism.

[0143] The term "animal" as used herein refers to eukaryotic organisms characterized by spontaneous movement. Examples of animals include, but are not limited to, vertebrates (e.g., humans, mammals, birds, reptiles, amphibians, fish, lampreys and amphioxus), tunicates (e.g., salva, ascidians, sorbella and ascidians), ectocarya (insects, myriapods, malacapods, arachnids, sea spiders, arthrostomes, crustaceans and annelids), arthropods (paraarthropods) and worms (e.g., rotifers).

[0144] The term "plant" as used herein means an organism belonging to the kingdom Plantae. Examples of plants include, but are not limited to, seed plants, bryophytes, ferns, and members of the pteridophyte family. Examples of seed plants include, but are not limited to, cycads, ginkgoes, conifers, gametophytes, and angiosperms. Examples of bryophytes include, but are not limited to, Marchantia polymorpha, and mosses. Examples of ferns include, but are not limited to, Ophioglossa (e.g., adder's tongue, silverleaf, and grape fern), leucanthemum vulgare, and scutellaria. Examples of ferns include, but are not limited to, lycopod ferns (e.g., club moss, spike moss, and water hyacinth), pine orchids (e.g., Lycopodiophyta and Equisetum arvensis), and horsetails (e.g., Equisetum arvensis).

[0145] The term "fungi" as used herein means eukaryotic organisms belonging to the kingdom Fungi. Examples of fungi include, but are not limited to, Chytridiomycota, Dictyostelium, Neocallimasticum, Mucor, Glomus mould, Ascomycota, and Basidiomycota.

[0146] The term "microorganism," as used herein, means an organism that is microscopic (e.g., on the length scale of a micrometer). Examples of microorganisms include, but are not limited to, bacteria, fungi, archaea, protozoa, and microscopic plants (e.g., green algae) and animals (e.g., plankton, planaria, and amoebae).

[0147] Some examples of conditions that the methods can treat include conditions that can be treated by parent drugs of HPP / HPC. v) Methods of using peptides HPP / HPC and pharmaceutical compositions thereof in therapy

[0148] Another aspect of the invention relates to methods of using peptide HPPs / HPCs or pharmaceutical compositions thereof in treating a condition in a biological system or subject by administering the peptide HPP / HPC or pharmaceutical composition thereof to the biological system or subject.

[0149] Peptides and peptide-related compounds can be used to regulate a wide range of biological processes in living systems, and conditions associated with such biological processes are treatable by the corresponding peptides or peptide-related compounds, and thus by peptide HPP / HPC and pharmaceutical compositions thereof.

[0150] Such conditions include aging, angina pectoris, antithrombin deficiency, arrhythmias, atherosclerosis, atrial fibrillation, atrial flutter, thrombus, cardiac ischemia, cardiac surgery, cardiomyopathy, circulatory abnormalities, carotid artery disease, chest pain, circulatory disorders, claudication, collagen vascular disease, congenital heart disease, congestive heart failure, coronary artery disease, diabetes, diabetes mellitus and hypertension, dyslipidemia, dysrhythmia, high triglycerides, heart defects, heart disease, heart failure, valvular heart disease, hemangiomas, high cholesterol, hypertriglyceridemia, intermittent claudication, hypertension, Kawasaki disease, heart attack, myocardial ischemia, orthostatic hypotension, peripheral arterial disease, peripheral arterial occlusive disease, peripheral Peripheral vascular disease, Reynold's disease, smoking cessation, tachycardia (fast heart rate), thrombosis, varicose veins, vascular disease, venous pulmonary ulcer, gingivitis, gum disease, halitosis, oral cancer, periodontal disease, temporomandibular disorders, temporomandibular joint syndrome, sunburn, acne, skin aging, alopecia, paresthesia, athlete's foot, atopic dermatitis, bedsores (decubitus ulcers), bunions, burns, burn infections, herpes (herpes labialis infection), congenital skin diseases, contact dermatitis, cutaneous lupus erythematosus, diabetic leg ulcers, eczema, excessive sweating, Fabry's disease, fungal infection, genital herpes, genital warts, hair loss, hair removal, hand dermatitis, head lice, hemangiomas, inherited Herpes simplex infection, Herpes zoster infection, Herpetic neuralgia, Skin rash, Ichthyosis, Ischemic leg ulcer, Keratosis, Lupus, Male pattern baldness, Malignant melanoma, Medical prosthetics, Melanoma, Molluscum contagiosum, Mycosis fungoides, Onychomycosis, Pemphigus vulgaris, Postherpetic neuralgia, Pressure ulcers, Psoriasis and psoriatic disorders, Psoriatic arthritis, Razor burn, Rosacea, Sarcoidosis, Scalp disorders, Traumatized tissue, Scleroderma, Seborrhea, Seborrheic dermatitis, Shingles, Skin cancer, Skin infection, Skin lipoma, Skin wound, Solar lentigo, Sporotrichosis, Staphylococcal skin infection, Stasis dermatitis, Stretch marks, Systemic fungal infection , phototoxicity, tinea, tinea capitis, tinea versicolor, urticaria, vitiligo, warts, wounds, acromegaly, adrenal cancer, congenital adrenal hyperplasia, diabetes mellitus (type I and type II), diabetes mellitus (type I), diabetes mellitus (type II), diabetic gastroparesis, diabetic kidney disease, diabetic macular edema, diabetic nephropathy, diabetic retinopathy, diabetic vitreous hemorrhage, dyslipidemia, female hormone deficiency / abnormality, Fredrickson type III, hyperlipoproteinemia, growth hormone deficiency / abnormality, gynecomastia, hair removal, hyperlipidemia, hormone deficiency, facial flushing, hyperparathyroidism, idiopathic dwarfism, indications: diabetes mellitus type II, male hormone deficiency / abnormality,McCune-Albright syndrome, menopause, metabolic syndrome, obesity, ovarian cancer, pancreatic cancer, pancreatic disorders, pancreatitis, parathyroid cancer, parathyroid disease, parathyroid disorders, menopause, pubertal disorders, polycystic ovarian syndrome, postmenopausal disorders, postmenopausal osteopenia, precocious puberty, primary insulin hypersecretion, severe dwarfism, sexual dysfunction, thyroid disease, thyroid disorders, Turner syndrome, Wilms' tumor, Wilson's disease, abdominal cancer, achalasia, alpha-1 antitrypsin deficiency, anal fissure, appendicitis, Barrett's esophagus, cholangiocarcinoma, colonic dysfunction, celiac disease, chronic diarrhea, Clostridium difficile-associated Diarrhea, colon cancer, colon polyps, colorectal cancer, constipation, Crohn's disease, diabetic gastroparesis, digestive tumors, duodenal ulcer, Fabry's disease, fecal incontinence, functional dyspepsia, gallbladder disorders, stomach cancer, gastric ulcer, gastroenteritis, gastroesophageal reflux disease, digestive diseases and disorders, gastroparesis, heartburn, Helicobacter pylori, hemorrhoids, hepatic encephalopathy, ileus, infectious colitis, inflammatory bowel disease, intraperitoneal infection, irritable bowel syndrome, liver disease, liver damage, non-erosive reflux disease, non-ulcer dyspepsia, organ rejection after organ transplantation, post-operative neuralgia and vomiting, vomiting, rectal cancer, rectal diseases, recurrent diarrhea, stomach cancer, stomach discomfort, ulcerative colitis, Abnormal blood vessels, acute myeloid leukemia, anemia, anemia (non-Hodgkin's lymphoma), non-small cell lung cancer, anemic cancer, aneurysm, antiphospholipid syndrome, antithrombin deficiency, aplastic anemia, thrombus, candidal sepsis / candidiasis, chronic renal anemia, Gaucher disease, blood cancer, blood disorder, paroxysmal hemoglobinuria, bleeding, hypercalcemia, hypogammaglobulinemia, hyponatremia, idiopathic thrombocytopenic purpura, islet cell carcinoma, leukemia, B-cell lymphoma, lymphoma, multiple myeloma, myelodysplastic syndrome, myocardial ischemia, obstructive disease, platelet deficiency, platelet disorder, red blood cell disorder, renal anemia, Sézary syndrome , sickle cell disease, T-cell lymphoma, thalassemia, thrombocytopenia, von Willebrand disease, white blood cell disorder, acquired immune deficiency syndrome (AIDS), AIDS-related infection, acute rhinitis, allergies, asthma, anal hypoplasia, bacterial infection, stomatitis, celiac disease, cervical dysplasia, chickenpox, chronic fatigue syndrome, common cold, common variable immunodeficiency, bacterial conjunctivitis, chronic obstructive pulmonary disease, cutaneous candidiasis, cutaneous T-cell lymphoma, cytomegalovirus infection, dermatomyositis, fever, graft-to-host disease, hepatitis, hepatitis B, hepatitis C, HIV infection, HIV / AIDS, human papillomavirus infection,Hypogammaglobulinemia, idiopathic inflammatory cardiomyopathy, influenza, intraperitoneal infections, Kaposi's sarcoma, lupus, Lyme tick disease, Mycobacterium avium complex infection, meningitis, onychomycosis, oral candidiasis, pneumonia, polymyositis, (inflammatory myopathy), postherpetic neuralgia, primary immunodeficiency disorders, respiratory syncytial virus infection, rheumatic fever, allergic rhinitis, rotavirus infection, sarcoidosis, septicemia and sepsis, sexually transmitted diseases, shingles, Sjogren's syndrome, smallpox, soft tissue infections, staphylococcal infections, staphylococcal skin infections, streptococcal pharyngitis, systemic candidiasis, systemic lupus rheumatoid arthritis, throat and tonsil infections, urticaria, vancomycin-resistant enterococci, West Nile virus infection, acromegaly, ankylosing spondylitis, bone loss, movement disorders, bone disease, bone metastases, chest pain, bunions, bursitis, carpal tunnel syndrome, cartilage damage, chest pain, chronic back pain, chronic leg pain, chronic pain, chronic shoulder pain, lameness, congenital lactic acidosis, connective tissue disease, dermatomyositis, Dupuytren's disease, fibromyalgia, frozen shoulder, adhesive capsulitis, gout (hyperuricemia), idiopathic inflammatory cardiomyopathy, intermittent claudication, joint injury, knee injury, multiple sclerosis, muscle pain, muscular dystrophy, musculoskeletal disorders, myasthenia gravis (chronic weakness), generalized myasthenia gravis, orthopedics, osteoarthritis, osteomyelitis, osteoporosis, osteosarcoma, Paget's disease, partial medial knee meniscectomy, parathyroid disease, postmenopausal osteopenia, postmenopausal osteoporosis, reflex sympathetic dystrophy syndrome, rheumatoid arthritis, sciatica, spinal cord disorders, spinal malignancies, spinal prosthesis, sprains, tendon trauma, tennis elbow, facial spasms, anal dysplasia, benign prostatic hyperplasia, bladder cancer, bladder disorders, blood cancers, catheter complications, chronic pelvic pain, diabetic kidney disease, enuresis, erectile dysfunction, Fabry's disease, nocturnal polyuria, genitourinary prolapse, glomerulonephritis , glomerulosclerosis, idiopathic membranous nephropathy, impotence, interstitial cystitis, kidney cancer, kidney disease, renal failure, kidney stones, liver cancer, low testosterone, mastectomy, medical prosthetics, nephropathy, Peroni's disease, premature ejaculation, prostate cancer, prostate disorders, prostatic intraepithelial neoplasia, proteinuria, Reiter's syndrome, renal artery disease, renal cell carcinoma, renal failure, testicular cancer, tyrosinemia, urethral stricture, urinary incontinence, ureteral infection, urinary tract cancer, male erectile dysfunction and female sexual impotence, systemic blood pressure, miscarriage, hypertension control, inhibition of platelet aggregation, pulmonary disease, digestive disease, inflammation, shock, reproduction, fertility, obesity.

