Atrial natriuretic peptide constructs for targeted payload delivery to NPR-c expressing cells

Abstract

The present disclosure relates to a polypeptide construct for targeted delivery of a payload, comprising a natriuretic peptide receptor (NPR-C) ligand. Also provided is a conjugate comprising; a polypeptide construct for targeted delivery of a payload to NPR-C expressing cells. Further provided are compositions comprising the construct or the conjugate, and kits comprising the construct and a crosslinker, and methods and uses of the same.

Description

ATRIAL NATRIURETIC PEPTIDE CONSTRUCTS FOR TARGETED PAYLOAD DELIVERY TO NPR-C EXPRESSING CELLS Related Applications

[0001] This application claims the benefit of U.S. Provisional Applications 63 / 638,062 and 63 / 638,127, each filed on April 24, 2024, both of which are herein incorporated by reference in their entirety. Incorporation of Sequence Listing

[0002] A computer readable form of the Sequence Listing “96418229_SequenceListing.xml ” (664.0 kilobytes), submitted electronically and created on April 24, 2025, is herein incorporated by reference. Field

[0003] The present disclosure relates to polypeptide constructs for targeted payload delivery to a natriuretic peptide receptor C (NPR-C)-expressing cell, for example, cells in the kidney, comprising a NPR-C-targeting ligand. The polypeptide constructs of the disclosure are useful in biotechnological applications, including therapeutic applications. Background

[0004] Systemic administration of therapeutic agents can lead to undesirable side effects and can interfere with the efficacy of in vivo treatments. Further, therapeutic agents can be degraded and / or metabolized before reaching the cells they are intended to treat, leading to the use of larger doses, which can result in over-medicating a subject. Many cells, such as cells of the vascular endothelium, the heart, and the kidney, as well as smooth muscle cells can benefit from targeted delivery of therapeutics. These cells highly express NPR-C.

[0005] Chronic kidney diseases such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy involve damage to the cells of the kidney. Many current treatments for kidney diseases are systemic treatments that do not specifically target the kidney, for example glucocorticoids. These can lead to negative side effects, such as gastrointestinal side-effects, impaired immune response, hematologic toxicity, and edema. Targeted methods of treating the cells in the kidney are useful for medical applications, for example to treat chronic kidney diseases while limiting systemic side effects. Summary

[0006] The inventors developed and validated polypeptide constructs that target cells expressing NPR-C for targeted payload to these cells. These polypeptide constructscan be conjugated to a payload, and the conjugates are internalized into cells that express NPR-C, including cells in the kidney. These polypeptide constructs can be used for selective delivery of a payload to kidney cells for treating diseases or injury of the kidney.

[0007] Accordingly, in an aspect, herein provided is a polypeptide construct for targeted delivery of a payload comprising a natriuretic peptide receptor C (NPR-C) ligand operably linked to a linker, wherein the NPR-C ligand comprises a polypeptide comprising an amino acid sequence represented by: (F / f / c / s / E62 / H52 / D15 / y) (S / s / e / B50) (J92 / E26 / SAR / s) (A61 / A99 / F / B16 / C71 / E65) (s / SAR / D19 / G)0-1(B83 / G / bALA / SAR / J43 / G60 / G77) (A64 / G39 / SAR / H30 / E76 / C) (I / E14 / H16 / NLE) (D / B38 / d / I14) (R / E80 / B33 / B48 / E66) (I / H16 / E82 / E94) (SEQ ID NO:389).

[0008] In another aspect, herein provided is a polypeptide construct for targeted delivery of a payload comprising a natriuretic peptide receptor C (NPR-C) ligand operably linked to a linker, wherein the NPR-C ligand comprises: 1 a polypeptide comprising the amino acid sequence according to any one of SEQ ID NOs: 15, 1-14, 16-66 and 196-245; 1 a polypeptide comprising an amino acid sequence with at least about 75%, 80%, 85%, 90%, 95%, sequence identity over its entire length to any one of SEQ ID NOs: 15, 1- 14, 16-66 and 196-245; or 1 a polypeptide comprising a conservatively substituted amino acid sequence of any one of SEQ ID NOs: 15, 1-14, 16-66 and 196-245.