[0151] Conditions associated with platelet aggregation include, for example, postoperative thromboembolism, carotid endarterectomy, recurrent stenosis after coronary angiogenesis, thromboembolic complications in chronic atrial fibrillation, occlusion of aortocoronary artery bypass grafts, heart attack, stroke, multi-infarct dementia, dementia, hemodialysis shunt thrombosis, and arterial embolism complications in prosthetic heart valves in patients.

[0152] Some examples of conditions treatable by methods involving using peptide HPP / HPC or pharmaceutical compositions thereof include, but are not limited to, peptide hormone-associated conditions, inflammation and related conditions, platelet aggregation-associated conditions, neuropeptide-associated conditions, microbe-associated conditions, and other conditions modulated by peptides or peptide-related compounds.

[0153] In certain embodiments, a method of treating a peptide-treatable condition comprises administering to a biological system a peptide or peptide-related compound, such as angiotensin, angiotensin II antagonists, angiotensin II AT2 receptor, antimicrobial peptides, antioxytocin, hormones, antidiuretic hormone, adrenocorticotropic hormone, antimicrobial peptides, anti-inflammatory peptides, bradykinin, bradykinin antagonists, endothelin peptides, endothelin peptide antagonists, gastrin, calcitonin, melanocyte-associated antigen peptides, laminin peptides, fibrinogen peptides, EAE-inducing peptides, growth hormone, growth hormone releasing peptide, somatostatin, hormone releasing hormone, luteinizing hormone releasing hormone, neuropeptides, melanocyte stimulating hormone, sleep-inducing peptides, amyloid peptides, tuftsin, retroinvasive tuftsin, enterostatin, melanocortin II, and opioid peptides and mimetics peptides HPP / HPC.

[0154] In certain embodiments, a method of treating a peptide hormone-related condition comprises administering a peptide hormone or HPP / HPC of a peptide hormone-related compound, or a pharmaceutical composition thereof, to a biological system. In biological systems, hormones regulate a wide range of processes, such as, for example, energy levels, reproduction, growth and development, homeostasis, and responses to environment, stress, and injury. Examples of peptide hormone-related conditions include, but are not limited to, the following: (a) Menopause; (b) Bone diseases: for example, osteoporosis, Paget's disease and bone metastases; (c) growth hormone deficiency; (d) Hyperthyroidism and hypothyroidism (e) Metabolic disorders, such as obesity, abnormal blood glucose levels, abnormal blood lipid levels, diabetes mellitus (type I and type II) and diabetes induced complications, including diabetic retinopathy, necrotic ulcers and diabetic proteinuria; (f) abnormal blood pressure, e.g., hypertension and hypotension; (g) skin conditions, such as psoriasis and psoriatic disorders, acne, cystic acne, purulent or red bumps, comedones, papules, pimples, nodules, epidermoid cysts, keratoses, hair follicles, abnormal vascular skin lesions, birthmarks, birthmarks (nerve spots), soft fibroma, scleroderma, vitiligo, and related disorders, or age spots (liver spots); (h) autoimmune diseases, such as discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes mellitus, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease; (i) Eye diseases, such as glaucoma, intraocular hypertension, decreased vision after eye surgery, vision in warm-blooded animals impaired by cystoid macular edema, and cataracts; (j) Preeclamptic toxemia in high-risk women; (k) Male and female impotence; (j) Allergies and asthma (k) insomnia; (l) depression and related conditions; (m) cardiovascular diseases, such as heart attack, unstable angina, peripheral arterial disease and stroke; (n) tumors, such as benign tumors, breast cancer, colorectal cancer, oral cancer, lung or other cancer of the respiratory system, skin cancer, uterine cancer, pancreatic cancer, prostate cancer, cancer of the reproductive organs, cancer of the urinary tract, leukemia, or other cancers of the blood and lymphatic tissues; and (o) Metastasis.

[0155] In certain embodiments, the method of treating a microbial-associated condition comprises administering to a biological system an HPP / HPC of an antimicrobial peptide or antimicrobial peptide-related compound, or a pharmaceutical composition thereof. Examples of microbial-associated conditions include, but are not limited to, inflammation and related conditions: (a) Pain; (b) trauma; (c) Microbial-associated conditions; (d) Inflammation-related conditions, such as inflammation of the prostate gland (prostatitis), prostatic cystitis, prostatic fibrosis, hemorrhoids, Kawasaki syndrome, gastroenteritis, type 1 membranoproliferative glomerulonephritis, Bartter's syndrome, chronic uveitis, ankylosing spondylitis, hemophilic arthropathy, inflammatory hemorrhoids, post-irradiation (prosthetic) proctitis, chronic ulcerative colitis, inflammatory bowel disease, crypt inflammation, periodontal disease, arthritis, and inflammatory conditions in organs selected from the group consisting of the liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum, stomach, colorectum, intestines, veins, respiratory system, blood vessels, anorectum, and pruritus ani.

[0156] In certain embodiments, a method of treating a neuropeptide-related condition comprises administering to a biological system a HPP / HPC of a neuropeptide or neuropeptide-related compound, or a pharmaceutical composition thereof. Examples of neuro-related conditions include, but are not limited to, pain, and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

[0157] Other conditions treatable by HPP / HPC, or pharmaceutical compositions thereof, include, but are not limited to, conditions associated with platelet aggregation, e.g., post-operative thromboembolism, carotid endarterectomy, recurrence of stenosis after coronary neovascularization, thromboembolic complications in chronic atrial fibrillation, occlusion of aortocoronary artery bypass grafts, heart attack, stroke, multi-infarct dementia, dementia, hemodialysis shunt thrombosis, and arterial embolism complications in prosthetic heart valves in patients; conditions related to pre- and post-partum, anti-AD activity, antidiuretic activity, brain trauma, calcium homeostasis, melanocytes, CNS activity, and phagocytosis.

[0158] In certain embodiments, a method of treating a condition in a subject ameliorative or treatable with a peptide or peptide-related compound comprises administering to the subject a therapeutically effective amount of a peptide HPP / HPC or a pharmaceutical composition thereof.

[0159] HPP / HPC or pharmaceutical compositions thereof can be administered to biological systems by routes of administration known in the art, including, but not limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ocular, pulmonary, subcutaneous, and / or parenteral. Pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration.

[0160] Parenteral administration refers to routes of administration typically involving injection, including, but not limited to, intravenous, intramuscular, intra-arterial, intramedullary, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intradermal, intra-articular, subcapsular, subarachnoid, intraspinal and / or intrasternal injection and / or infusion.

[0161] The HPP / HPC or pharmaceutical composition thereof can be given to the subject in the form of a formulation or preparation suitable for each administration route. The formulation useful in the method of the present invention comprises one or more HPP / HPCs, one or more pharma- ceutically acceptable carriers therefor, and optionally other therapeutic ingredients. The formulation may be conveniently presented in unit dosage form and may be prepared by methods known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the subject being treated and the particular mode of administration. The amount of HPP / HPC that can be combined with a carrier material to produce a pharma- ceutical effective dose is generally the amount of HPP / HPC that produces a therapeutic effect. Generally, from 100 percent, this amount ranges from about 1 percent to about 99 percent of the HPP / HPC, preferably from about 20 percent to about 70 percent.

[0162] Methods of preparing these formulations or compositions include the step of bringing into association the HPP / HPC with one or more pharma- ceutically acceptable carriers and one or more accessory ingredients. In general, the formulations are prepared by intimately bringing into association the HPP / HPC with a liquid carrier or a finely divided solid carrier, and then, if necessary, shaping the product.

[0163] Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with flavored bases, usually sucrose and acacia or tragacanth), powders, granules, as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a troche (with an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc., each containing a predetermined amount of HPP / HPC as the active ingredient. The compound may also be administered as a bolus, electuary, or paste.

[0164] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the HPP / HPC may be mixed with one or more pharma- ceutically acceptable carriers, e.g., sodium citrate or calcium phosphate, and / or the following: (1) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum acacia; (3) humectants, e.g., glycerol; (4) sorbitol, e.g., agar-agar, Disintegrating agents such as calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose and milk sugar, as well as high molecular weight polyethylene glycols.

[0165] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared with binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of powdered peptide or peptidomimetic moistened with an inert liquid diluent. Tablets and other dosage forms, such as dragees, capsules, pills, and granules, may optionally be segmented or prepared with coatings or shells, such as, for example, enteric coatings and other coatings well known in the pharmaceutical art. For example, they may be formulated with hydroxypropylmethylcellulose in various proportions to provide the desired release characteristics, other polymer matrices, liposomes and / or microspheres to provide delayed or controlled release of the HPP / HPC therein. They may also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium immediately prior to use. These compositions may also optionally contain an opacifying agent, and may be of a composition which releases the HPP(s) / HPC(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Implantable compositions which may be used include polymeric substances and waxes. The HPP / HPC may also be in microencapsulated form, optionally with one or more of the above-mentioned excipients.

[0166] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to HPP / HPC, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain auxiliary agents, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, aromatic agents, and preservatives.

[0167] Suspensions may contain, in addition to HPP / HPC, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0168] Formulations for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing one or more HPP / HPC with one or more suitable excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository waxes or salicylates, which are solid at room temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity and release the active agent. Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations, containing carriers as known in the art, as appropriate.

[0169] Formulations for topical or transdermal or epidermal or cutaneous administration of the HPP compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. Under sterile conditions, the active ingredient may be mixed with a pharma- ceutically acceptable carrier, such as water, ethanol and ethanol solutions, and with any preservatives, buffers or propellants that may be required. Ointments, pastes, creams and gels may contain, in addition to the HPP compositions, excipients such as animal and vegetable fats, waxes, paraffins, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, and mixtures thereof. Powders and sprays may contain, in addition to the HPP compositions, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0170] Alternatively, HPP / HPC or pharmaceutical compositions thereof may be administered by aerosol. This can be accomplished by preparing aqueous aerosols, liposomal preparations or solid particles containing the HPPs / HPCs. Non-aqueous (e.g., fluorocarbon propellants) suspensions may be used. Sonic nebulizers may also be used. Aqueous aerosols are made by formulating an aqueous solution or suspension of the agent with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the requirements of the particular compound, but typically include non-ionic surfactants (Tween, Pluronics or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0171] A transdermal patch can also be used to deliver the HPP composition to the tumor site. Such a formulation may be made by dissolving or dispersing the agent in a suitable medium. Absorption enhancers can be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.

[0172] In certain embodiments, the transdermal therapeutic application system comprises peptide HPP / HPC as an active agent for treating a condition treatable by its parent compound, the system being a spray or spreadable solution further comprising a solvent capable of dissolving peptide HPP / HPC, such as, but not limited to, organic and inorganic solvents, such as water, ethanol, isopropanol, acetone, DMSO, DMF, and combinations thereof.

[0173] In certain embodiments, the transdermal therapeutic application system comprises peptide HPP / HPC as an active agent for treating a condition treatable by its parent compound, the system further comprising a body comprising a matrix layer containing the active agent and a non-permeable backing layer. In certain embodiments, such body is a patch or bandage. In certain embodiments, such body is a reservoir of the active agent comprising a permeable bottom facing the skin, whereby by controlling the rate of release, the system allows the active agent or a metabolite of the active agent to reach a constant optimal therapeutic blood level, enhancing efficacy and reducing side effects of the active agent or a metabolite of the active agent.

[0174] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0175] Formulations suitable for parenteral administration comprise HPP / HPC in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that may be reconstituted immediately before use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0176] Examples of suitable aqueous and non-aqueous carriers that may be employed in formulations suitable for parenteral administration include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0177] Preparations suitable for parenteral administration may also contain auxiliary agents such as, for example, preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by including agents which delay absorption, for example, aluminum monostearate and gelatin.

[0178] Injectable depot forms are made by forming microencapsule matrices of HPP / HPC or in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled by the ratio of HPP / HPC to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping HPP / HPC in liposomes or microemulsions that are compatible with body tissues.

[0179] In a particular embodiment, the peptide HPP / HPC or a pharmaceutical composition thereof is delivered to the site of the disease or tumor in a therapeutically effective dose. As is known in the pharmaceutical art, the exact amount of the pharmacologic effective dose of HPP / HPC that produces the most effective outcome in terms of therapeutic efficacy in a given patient depends, for example, on the activity, specific properties, pharmacokinetics, pharmacodynamics, and bioavailability of the particular HPP / HPC, the physiological condition of the subject (race, age, sex, weight, diet, type and stage of disease, general condition, response to a given dose and type of drug), the nature of the pharmacologic acceptable carrier in the formulation, the route and frequency of administration used, and the severity and tendency of the disease caused by the pathogenic target microorganism, to name a few. However, the above guidelines can be used as a basis for fine-tuning the treatment, for example, to determine the optimal dose of administration, requiring only routine experimentation consisting of monitoring the subject and adjusting the dosage. Remington: The Science and Practice of Pharmacy (ed. Gennaro, 20.sup.th edition, Williams & Wilkins PA, USA) (2000). IV. Advantages

[0180] Peptides and related compounds are hydrophilic and have limited ability to penetrate the skin membrane barrier. When taken orally, peptides and related compounds can be rapidly proteolyzed by proteolytic enzymes in the digestive tract within minutes. When injected, administration of peptides is painful and often requires frequent and costly hospital visits to treat chronic conditions.

[0181] In certain embodiments, because the peptide HPP / HPC is capable of crossing one or more biological barriers more efficiently than the parent compound, the HPP / HPC can be administered locally (topically or transdermally) to reach the location where the condition occurs without the need for systemic administration (e.g., oral or parenteral administration). Local administration and penetration of the HPP / HPC allows the HPP / HPC to reach the same level of local concentration of the agent or drug with a smaller amount or dose of the HPP / HPC compared to systemic administration of the parent agent or drug, or to reach higher levels of local concentration that may not be obtained with systemic administration or that would potentially require significantly higher doses of the agent with systemic administration. The higher local concentrations of the HPP / HPC, or its parent drug if cleaved, allow for more effective and faster treatment of conditions than the parent drug delivered systemically, and also allow for the treatment of new conditions that may not have been possible or observed before. Local administration of HPP / HPCs allows a biological subject to mitigate potential distress from systemic administration, e.g., adverse reactions associated with systemic exposure to the agent, gastrointestinal / renal effects, etc. Furthermore, local administration allows the HPP / HPCs to traverse multiple biological barriers and reach the entire body, e.g., via the systemic circulation, thereby avoiding the need for systemic administration (e.g., injection) and obviating pain associated with parenteral injections.

[0182] In certain embodiments, HPP / HPCs or pharmaceutical compositions thereof of the present invention can be administered systemically (e.g., transdermally, orally, or parenterally). HPP / HPCs or active agents of HPP / HPCs (e.g., drugs or metabolites) may enter the systemic circulation at a faster rate than the parent drug, providing faster access to the site of action for the condition. Additionally, HPP / HPCs can cross biological barriers (e.g., the blood-brain barrier) that the parent drug could not penetrate when administered alone, providing novel treatments for conditions that may not have been possible or appreciated before.

[0183] For example, peptide HPP / HPC may exhibit high penetration through biological barriers (e.g., >about 10-fold, >about 50-fold, >about 100-fold, >about 200-fold, >about 300-fold, >about 1000-fold higher than the peptide or peptide-related compound administered alone), and subjects receiving peptide HPP / HPC may experience little or no adverse side effects while subjects receiving similar doses of the parent peptide may experience side effects (e.g., vomiting, hair loss, increased susceptibility to infection). V. Working Examples

[0184] The following examples are provided to better illustrate the claimed invention, but should not be construed as limiting the scope of the invention in any way. The specific compositions, materials, and methods described below all fall within the scope of the present invention, in whole or in part. These specific compositions, materials, and methods are not intended to limit the invention, but merely to describe specific embodiments that fall within the scope of the present invention. Those skilled in the art may develop equivalent compositions, materials, and methods without exercising their inventive abilities and without departing from the scope of the present invention. It will be understood that numerous variations can be made in the procedures described herein, which still fall within the bounds of the present invention. It is the intention of the inventors that such variations are included within the scope of the present invention. Example 1. Preparation of HPP / HPC from parent drug Preparation of HPP / HPC from parent drugs containing at least one carboxyl group

[0185] In certain embodiments, the following structure FC [ka] Structure FC The parent compound having the structure L-1 [ka] Structure L-1 and HPP / HPC having the formula: F, L 1C , L 1N , L 2C , L 2N , L 4C and L 4N is defined above; T C is the transport unit of the peptide HPP / HPC. For example, T C is selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above: T N is selected from the group consisting of zero, H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups.

[0186] In a particular embodiment of the present invention, the HPP / HPC having structure L-1 is [ka] Structure D (e.g., acid halides, mixed anhydrides of the parent compound, etc.) C -L 2C-H (Scheme 1), W C is selected from the group consisting of OH, halogen, alkoxycarbonyl, and substituted aryloxycarbonyl; F, L 1C , L 1N , L 2C , L 2N , L 4C , L 4N , T C and T N is defined as above. [ka] Scheme 1. Preparation of HPP / HPC from parent compounds (I)

[0187] In certain embodiments, HPP / HPC having structure L-1 is prepared according to Scheme 1 as described above, where L 4C is C=O.

[0188] In certain embodiments, the following structure F: [ka] Structure FN The parent compound has the following structure W: [ka] Structure W by reacting with a compound having the structure L [ka] Structure L-1 and a HPP / HPC of the formula: F, L 1C , L 1N , L 2C , L 2N , L 4C , and L 4N is defined as above. TN is the transport unit of the peptide HPP / HPC. For example, T N is selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above: T C is selected from the group consisting of zero, H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups; W N is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy (Scheme 2). [ka] Scheme 2. Preparation of HPP / HPC from the parent compounds (II)

[0189] In certain embodiments, HPP / HPC having the structure of structure L-2 is prepared by organic synthesis in which undesired reactive sites such as, for example, -COOH, -NH2, -OH or SH are protected before linking the transport unit to the functional unit according to one of the synthetic routes as described above. In certain embodiments, the resulting protected HPP / HPC may be further partially or fully deprotected to give partially protected HPP / HPC or deprotected HPP / HPC, respectively. Preparation of Ac-Val-Pro-Asp(OEt)-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·HCl

[0190] Preparation of H-Arg(diAc)-OCH2CH2N(CH2CH3)2: 30.8 g of A-Arg-OH was dissolved in 500 mL of acetone. 200 mL of 20% NaOH was added to the reaction mixture. 40 g of acetic anhydride was added dropwise to the reaction mixture. The mixture was stirred at room temperature (RT) for 2 h. The solvent was evaporated. The residue was extracted with 500 mL of ethyl acetate. The ethyl acetate solution was washed with water (3 x 100 mL). The ethyl acetate layer was dried over magnesium sulfate. The ethyl acetate solution was evaporated to dryness. The residue (Z-Arg(diAc)-OH, 30 g) was dissolved in 300 mL of acetonitrile. The mixture was cooled to 0° C. in an ice-water bath. 12 g of N,N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine, and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 h and at RT overnight. The solids were removed by filtration and the solution was evaporated to dryness. The residue was extracted with ethyl acetate (2 x 250 mL). The ethyl acetate solution was washed with 5% sodium bicarbonate (1 x 500 mL) and water (3 x 100 mL). The ethyl acetate solution was dried over magnesium sulfate. The solution was evaporated to dryness. The residue [Z-Arg(diAc)-OCH2CH2N(CH2CH3)2, 28 g] was dissolved in 300 mL of methanol. 2 g of 10% Pd / C was added to the solution. The mixture was stirred at RT under hydrogen for 10 h. The Pd / C was removed by filtration. The solution was evaporated to dryness to give 22 g of H-Arg(diAc)-OCH2CH2N(CH2CH3)2.