[0009] In some embodiments, the NPR-C ligand comprises a polypeptide comprising an amino acid sequence represented by: (F / f / c) (S / s) J92 A99 s0-1 (G / A64 / B38 / G77) (A64 / E76) (I / NLE / H16) (D / I14) E80 (I / H16 / E82) (SEQ ID NO: 390).

[0010] In some embodiments, the linker comprises a plurality of N-methylated amino acid residues.

[0011] In some embodiments, the plurality of N-methylated amino acid residues comprises at least one sarcosine residue.

[0012] In some embodiments, the linker comprises amino acid sequence SEQ ID NO: 67-76.

[0013] In some embodiments, the linker is a flexible linker.

[0014] In some embodiments, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 93, 94, 99-118, 123-155, 162-171 and 246-295.

[0015] In some embodiments, the polypeptide construct further comprises an endosomal escape motif operably linked to the NPR-C ligand.

[0016] In some embodiments, the endosomal escape motif comprises a proton sponge, a membrane active peptide, a pH sensitive peptide, a cell penetrating peptide, a hydrophobic region, or a combination thereof.

[0017] In some embodiments, proton sponge is a his-sponge, optionally comprising two or more histidine residues.

[0018] In some embodiments, the endosomal escape motif comprises an amino acid sequence selected from SEQ ID NOs: 77-92.

[0019] In some embodiments, the endosomal escape motif is located on the N-terminus side or the C-terminus side of the NPR-C ligand.

[0020] In some embodiments, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 95-98, 119-122, 156-161, 172-192 and 296-384.

[0021] In some embodiments, the linker is conjugated to the payload.

[0022] In some embodiments, the linker is conjugated to the payload by a crosslinker, an amide bond, an ester bond, a hydrazone bond, a carbonate bond, an oxime bond, a disulphide bond, a triazole linkage, or a thioether linkage.

[0023] In some embodiments, the crosslinker comprises succinimidyl 3-(2- pyridyldithio)propionate (SPDP) and a thiol, an azide and terminal alkyne or strained alkyne, a thiol and a thiol, a thiol and a maleimide, an amine and a maleimide, or an alcohol and a carbonate group.

[0024] In some embodiments, the payload comprises a small interfering RNA (siRNA), an antisense oligonucleotide (ASO), a microRNA (miRNA), a small molecule, a polypeptide or a radioisotope.

[0025] In some embodiments, the payload comprises the siRNA.

[0026] In another aspect, herein provided is a conjugate comprising a polypeptide construct herein disclosed conjugated to a payload herein disclosed.

[0027] In another aspect, herein provided is a composition comprising a polypeptide construct herein disclosed or a conjugate herein disclosed and a pharmaceutically acceptable carrier.

[0028] In another aspect, herein provided is a kit comprising a polypeptide construct herein disclosed and a crosslinker.

[0029] In a further aspect, herein provided is a method of treating a disease or injury of NPR- C expressing cells in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a polypeptide construct herein disclosed, a conjugate herein disclosed, or a composition herein disclosed.

[0030] In some embodiments, the payload targets expression of a target gene and / or activity of a target protein.

[0031] In some embodiments, the payload targets expression of a gene and / or activity of a protein upstream and / or downstream of a target protein.

[0032] In some embodiments, the target gene has increased transcription, a gain-of-function mutation or is duplicated.

[0033] In some embodiments, the disease or injury of NPR-C expressing cells comprises a disease or injury of the kidney.

[0034] In some embodiments, the disease or injury of the kidney comprises a glomerulopathy, a podocytopathy, a proximal tubular disorder, a renal amyloidosis, a vascular disorder, an acute or chronic kidney disease, or a combination thereof.