[0191] Preparation of Boc-Asp(OEt)-Pro-OSu: 15 g of L-proline was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 36 g of Boc-Asp(OEt)-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. The mixture was washed with ether (1×300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3×300 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 25 g of the residue (Boc-Asp(OEt)-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethylene. The mixture was cooled to 0 °C. 16 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 hour. The solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1×200 mL) and water (3×200 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness to give 28 g of Boc-Asp(OEt)-Pro-OSu.

[0192] Preparation of H-Asp(OEt)-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2.2TFA: 22 g of H-Arg(diAc)-OCH2CH2N(CH2CH3)2 was dissolved in 300 mL of 5% NaHCO3. 24 g of Boc-Asp(OEt)-Pro-OSu in 150 mL of acetone was added to the reaction mixture. The mixture was stirred at RT for 5 h. 500 mL of ethyl acetate was added to the mixture. The ethyl acetate solution was washed with water (3 times with 100 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 mL of dichloromethylene. 200 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to give 32 g of H-Asp(OEt)-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2.2TFA.

[0193] Preparation of Ac-Val-Pro-OSu: 15 g of L-proline was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 26 g of Ac-Val-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. The mixture was washed with ether (1×300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3×300 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 20 g of the residue (Ac-Val-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethylene. The mixture was cooled to 0 °C. 16 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0 °C for 1 h. The solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1×200 mL) and water (3×200 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness to give 20 g of Ac-Val-Pro-OSu.

[0194] Preparation of Ac-Val-Pro-Asp(OEt)-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·HCl: 31 g of H-Asp(OEt)-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·2TFA was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 15 g of Ac-Val-Pro-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. 500 mL of ethyl acetate was added to the mixture. The organic layer was washed with water (100 mL x 3). The ethyl acetate layer was dried over sodium sulfate. The sodium sulfate was removed by filtration. 15 g of HCl gas in dioxane (200 mL) was added to the solution. The solid was collected and washed with ether (50 mL x 3). After drying, 20 g of the desired product (hygroscopic product) was obtained. Elemental analysis: C 39 H 66 ClNO 11; Molecular weight: 872.45. Calculated %C: 53.69; H: 7.62; Cl: 4.06; N: 14.45; Preparation of Ac-Tyr(Ac)-Gly-Gly-Phe-Met-OCH2CH2N(CH2CH3)2·HCl

[0195] Preparation of H-Met-OCH2CH2N(CH2CH3)2·TFA: 25 g of Boc-Met-OH was dissolved in 300 mL of dichloromethylene. The mixture was cooled to 0 °C in an ice-water bath. 12 g of N,N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture was stirred at 0 °C for 1 h and at RT overnight. The solid was removed by filtration and the dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 500 mL) and water (3 x 100 mL). The ethyl acetate solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue [Boc-Met-OCH2CH2N(CH2CH3) 2, 30 g] was dissolved in 250 mL of dichloromethylene. 250 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 min. The solution was evaporated to dryness to give 26 g of H-Met-OCH2CH2N(CH2CH3)2·TFA.

[0196] Preparation of Boc-Gly-Phe-OSu: 20 g of L-phenylalanine was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 28 g of Boc-Gly-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. The mixture was washed with ether (1x300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3x300 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 22 g of the residue (Boc-Gly-Phe-OH) and 10 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethylene. The mixture was cooled to 0 °C. 15 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 h. The solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1×200 mL) and water (3×200 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness to give 25 g of Boc-Gly-Phe-OSu.

[0197] Preparation of Gly-Phe-Met-OCH2CH2N(CH2CH3)2·TFA: 25 g of H-Met-OCH2CH2N(CH2CH3)2·TFA was dissolved in 300 mL of 5% NaHCO3. 22 g of Boc-Gly-Phe-OSu in 150 mL of acetone was added to the reaction mixture. The mixture was stirred at RT for 5 h. 500 mL of ethyl acetate was added to the mixture. The ethyl acetate solution was washed with water (3 times with 100 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 mL of dichloromethylene. 200 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to give 25 g of Gly-Phe-Met-OCH2CH2N(CH2CH3)2·TFA.

[0198] Preparation of Ac-Tyr(Ac)-Gly-OSu: L-glycine was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 36 g of Ac-Tyr(Ac)-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. The mixture was washed with ether (1x300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3x300 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 28 g of the residue (Ac-Tyr(Ac)-Gly-OH) and 13 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethylene. The mixture was cooled to 0 °C. 18 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 h. The solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1×200 mL) and water (3×200 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness to give 20 g of Ac-Tyr(Ac)-Gly-OSu.

[0199] Preparation of Ac-Tyr(Ac)-Gly-Gly-Phe-Met-OCH2CH2N(CH2CH3)2·HCl: 24 g of H-Gly-Phe-Met-OCH2CH2N(CH2CH3)2·TFA was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 15 g of Ac-Tyr(Ac)-Gly-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. 500 mL of ethyl acetate was added to the mixture. The organic layer was washed with water (100 mL x 3). The ethyl acetate layer was dried over sodium sulfate. The sodium sulfate was removed by filtration. 15 g of HCl gas in dioxane (200 mL) was added to the solution. The solid was collected and washed with ether (50 mL x 3). After drying, 18 g of the desired product (hygroscopic product) was obtained. Elemental analysis: C 37 H 53ClN6O9S; MW: 793.37. Calculated %C: 56.01; H: 6.73; Cl: 4.47; N: 10.59; O: 18.15; S: 4.04. Observed %C: 55.96; H: 6.76; Cl: 4.52; N: 10.54, O: 18.19; S: 4.03. MS: m / e: 757.4; m / e+1: 758.4. Preparation of Ac-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·HCl

[0200] Preparation of Boc-Gly-Pro-OSu: 15 g of L-proline was added to 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 27.2 g of Boc-Gly-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. The mixture was washed with ether (1×300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3×300 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 21 g of the residue (Boc-Gly-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethylene. The mixture was cooled to 0 °C. 17 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0 °C for 1 h. The solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1×200 mL) and water (3×200 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness to give 23 g of Boc-Gly-Pro-OSu.

[0201] Preparation of H-Gly-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·2TFA: 22 g of H-Arg(diAc)-OCH2CH2N(CH2CH3)2 was dissolved in 300 mL of 5% NaHCO3. 20 g of Boc-Gly-Pro-OSu in 150 mL of acetone was added to the reaction mixture. The mixture was stirred at RT for 5 h. 500 mL of ethyl acetate was added to the mixture. The ethyl acetate solution was washed with water (3 times with 100 mL). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 mL of dichloromethylene. 200 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to give 28 g of H-Gly-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·2TF.

[0202] Preparation of Ac-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·HCl: 26 g of H-Gly-Pro-Arg(diAc)-OCH2CH2N(CH2CH3)2·2TFA was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 15 g of Ac-Val-Pro-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 h. 500 mL of ethyl acetate was added to the mixture. The organic layer was washed with water (3×100 mL). The ethyl acetate layer was dried over sodium sulfate. The sodium sulfate was removed by filtration. 15 g of HCl gas in dioxane (200 mL) was added to the solution. The solid was collected, washed with ether (3×50 mL) and dried to give 18 g of the desired product (hygroscopic product). Elemental analysis: C 35 H 60 ClN9O9; MW: 786.36. Calculated %C: 53.46; H: 7.69; Cl: 4.51; N: 16.03; O: 18.31; Observed %C: 53.43; H: 7.73; Cl: 4.55; N: 16.01, O: 18.29. MS: m / e: 750.4; m / e+1: 751.4. Preparation of cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH2CH2N(CH2CH3)2·HCl

[0203] Preparation of Ac-Nle-Asp(OFm)-OH: 43 g of H-Asp(OFm)-OH·TFA and 27 g of Ac-Nle-OSu were dissolved in 300 mL of acetone. 300 mL of 5% NaHCO3 was added to the reaction mixture. The mixture was stirred at RT for 5 h. The mixture was washed with ether (1×300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (300 mL x 3). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness to give 42 g of Ac-Nle-Asp(OFm)-OH.

[0204] Preparation of Fmoc-Trp-Lys(4-Pyoc)-OH: 3567 , 1984; H. Kunz and R. Barthels, Angew. Chem., Int. Ed. Engl., 22 H-Lys(4-Pyoc)-OH was prepared according to (J. Chem. Soc., 783, 1983). 33 g of H-Lys(4-Pyoc)-OH was suspended in 300 mL of 5% NaHCO3. 300 mL of acetone and 52 g of Fmoc-Yrp-OSu were added to the reaction mixture. The mixture was stirred at RT overnight. The mixture was washed with ether (1x500 mL). 500 mL of ethyl acetate was added to the mixture. The pH of the mixture was adjusted to 2.2-2.3 with 3N HCl. The ethyl acetate layer was collected and washed with water. The organic solution was dried over sodium sulfate. The organic solution was evaporated to dryness to give 55 g of Fmoc-Trp-Lys(4-Pyoc)-OH.

[0205] Preparation of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OH: 100 g of Wang's resin was suspended in 700 mL of DMF solution containing 50 g of Fmoc-Trp-Lys(4-Pyoc)-OH, 13 g of 1-hydroxybenzotriazole, 2 g of 4-dimethylaminopyridine and 12 g of N,N'-diisopropylcarbodiimide. The mixture was stirred overnight at RT. The resin was collected by filtration and washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 min. The resin was collected by filtration and washed with DMF (3×400 mL), methanol (3×400 mL) and dichloromethylene (3×400 mL). 700 mL of DMF, 48 g of Fmoc-Arg(diAc)-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium were added to the resin. The mixture was stirred at RT for 2 h. The resin was collected by filtration and washed with DMF (400 mL). The resin was washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 min. The resin was collected by filtration and washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). 700 mL of DMF, 39 g of Fmoc-Phe-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium were added to the resin. The mixture was stirred for 2 h at RT. The resin was collected by filtration and washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 min. The resin was collected by filtration and washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). 700 mL of DMF, 60 g of Fmoc-His(Fmoc)-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium were added to the resin. The mixture was stirred for 2 h at RT. The resin was collected by filtration and washed with DMF ( The resin was washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 min. The resin was collected by filtration and washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). 700 mL of DMF, 60 g of Ac-Nle-Asp(OFm)-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium were added to the resin. The mixture was stirred for 2 h at RT. The resin was collected by filtration and washed with DMF (3 times with 400 mL), methanol (3 times with 400 mL) and dichloromethylene (3 times with 400 mL). The mixture was washed with dichloromethylene (400 mL x 3) and dichloromethylene (400 mL x 3). The peptidated resin was suspended in 700 mL of DMF. 50 g of Mel was added to the reaction mixture. The mixture was stirred for 1 h at RT and 1 h at 50° C. The resin was collected by filtration and washed with DMF (3×400 mL), methanol (3×400 mL) and dichloromethylene (3×400 mL). 700 mL of 30% piperidine was added to the resin. The mixture was stirred for 60 min. The resin was collected by filtration and washed with DMF (3×400 mL), methanol (3×400 mL) and dichloromethylene (3×400 mL). 700 mL of DMF, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium were added to the resin. The mixture was stirred for 10 h at RT. The resin was collected by filtration and washed with DMF (3×400 mL), methanol (3×400 mL) and dichloromethylene (3×400 mL). 700 mL of DMF, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium were added to the resin. The resin was washed with DMF (3×400 mL), methanol (3×400 mL) and dichloromethylene (3×400 mL). 500 mL of trifluoroacetic acid was added to the resin and the mixture was stirred at RT for 1 h. The resin was removed by filtration and the solution was evaporated to dryness. The residue was washed with ether (3×100 mL).

[0206] Preparation of cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH2CH2N(CH2CH3)·HCl: 10 g of cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OH was dissolved in 300 mL of DMF. The mixture was cooled to 0 °C in an ice-water bath. 12 g of N,N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture was stirred at 0 °C for 1 h and at RT overnight. The solids were removed by filtration and the dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 500 mL) and water (1 x 100 mL). The ethyl acetate solution was dried over sodium sulfate. 2 g of HCl in dioxane (20 mL) was added to the solution. The solid was collected and washed with ether (30 mL x 3). The yield was 8 g of the final product. Solid-phase synthesis of peptides HPP / HPC

[0207] Peptide HPP / HPC was prepared using trityl chloride resin and 2-(4-nitrophenylsulfonyl)ethyl group as the carboxyl group protecting group (Scheme 3). [ka] is a resin; X 1 is selected from the group consisting of H, Cl, methyl and methoxyl; R 1 , R 2 ···R n are the side chains of amino acids in peptide HPP / HPC, numbered 1, 2···n, respectively, from the N-terminus to the C-terminus; The coupling reagent is selected from the group consisting of HBTU / DIPEA / HOBt, TBTU / DIPEA / HOBt, BOP / DIPEA / HOBt, HATU / DIPEA / HOBt, DIC / HOB, and combinations thereof; R Tis selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, and transport units selected from the group consisting of Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined above. [ka] [ka] Scheme 3. Synthesis of peptide HPP / HPC using trityl chloride resin and 2-(4-nitrophenylsulfonyl)ethyl group as carboxyl group protecting group

[0208] As used herein, unless otherwise defined, "DCM" means dichloromethane.

[0209] In a particular embodiment, peptide HPP / HPC is prepared using trityl chloride resin and 9-fluorenylmethyl group as the carboxyl group protecting group (Scheme 4), wherein: [ka] X 1 , R 1 , R 2 ···R n , R T and the coupling reagent are as defined above. [ka] Scheme 4. Synthesis of peptides HPP / HPC using trityl chloride resin and 9-fluorenylmethyl group as carboxyl group protecting group

[0210] In a particular embodiment, peptide HPP / HPC is prepared using a carbonate resin and a 9-fluorenylmethyl group as the carboxyl protecting group (Scheme 5), wherein: [ka] R 1 , R 2 ···R n , R T and the coupling reagent are as defined above. [ka] Scheme 5. Synthesis of peptides HPP / HPC using carbonate resin and 9-fluorenylmethyl group as carboxyl group protecting group

[0211] In a particular embodiment, peptide HPP / HPC is prepared using a carbonate resin and a 2-(4-nitrophenylsulfonyl)ethyl group as the carboxyl protecting group (Scheme 6), wherein: [ka] R 1 , R 2 ···R n , R T and the coupling reagent are as defined above. [ka] Scheme 6. Synthesis of peptide HPP / HPC using carbonate resin and 2-(4-nitrophenylsulfonyl)ethyl group as carboxyl group protecting group Example 2. Peptides HPP / HPC exhibited higher in vitro permeation rates across human skin compared to their parent drugs

[0212] The permeation rates of HPPs / HPCs and their parent drugs through human skin were measured in vitro by a modified Franz cell. The Franz cell has two chambers, an upper sample chamber and a lower receiving chamber. Human skin tissue separating the upper and lower receiving chambers was isolated from the anterior and posterior thigh regions.

[0213] Test compounds (2 mL of 20% in 0.2 M phosphate buffer, pH 7.4) were added to the sample chamber of the Franz cell. The receiving chamber contained 10 mL of phosphate buffer (0.2 M), pH 7.4, stirred at 600 rpm. The amount of test compound penetrating the skin was determined by high performance liquid chromatography (HPLC) method. The results are shown in Figure 2. The apparent fluxes of the test compounds were calculated from the slopes in Figure 2 and are summarized in Table 1, respectively.

[0214] The lowest detectable flow rate with this method is 1 μg / cm 2 / hour, so 1μg / cm 2 Parent drugs that exhibited an apparent flux of 1 μg / cm or less were considered undetectable for permeation across skin tissue. HPPs / HPCs of these parent compounds (e.g., enterostatin, Val-Pro-Gly-Pro-Arg (VPGPR), melanocortin II (cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH), opioid peptides (e.g., Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH)) were considered undetectable for permeation across skin tissue. 2 / hr, there was no detectable penetration across the skin tissue. However, the HPPs / HPCs had a detectable apparent flux. Thus, the peptide HPPs / HPCs showed a high permeation rate (340-600 times higher) across the skin tissue compared to their parent compounds. [Table 4] Example 3. Conversion of HPPs / HPCs to parent drugs

[0215] Peptide HPPs / HPCs were rapidly converted to the parent peptide or peptide-related compounds in human plasma.

[0216] Peptide HPP / HPC (20 mg) was incubated with whole blood (1 mL) for 30 min at 37° C. and analyzed by HPLC. The results showed that most of the peptide HPPs / HPCs were converted back to the parent peptide or peptide-related compounds. [Table 5] [Table 6] [Table 7] Example 4. Treatment of obesity using peptide HPPs / HPCs

[0217] Enterostatin [Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg (VPGPR) and Ala-Pro-Gly-Pro-Arg (APGPR)] are pentapeptides derived from the NH2-terminus of procolipase after trypsin cleavage and belong to the family of gut-brain peptides. They regulate fat intake and can be used to treat obesity (Erlanson-Albertsson C, York D, Obes. Rev. 1997 Jul; 5(4): 360-72 and Sorhede M, Mei J, Erlanson-Albertsson C., J Physiol. 87:273275,1993). When injected intraperitoneally into overnight fasted Osborne-Mendel rats, H-Val-Pro-Asp-Pro-Arg-OH produced a dose-dependent reduction in food intake. This inhibition of feeding was observed when rats were fed a high-fat diet, but not when they were fed a high-carbohydrate, low-fat diet (Okada S. et al. Physiol Behav., 1991 Jun; 49(6): 1185-9). H-Val-Pro-Gly-Pro-Arg(NO) in Sprague Dawley rats and DB / DB mice 2 )-OCH(CH 3) 2 Anti-obesity activity of HCl

[0218] H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl (administered dermally, at a dose as low as 0.3 mg / kg in rats) reduced food intake and body weight in Sprague Dawley (SD) rats and DB / DB mice. The results are shown in Tables 3, 4, and 5.

[0219] In the first experiment, 40 female Sprague Dawley rats (15 weeks old, 318-346g) were divided into four groups. In group A, 0.2mL of water was administered twice daily to the rats' backs for 30 days (n=10). In groups B, C and D, 10mg / kg, 1mg / kg and 0.3mg / kg of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl in 0.2mL of water were administered transdermally to the rats' backs for 30 days (n=10), respectively. The results showed that H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl effectively reduced the rats' body weight (Table 3). [Table 8]

[0220] In the second experiment, 40 juvenile female Sprague Dawley (SD) rats (180-225 g) were divided into four groups. In group A, 0.2 mL of water was administered to the rats' backs twice a day for 30 days (n=10). In groups B, C, and D, 10 mg / kg, 1 mg / kg, and 0.3 mg / kg of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl in 0.2 mL of water were administered transdermally to the rats' backs twice a day for 30 days (n=10). The results showed that H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl effectively controlled overweight in juvenile rats (Table 4). [Table 9]

[0221] In the third experiment, 40 obese female DB / DB mice (SLAC / DB / DB mice, 16 weeks old, 55-60 g) were divided into four groups. In group A, 0.1 mL of water was administered twice a day to the backs of the mice for 30 days (n=10). In groups B, C, and D, 15 mg / kg, 1.5 mg / kg, and 0.5 mg / kg of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl in 0.1 mL of water were administered transdermally to the backs of the mice for 30 days (n=10), respectively. The results showed that H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl effectively reduced the body weight and blood glucose levels of obese mice (Table 5). [Table 10] H-Val-Pro-Gly-Pro-Arg(diAc)-OCH in Sprague Dawley rats 2 CH 2 CH 2 CH 3 HCl Anti-obesity

[0222] H-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2CH2CH3·HCl (administered dermally, at doses as low as 0.3 mg / kg in rats) reduced food intake and body weight in SD rats and DB / DB mice. The results are shown in Tables 6, 7, and 8.