[0035] In some embodiments, the disease or injury of the kidney comprises membranous nephropathy (MN), diabetic nephropathy, focal segmental glomerulosclerosis (FGSF), thin basement membrane disease (TBMN), light-chain deposition disease (LCDD), HIV nephropathy, Alport syndrome, drug-induced glomerulopathies, minimal-change disease (MCD), lupus nephritis, anti-glomerular basement membrane disease, IgA nephropathy (Berger’s Disease), membranoproliferative Glomerulonephritis (MPGN), Polycystic Kidney Disease (PKD), Phenylketonuria (PKU) or a combination thereof.

[0036] In some embodiments, the disease or injury of the kidney comprises focal segmental glomerulosclerosis (FSGS) and / or diabetic nephropathy.

[0037] In some embodiments, the disease or injury of the kidney comprises disease or injury of proximal tubules, podocytes, mesangial and / or endothelial cells.

[0038] In some embodiments, the disease or injury of the NPR-C expressing cells comprises a disease or injury of peripheral organ systems due to renal malfunction.

[0039] In some embodiments, the disease or injury of peripheral organ systems comprises metabolic acidosis, mineral and bone disorders, anemia, and / or cardiorenal syndrome.

[0040] In some embodiments, the construct or conjugate is administered intravenously, through subcutaneous injection, or through intra-arterial administration.

[0041] In some embodiments, the polypeptide construct or conjugate is administered in a single dose.

[0042] In some embodiments, the polypeptide construct or conjugate is administered in repeat doses.

[0043] In some embodiments, the subject is a human.

[0044] In some embodiments, the payload targets expression and / or the activity of transient receptor potassium channel 6 (TRPC6), apolipoprotein A1 (APOL1), alpha actinin-4 (ACTN4), solute carrier family 22 member 2 (SLC22A2 / OCT2), solute carrier family 5 member 2 (SGLT2) or sodium-dependent neutral amino acid transporter B(0)AT1.

[0045] In some embodiments, the polypeptide construct or the conjugate is comprised in a pharmaceutical composition, optionally further comprising a pharmaceutically acceptable carrier or diluent.

[0046] Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the disclosure, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole. Brief Description of the Drawings

[0047] For a better understanding of the various embodiments described herein, and to show more clearly how these various embodiments may be carried into effect, reference will be made, by way of example, to the accompanying drawings which show at least one example embodiment, and which are now described. The drawings are not intended to limit the scope of the teachings described herein.

[0048] FIG.1 shows the immunohistochemical staining of NPR-C in a human kidney tissue slice in an example embodiment of the disclosure. NPR-C, as evident from the intensity of staining, is observed strongly in proximal tubules and mildly in the glomerulus. Nuclei (small, rather opaquely stained, ovoid structures) stained with hematoxylin.

[0049] FIGs. 2A-2B show the immunohistochemical staining of NPR-C in a mouse kidney tissue slice in an example embodiment of the disclosure. FIG.2A is a coronal slice of mouse kidney tissue. NPR-C, as evident from the intensity of staining, is observed strongly in the kidney cortex and to a lesser degree in the kidney medulla. FIG. 2B is a close-up view of mouse kidney, showing NPR-C staining strongly in proximal tubules and mildly in the glomerulus. Nuclei (small, rather opaquely stained, ovoid structures) are separately stained with hematoxylin.

[0050] FIG. 3 shows binding affinities between two NPR-C ligands and NPR-C using a fluorescence polarization assay in increasingly acidic solutions in an example embodiment of the disclosure. POL-1-1 is the NPR-C ligand rANP 4-23 [Des18-22] (SEQ ID NO: 1) tagged with fluorophore Alexa Fluor 488. POL-1-15 is the NPR-C ligand Musc23 (SEQ ID NO: 2) tagged with fluorophore Alexa Fluor 488.