[0223] In the first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old, 315-340 g) were divided into four groups. In group A, 0.2 mL of water was administered twice a day to the rats' backs for 30 days (n=10). In groups B, C and D, 10 mg / kg, 1 mg / kg and 0.3 mg / kg of H-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2CH2CH3·HCl in 0.2 mL of water were administered transdermally to the rats' backs for 30 days (n=10), respectively. The results showed that H-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2CH2CH3·HCl effectively reduced the rats' body weight (Table 6). [Table 11]

[0224] In the second experiment, 40 juvenile female Sprague Dawley (SD) rats (180-230 g) were divided into four groups. In group A, 0.2 mL of water was administered twice daily to the rats' backs for 30 days (n=10). In groups B, C, and D, 10 mg / kg, 1 mg / kg, and 0.3 mg / kg of H-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2CH2CH3·HCl in 0.2 mL of water were administered transdermally to the rats' backs for 30 days (n=10), respectively. The results showed that H-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2CH2CH3·HCl effectively controlled overweight in juvenile rats (Table 7). [Table 12]

[0225] In the third experiment, 40 obese female DB / DB mice (SLAC / DB / DB mice, 16 weeks old, 55-60 g) were divided into four groups. In group A, 0.1 mL of water was administered twice a day to the backs of the mice for 30 days (n=10). In groups B, C and D, 15 mg / kg, 1.5 mg / kg and 0.5 mg / kg of H-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2CH2CH3·HCl in 0.1 mL of water were administered transdermally to the backs of the mice for 30 days (n=10), respectively. The results showed that H-Val-Pro-Gly-Pro-Arg(diAc)-OCH2CH2CH2CH3·HCl effectively reduced the body weight and blood glucose levels of obese mice (Table 8). [Table 13] H-Ala-Pro-Gly-Pro-Arg(NO 2 )-OCH 2 CH 2 CH 2 CH 3 HCl Anti-obesity

[0226] H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl (administered dermally, at doses as low as 0.3 mg / kg in rats) reduced food intake and body weight in SD rats and DB / DB mice. The results are shown in Tables 9, 10, and 11.

[0227] In the first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old, 320-345 g) were divided into four groups. In group A, 0.2 mL of water was administered twice a day to the rats' backs for 30 days (n=10). In groups B, C and D, 10 mg / kg, 1 mg / kg and 0.3 mg / kg of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl in 0.2 mL of water were administered transdermally to the rats' backs for 30 days (n=10), respectively. The results showed that H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl effectively reduced the rats' body weight (Table 9). [Table 14]

[0228] In the second experiment, 40 juvenile female Sprague Dawley (SD) rats (182-223 g) were divided into four groups. In group A, 0.2 mL of water was administered twice daily to the rats' backs for 30 days (n=10). In groups B, C and D, 10 mg / kg, 1 mg / kg and 0.3 mg / kg of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl in 0.2 mL of water were administered transdermally to the rats' backs for 30 days (n=10), respectively. The results showed that H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl effectively controlled overweight in juvenile rats (Table 10). [Table 15]

[0229] In the third experiment, 40 obese female DB / DB mice (SLAC / DB / DB mice, 16 weeks old, 53-61 g) were divided into four groups. In group A, 0.1 mL of water was administered twice a day to the backs of the mice (n=10). In groups B, C and D, 15 mg / kg, 1.5 mg / kg and 0.5 mg / kg of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl in 0.1 mL of water were administered transdermally to the backs of the mice (n=10) twice a day for 30 days. The results showed that H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl effectively reduced the body weight and blood glucose levels of obese mice (Table 11). [Table 16] H-Val-Pro-Asp(OEt)-Pro-Arg(NO 2 )-OCH 2 CH 2 CH 2 CH 3 HCl Anti-obesity

[0230] H-Val-Pro-Asp(OEt)-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl (administered dermally, at a dose as low as 0.3 mg / kg in rats) reduced food intake and body weight in SD rats and DB / DB mice. The results are shown in Tables 12, 13, and 14.

[0231] In the first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old, 320-350 g) were divided into four groups. In group A, 0.2 mL of water was administered twice a day to the rats' backs for 30 days (n=10). In groups B, C and D, 10 mg / kg, 1 mg / kg and 0.3 mg / kg of H-Val-Pro-Asp(OEt)-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl in 0.2 mL of water were administered transdermally to the rats' backs for 30 days (n=10), respectively. The results showed that H-Val-Pro-Asp(OEt)-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl effectively reduced the rats' body weight (Table 12). [Table 17]

[0232] In the second experiment, 40 juvenile female Sprague Dawley (SD) rats (185-220 g) were divided into four groups. In group A, 0.2 mL of water was administered twice daily to the rats' backs for 30 days (n=10). In groups B, C and D, 10 mg / kg, 1 mg / kg and 0.3 mg / kg of H-Val-Pro-Asp(OEt)-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl in 0.2 mL of water were administered transdermally to the rats' backs for 30 days (n=10), respectively. The results showed that H-Val-Pro-Asp(OEt)-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl effectively controlled overweight in juvenile rats (Table 13). [Table 18]

[0233] In the third experiment, 40 obese female DB / DB mice (SLAC / DB / DB mice, 16 weeks old, 53-61 g) were divided into four groups. In group A, 0.1 mL of water was administered twice a day to the backs of the mice for 30 days (n=10). In groups B, C and D, 15 mg / kg, 1.5 mg / kg and 0.5 mg / kg of H-Val-Pro-Asp(OEt)-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl in 0.1 mL of water were administered transdermally to the backs of the mice for 30 days (n=10), respectively. The results showed that H-Val-Pro-Asp(OEt)-Pro-Arg(NO2)-OCH2CH2CH2CH3·HCl effectively reduced the body weight and blood glucose levels of obese mice (Table 14). [Table 19] Example 5. Treatment of erectile dysfunction (ED) and female impotence with peptide HPPs / HPCs

[0234] Melanocortin II is a cyclic lactam peptide, cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH. It is Palatin's (AMEX:PTN) novel drug candidate for the treatment of male and female sexual impotence. As the first of a new class of therapeutics called melanocortin agonists, Melanocortin II has shown promise in effectively treating erectile dysfunction (ED) and female sexual impotence without the cardiovascular effects seen with currently available ED medications. Melanocortin II does not act directly on the vasculature, but rather through a mechanism involving the central nervous system. As a result, it offers significant safety and efficacy benefits over currently available products.

[0235] The HPP / HPC of melanocortin II diffuses through human skin at extremely high rates (approximately 0.3-0.5 mg / hr / cm2), providing a method to treat erectile dysfunction or increase sexual arousal in women with few side effects.

[0236] Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH2CH2N(CH2CH3)2·HCl (peptide A) was applied once a day in 0.2 mL of pH 7.0 phosphate buffer (0.1 M) to the backs of male rats (group A-1, 30 rats) for 5 days. The same dose of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(NO2)-Trp-Lys-OCH2CH2N(CH2CH3)2·HCl (peptide B) was applied to the backs of another group of rats (group B-1, 30 rats). The control group of rats was not treated with the drug. The results showed a 5-fold increase in seduction behavior and a 3-fold increase in mating behavior for group A-1 compared to the negative control. A six-fold increase in seduction behavior and a three-fold increase in mating behavior were observed for group B-1 compared to the control group (Table 15).

[0237] Peptide A and peptide B at 2 mg / kg in 0.2 mL of pH 7.0 phosphate buffer (0.1 M) were applied once a day to the backs of both male rats (30 rats) and female rats (30 rats) for 5 days. The rats in the control group were not treated with any drugs. The results showed a 6-fold increase in luring behavior and a 5-fold increase in mating behavior in both A-2 and B-2 groups compared to the control group (Table 15). [Table 20] X: Treatment with HPP / HPC (2 mg / kg in 0.2 mL of phosphate buffer (0.1 M), pH 7.0) on the back once a day for 5 days. Example 6. Pain suppression by HPPs / HPCs of enkephalins and related compounds

[0238] Opioid peptides (e.g., Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL and H-Tyr-D-Ala-Gly-Phe-Leu-OH) exert morphine-like analgesic effects. When an acidic solution was intraperitoneally administered to mice, the number of pains produced was counted and the inhibition rate was calculated based on the control group. HCl·H-Tyr(Ac)-D-Ala-Gly-Phe-Leu-OCH2(CH2)4CH3 (10 mg / kg, B), Ac-Tyr(Ac)-D-Ala-Gly-Phe-Leu-OCH2CH2N(CH2CH3)·HCl (10 mg / kg, C) and HCl·H-Tyr(Ac)-D-Ala-Gly-Phe-Met(O)-OL (10 mg / kg, D) were administered percutaneously to the neck of mice, and 30 minutes later, acidic solution was administered. Group A was the control group. The results are shown in Table 16. [Table 21]

[0239] Opioid peptides are natural peptides produced by animals and are not stable in biological systems. They are not addictive and are used for the treatment of pain from toothache, headache, arthritis and other inflammations, fever, cancer, dysmenorrhea, and acute migraine, as well as for the treatment of drug abuse. The corresponding parent peptides of the HPPs / HOCs appearing in the Examples are listed below in Table D. [Table 22]

Claims

1. 1. A highly penetrant composition of a peptide or peptide-related compound, comprising: (a) a functional unit; (b) a linker; (c) a transport unit; The functional unit is covalently linked to the transport unit via a linker, The functional unit comprises a portion of a peptide or peptide-related compound, the transport unit comprises a protonatable amine group; The linker comprises a chemical bond that is capable of being cleaved after the highly permeable composition crosses one or more biological barriers.

2. 2. The highly permeable composition of claim 1, wherein the chemical bond is selected from the group consisting of a covalent bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond.

3. 2. The highly penetrating composition of claim 1, wherein upon cleavage of the cleavable bond, a portion of the peptide or peptide-related compound is converted to a peptide or peptide-related compound.

4. 2. The highly penetrating composition of claim 1, wherein the functional unit comprises a lipophilic derivative of a peptide or a portion of a peptide-related compound.

5. 5. The highly penetrating composition according to claim 4, wherein the lipophilic derivative is selected from the group consisting of carbonates, amides, carbamates, N-Mannich bases, ethers, thioethers, thioesters, phosphates, oximes and imines.

6. 2. The highly permeable composition of claim 1, wherein the peptide or peptide-related compound is selected from the group consisting of a peptide, a peptide metabolite, or an agent that can be metabolized to a peptide or a peptide metabolite, and analogs thereof.

7. 2. The highly penetrative composition of claim 1, wherein the protonatable amine groups are selected from the group consisting of substituted and unsubstituted primary amine groups, substituted and unsubstituted secondary amine groups, and substituted and unsubstituted tertiary amine groups.

8. The protonatable amine group is either unique or can be represented by any one of structures Na, Nb, Nc, Nd, Ne, Nf, Ng, Nh, Ni, Nj, Nk, Nl, Nm, Nn, No, Np, Nq, and Nr: 【Chemistry 1】 and including stereoisomers thereof and pharma- ceutically acceptable salts thereof, wherein R 11 ~R 16 are independently: None, H, CH 2 COOR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein the carbon or hydrogen is further independently selected from the group consisting of O, S, P, NR 11 The highly permeable composition according to claim 7, which may be substituted with any other pharma- ceutically acceptable group.

9. The chemical structure below 【Chemistry 2】 Structure L-1 and pharma- ceutically acceptable salts thereof, wherein: F has the structure F-1: 【Chemistry 3】 a portion of a peptide or peptide-related compound having the formula: Each A 1 ~A m are independently selected from the residues of 2-naphthylalanine, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure A and Structure B: 【Chemistry 4】 Structure A 【Chemistry 5】 Structure B selected from the group consisting of: Each A 1 ~A m each p is an independently selected integer; Each A 1 ~A m Z at each carbon A-1 , each A 1 ~A m About Z A-2 , Z NT , Z CT-1 and Z CT-2 are independently H, CH 3 , C 2 H 5、 C 3 H 7 , C.F. 3 , C 2 F 5 , C 3 F 7 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl groups, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalides; Each A 1 ~A m R at each carbon A , each A 1 ~A m R at each carbon B , R NT and R CT is selected from the group consisting of substituted and unsubstituted imidazolyl, substituted and unsubstituted guanidino, substituted and unsubstituted carboxyl, substituted and unsubstituted carboxamido, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups; A 1 ~A m When p is an integer of 2 or more, R A Or R B may be the same or different, and Z on each carbon A-1 may be the same or different; The amino and carboxyl functional groups in the peptide chain may further form lactam bridges; The thiol groups may further form disulfide bridges; Each A 1 ~A m T B , T C and T N are independently no, H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr: 【Chemistry 6】 is selected from the group consisting of Each R 11 ~R 16 are independently: None, H, CH 2 COOR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein the carbon or hydrogen is further independently selected from the group consisting of O, S, P, NR 11 or may be substituted by other pharma- ceutically acceptable groups; Each A 1 ~A m L 1B , L 1C and L 1N is nothing, O, S, -N (L 3 ) -, -N(L 3 )-CH 2 -O, -N(L 3 )-CH 2 -N(L 5 ) -, -O-CH 2 -O-, -O-CH(L 3 )-O and -S-CH(L 3 )-O- is selected from the group consisting of: Each A 1 ~A m L 2B , L 2C and L 2N is nothing, O, S, -N (L 3 ) -, -N(L 3 )-CH 2 -O, -N(L 3 )-CH 2 -N(L 5 ) -, -O-CH 2 -O-, -O-CH(L 3 )-O, -S-CH(L 3 ) -O-, -O-L 3 -, -N-L 3 -, -SL 3 -, -N(L 3 ) -L 5 - and L 3 Selected from the group consisting of: Each A 1 ~A m , L 4C and L 4N L 4B are independently none, C=O, C=S, 【Chemistry 7】 【Chemistry 8】 and 【Chemistry 9】 Selected from the group consisting of: Each L 1B , L 1C , L 1N , L 2B , L 2C , L 2N , L 4B , L 4C and L 4N About L 3 and L 5 are independently: None, H, CH 2 COOL 6 , substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein carbon or hydrogen is further independently selected from the group consisting of O, S, P, NL, 3 or may be substituted by other pharma- ceutically acceptable groups; L 6 is selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein carbon or hydrogen is further independently selected from the group consisting of O, S, N, P(O)OL, 6 , CH=CH, C≡C, CHL 6 , C.L. 6 L 7 , optionally substituted by an aryl, heteroaryl or cyclic group; L 7 is selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein carbon or hydrogen is further independently selected from the group consisting of O, S, N, P(O)OL, 6 , CH=CH, C≡C, CHL 6 , C.L. 6 L 7 , optionally replaced by an aryl, heteroaryl or cyclic group, Highly permeable composition.

10. 10. The method of claim 9, wherein the peptide is selected from the group consisting of enterostatin, melanocortin II, and an opioid peptide.

11. Structure 2, structure 3, structure 4, structure 5, structure 6, structure 7, structure 8, structure 9, structure 10, structure 11, structure 12, structure 13, structure 14, structure 15, structure 16, structure 17, structure 18, structure 19, structure 20, structure 21, structure 22, structure 23, structure 24, structure 25, structure 26, structure 27, structure 28, structure 37, structure 38, structure 39, structure 40, structure 41, structure 42, structure 43, structure 44, structure 45, structure 46, structure 47, structure 48, structure 49, structure 50, structure 51, structure 52, structure 53, structure 54, structure 55, structure 56, structure 57, structure 58, structure 5 ... , structure 60, structure 61, structure 62, structure 63, structure 64, structure 65, structure 66, structure 67, structure 68, structure 69, structure 70, structure 71, structure 72, structure 73, structure 74, structure 75, structure 76, structure 77, structure 78, structure 79, structure 80, structure 81, structure 82, structure 83, structure 8 4, structure 85, structure 86, structure 87, structure 88, structure 89, structure 90, structure 91, structure 92, structure 93, structure 94, structure 95, structure 96, structure 97, structure 98, structure 99, structure 100, structure 101, structure 102, structure 103, structure 104, structure 105, structure 106, structure 107, Structure 108, Structure 109, Structure 110, Structure 111, Structure 112, Structure 113, Structure 114, Structure 115, Structure 116, Structure 117, Structure 118, Structure 119, Structure 120, Structure 121, Structure 122, Structure 123, Structure 124, Structure 125, Structure 126, Structure 127, Structure 12 8. Structure 137, Structure 138, Structure 139, Structure 140, Structure 141, Structure 142, Structure 143, Structure 144, Structure 145, Structure 146, Structure 147, Structure 148, Structure 149, Structure 150, Structure 151, Structure 152, Structure 153, Structure 154, Structure 155, Structure 156, Structure 1 57, structure 158, structure 159, structure 160, structure 161, structure 162, structure 163, structure 164, structure 165, structure 166, structure 167, structure 168, structure 169, structure 170, structure 171, structure 172, structure 173, structure 174, structure 175, structure 176, structure 177, structure structure 178, structure 179, structure 180, structure 181, structure 182, structure 183, structure 184, structure 185, structure 186, structure 187, structure 188, structure 189, structure 190, structure 191, structure 192, structure 193, structure 194, structure 195, structure 196, structure 197, structure 198,Structure 199, Structure 200, Structure 201, Structure 202, Structure 203, Structure 204, Structure 205, Structure 206, Structure 207, Structure 208, Structure 209, Structure 210, Structure 211, Structure 212, Structure 213, Structure 214, Structure 215, Structure 216, structure 217, structure 218, structure 219, structure 220, structure 221, structure 222, structure 223, structure 224, structure 225, structure 226, structure 227, structure 228, structure 237, structure 238, structure 239, structure 240, structure 24 1, structure 242, structure 243, structure 244, structure 245, structure 246, structure 247, structure 248, structure 249, structure 250, structure 251, structure 252, structure 253, structure 254, structure 255, structure 256, structure 257, structure 258, Structure 259, Structure 260, Structure 261, Structure 262, Structure 263, Structure 264, Structure 265, Structure 266, Structure 267, Structure 268, Structure 269, Structure 270, Structure 271, Structure 272, Structure 273, Structure 274, Structure 275, Structure 2 76, structure 277, structure 278, structure 279, structure 280, structure 281, structure 282, structure 283, structure 284, structure 285, structure 286, structure 287, structure 288, structure 289, structure 290, structure 291, structure 292, structure 293 , structure 294, structure 295, structure 296, structure 297, structure 298, structure 299, structure 300, structure 301, structure 302, structure 303, structure 304, structure 305, structure 306, structure 307, structure 308, structure 309, structure 310, structure The compound of formula (I) comprises a structure selected from the group consisting of structure 311, structure 312, structure 313, structure 314, structure 315, structure 316, structure 317, structure 318, structure 319, structure 320, structure 321, structure 322, structure 323, structure 324, structure 325, structure 326, structure 327, structure 328, structure 337, structure 338, structure 339, structure 340, structure 341, structure 342, structure 343, structure 344 and structure 345, including stereoisomers thereof and pharma- ceutically acceptable salts thereof, wherein R is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues; X, X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 21 , X 22 , X 23 , X 24 , X 25 , X 26 and X 27 are independently C=O, C=S, COO, CSO, CH 2 OCO, COOCH 2 OCO, COCH 2 OCO, C.H. 2 -O-CH(CH 2 OR 4 ) 2 , C.H. 2 -O-CH(CH 2 O.C.O.R. 4 ) 2 , S.O. 2 , PO(OR), NO, O, S, NR 5 and none; R 1 , R 2 , R 4 , R 5 , R 6、 R 7 , R 8 , R 9 , R 10 , R 21 , R 22 , R 23 , R 24、 R 25 , R 26 and R 27 are independently H, O, and NO 2 , substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues; Ar is selected from the group consisting of phenyl, 2'-naphthyl, 4-iodophenyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues; The HA is selected from the group consisting of none, hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfuric acid, bisulfate, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or pamoic acid. The highly permeable composition of claim 9.

12. comprising a structure selected from the group consisting of structure 1a, structure 1b, structure 1c, structure 1d, structure 1e, structure 1f, structure 1g, and structure 1h; 【Chemistry 10】 Structure 1a 【Chemistry 11】 Structure 1b 【Chemistry 12】 Structure 1c 【Chemistry 13】 Structure 1d 【Chemistry 14】 Structure 1e 【Chemistry 15】 Structure 1f 【Chemistry 16】 structure 1g 【Chemistry 17】 structure 1h including its stereoisomers and pharma- ceutically acceptable salts thereof, wherein: X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , R 4 , R 5 , R 6、 R 7 , R 8 , R 9 The highly permeable composition of claim 9, wherein HA has the same meaning as in claim 11.

13. A pharmaceutical composition comprising the highly permeable composition of claim 9 and a pharma- ceutically acceptable carrier.

14. 14. The pharmaceutical composition of claim 13, wherein the pharma- ceutically acceptable carrier is polar.

15. 14. The pharmaceutical composition of claim 13, wherein the pharma- ceutically acceptable carrier is selected from the group consisting of alcohol, acetone, esters, water and aqueous solutions.

16. A method for permeabilizing a biological barrier, comprising administering to the biological barrier the pharmaceutical composition of claim 13.

17. A method for screening HPPs of peptides or peptide-related compounds for desired properties comprising the steps of: (1) covalently linking a functional unit comprising a peptide or peptide-related compound to a transport unit via a linker to form a test composition; (2) administering a test composition to a biological subject or biological barrier; (3) determining whether the test composition has the desired properties; Methods including:

18. The desired characteristics are (1) the ability of the test composition to penetrate a biological barrier; (2) the ability of the test composition to convert to the parent drug or active agent; (3) Permeability of the test composition; (4) the efficacy of the test composition, and (5) Efficacy of the test composition 18. The method of claim 17, selected from the group consisting of:

19. 1. A method of diagnosing a condition in a biological subject, comprising the steps of: (1) administering to a biological subject the composition of claim 9; (2) detecting the presence, location, or amount of the composition in a biological subject; (3) Detecting a state in a biological subject Methods including:

20. 20. The method of claim 19, wherein the composition is labeled.

21. 1. A method of diagnosing a condition in a biological subject, comprising the steps of: (1) administering to a biological subject the composition of claim 13; (2) detecting the presence, location, or amount of the composition in a biological subject; (3) Detecting a state in a biological subject Methods including:

22. 22. The method of claim 21, wherein the composition is labeled.

23. 17. A method of treating a condition in a biological subject, comprising administering to the biological subject a highly permeable composition according to claim 9 or a pharmaceutical composition according to claim 13.

24. 24. The method of claim 23, wherein the condition is selected from the group consisting of pain, trauma, inflammation-related conditions, microbial-related conditions, neuropeptide-related conditions, hormone-related conditions, tumors, abnormal blood pressure, obesity, brain injury, allergies, male and female impotence, metastasis, and other conditions related to tuftsin, prepartum, postpartum, anti-AD activity, antidiuretic activity, calcium homeostasis, melanocytes, hormone release, platelet aggregation, CNS activity, and phagocytosis.

25. 25. The method of claim 24, wherein the hormone-related condition is selected from the group consisting of menopause, bone disease, growth hormone deficiency, hyperthyroidism, hypothyroidism, metabolic disorder conditions, abnormal blood pressure, skin conditions, autoimmune diseases, eye diseases, pre-eclamptic toxemia in high risk women, sexual impotence in men and women, allergies, asthma, insomnia, depression and related conditions, cardiovascular disease and tumors.

26. 26. The method of claim 25, wherein the bone disease is selected from the group consisting of osteoporosis, Paget's disease and bone metastasis.

27. 26. The method of claim 25, wherein the metabolic disorder condition is selected from the group consisting of obesity, abnormal blood glucose levels, abnormal blood lipid levels, diabetes (type I and / or type II) and diabetes-induced complications including diabetic retinopathy, necrotic ulcers and diabetic proteinuria.

28. 26. The method of claim 25, wherein the abnormal blood pressure is selected from the group consisting of hypertension and hypotension.

29. 26. The method of claim 25, wherein the skin condition is selected from the group consisting of psoriasis and psoriatic disorders, acne, cystic acne, purulent or red bumps, comedones, papules, pustules, nodules, epidermoid cysts, keratinized hair follicles, abnormal vascular skin lesions, birthmarks, moles (nevus), soft fibroma, scleroderma, vitiligo, and related disorders, or age spots (liver spots).

30. 26. The method of claim 25, wherein the autoimmune disease is selected from the group consisting of discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, scleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes mellitus, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease.

31. 26. The method of claim 25, wherein the eye disease is selected from the group consisting of glaucoma, intraocular hypertension, decreased vision following eye surgery, vision in warm-blooded animals impaired by cystoid macular edema, and cataracts.

32. 26. The method of claim 25, wherein the cardiovascular disease is selected from the group consisting of heart attack, unstable angina, peripheral arterial disease and stroke.

33. 26. The method of claim 25, wherein the tumor is selected from the group consisting of benign tumors, breast cancer, colorectal cancer, oral cancer, lung or other respiratory cancer, skin cancer, uterine cancer, pancreatic cancer, prostate cancer, reproductive cancer, urinary cancer, leukemia, or other cancers of the blood and lymphatic tissues.

34. 25. The method of claim 24, wherein the microbial-associated condition is selected from the group consisting of pain, trauma, and inflammation-associated conditions.

35. 35. The method of claim 34, wherein the inflammation-related condition is selected from the group consisting of inflammation of the prostate gland (prostatitis), prostatic cystitis, prostatic fibrosis, hemorrhoids, Kawasaki syndrome, gastroenteritis, type 1 membranoproliferative glomerulonephritis, Bartter's syndrome, chronic uveitis, ankylosing spondylitis, hemophilic arthropathy, inflammatory hemorrhoids, post-irradiation (prosthetic) proctitis, chronic ulcerative colitis, inflammatory bowel disease, crypt inflammation, periodontal disease, arthritis, and inflammatory conditions in organs selected from the group consisting of the liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum, stomach, colorectum, intestines, veins, respiratory system, blood vessels, anorectum, and pruritus ani.

36. 25. The method of claim 24, wherein the neuropeptide-associated condition is selected from the group consisting of Alzheimer's disease and Parkinson's disease.

37. 24. The method of claim 23, wherein the composition is administered to a biological subject via a route selected from oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, intradermal, ocular, pulmonary, subcutaneous, and parenteral administration.

38. 24. The method of claim 23, wherein the peptide is selected from the group consisting of angiotensin, angiotensin II antagonists, angiotensin II AT2 receptor, antimicrobial peptides, antioxytocin, hormones, antidiuretic hormone, adrenocorticotropic hormone, antimicrobial peptides, anti-inflammatory peptides, bradykinin, bradykinin antagonists, endothelin peptides, endothelin peptide antagonists, gastrin, calcitonin, melanoma-associated antigenic peptides, laminin peptides, fibrinogen peptides, EAE-inducing peptides, growth factors, growth hormone releasing peptides, somatostatin, hormone releasing hormone, luteinizing hormone releasing hormone, neuropeptides, melanocyte stimulating hormone, sleep-inducing peptides, amyloid peptides, tuftsin, retroinvasive tuftsin, enterostatin, melanocortin II, and opioid peptides and mimetics.

39. 39. The method of claim 38, wherein enterostatin is selected from the group consisting of Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg (VPGPR), and Ala-Pro-Gly-Pro-Arg (APGPR).

40. 39. The method of claim 38, wherein the opioid peptide is selected from the group consisting of Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL and H-Tyr-D-Ala-Gly-Phe-Leu-OH).

41. A method for solid phase synthesis of peptide HPC, comprising: (a) providing a chemically modified resin; (b) protecting the carboxyl groups of all natural or modified amino acid residues as desired according to the peptide HPC with protecting groups to provide COOH-protected amino acid residues; (c) coupling a COOH-protected amino acid residue at the N-terminus of the peptide HPC to a chemically modified resin to provide an immobilized COOH-protected peptide HPC precursor having one amino acid residue; (d) deprotecting the protected carboxyl group of the immobilized COOH-protected peptide HPC precursor with a deprotection reagent to provide an immobilized COOH-unprotected peptide HPC precursor having one amino acid residue; (e) repeating steps c) and d) with COOH-protected amino acid residues of the peptide HPC until an immobilized C-unprotected peptide HPC precursor is provided having all amino acids except the C-terminal amino acid residue; (f) connecting the C-terminal amino acid residue to R via a covalent bond T and providing a modified C-terminal amino acid, wherein R T is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr as defined in claim 8: (g) coupling a modified C-terminal amino acid to the immobilized C-unprotected peptide HPC precursor resulting from step e) to provide an immobilized peptide HPC; h) releasing the immobilized peptide HPC from the resin to provide the peptide HPC. A synthetic method including

42. 42. The method of claim 41, wherein the resin used is selected from the group consisting of trityl chloride resins and carbonate ester resins.

43. 42. The method of claim 41, wherein the protecting group is selected from the group consisting of 2-(4-nitrophenylsulfonyl)ethyl and 9-fluorenylmethyl groups.

44. 42. The method of claim 41, wherein the coupling reaction is carried out in the presence of a coupling reagent selected from the group consisting of HBTU / DIPEA / HOBt, TBTU / DIPEA / HOBt, BOP / DIPEA / HOBt, HATU / DIPEA / HOBt and DIC / HOB and combinations thereof.

45. 17. A transdermal therapeutic application system comprising a compound or composition according to claim 9, 10, 11, 12 or 13 as an active agent for treating a condition treatable by its parent compound, the system being a spray or paint-on solution further comprising a solvent selected from the group consisting of water, ethanol, isopropanol, acetone, DMSO, DMF and combinations thereof.

46. A transdermal therapeutic application system comprising a compound or composition according to claim 9, 10, 11, 12 or 13 as an active agent for treating a condition treatable by its parent compound, the system further comprising a body comprising a matrix layer containing the active agent and a non-permeable backing layer.

47. 47. The transdermal therapeutic application system of claim 46, wherein the body is a patch or a bandage.

48. The transdermal therapeutic application system of claim 46, wherein the main portion is a reservoir of active substance with a permeable bottom facing the skin, and by controlling the release rate, the system enables the active ingredient or a metabolite of the active ingredient to always reach an optimal therapeutic blood level, thereby enhancing efficacy and reducing side effects of the active ingredient or a metabolite of the active ingredient.

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