[0051] FIG.4 shows binding affinities between an NPR-C ligand and its D-enantiomer and NPR-C or natriuretic peptide receptor A (NPR-A) using a fluorescence polarization assay in an example embodiment of the disclosure. POL-1-1 is the NPR-C ligand rANP 4-23 [Des18- 22] (SEQ ID NO: 1) tagged with fluorophore Alexa Fluor 488. POL-1-3 is the D-enantiomer of rANP 4-23 [Des18-22] tagged with fluorophore Alexa Fluor 488.

[0052] FIG.5 shows binding affinities between an NPR-C ligand and its D-enantiomer and human NPR-C or mouse NPR-C using a fluorescence polarization assay in an example embodiment of the disclosure. POL-1-1 is the NPR-C ligand rANP 4-23 [Des18-22] (SEQ ID NO: 1) tagged with fluorophore Alexa Fluor 488. POL-1-3 is the D-enantiomer of rANP 4-23 [Des18-22] tagged with fluorophore Alexa Fluor 488. hNPRC is human NPR-C, and mNPRC is mouse NPR-C.

[0053] FIG. 6 shows binding affinities of constructs comprising NPR-C ligands using a fluorescence polarization competition assay in an example embodiment of the disclosure. POL-1-4 comprises the D-enantiomer of rANP 4-23 [Des18-22]. POL-1-6 comprises the NPR-C ligand Musc23 (SEQ ID NO: 2). POL-1-11 and POL-1-12 each comprise the NPR-C ligand rANP 4-23 [Des18-22], a his-sponge, and a linker. POL-1-13 and POL-1-14 each comprise the NPR-C ligand Musc23, a his-sponge, and a linker. In both POL-1-11 and POL- 1-13, the his-sponge is located between the linker and the NPR-C ligand on the N-terminus end of the NPR-C ligand, whereas in both POL-1-12 and POL-1-14, the his-sponge is located at the C-terminus end of the NPR-C ligand.

[0054] FIG.7 shows binding affinities of a subset of constructs to human NPR-C comprising NPR-C ligands using fluorescence polarization competition assay in an example embodiment of the disclosure. Peptide ligands exhibit IC50 values in the range of 15 nM to ~ 3 µM. All peptide ligands comprise an NPR-C binding domain. In some examples, the peptide ligands further include an endosomal escape domain, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus.

[0055] FIG.8 shows binding affinities of a subset of constructs to mouse NPR-C comprising NPR-C ligands using fluorescence polarization competition assay in an example embodiment of the disclosure. Peptide ligands exhibit IC50 values in the range of 3 nM to ~ 8 µM. All peptide ligands comprise an NPR-C binding domain. In some examples, the peptide ligand also includes an endosomal escape domain, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus.

[0056] FIG. 9 shows binding affinities of constructs to human NPR-C comprising NPR-C ligands using fluorescence polarization competition assay in an example embodiment of the disclosure. Peptide ligands exhibit IC50 values in the range of 5 nM to >5 µM. POL-1-10-2 comprises the NPR-C ligand Musc23 (SEQ ID NO:2), a His-sponge, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-78 comprises a non-binding domain, an endosomal escape domain, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-80 comprises an NPR-C binding domain, an endosomal escape domain, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus.

[0057] FIGs. 10A-10B show that NPR-C ligands have increased binding to HEK293 cells which overexpress NPR-C using flow cytometry in an example embodiment of the disclosure. FIG. 10A shows the intensity of fluorescence of POL-1-1 bound to NPR-C receptors (top) and NPR-C antibody (Ab1; rabbit polyclonal NPR3 antibody, Invitrogen Cat# PA5-120508) bound to NPR-C receptors (bottom) in standard HEK293 cells (left) compared to HEK293 cells overexpressing NPR-C (right). FIG 10B shows the normalized fluorescence intensity across these experiments, and including when repeated using an NPR-C antibody that detects an epitope not available to the cell surface (Ab2; mouse monoclonal NPR3 antibody, Origene Cat#: TA501021). POL-1-1 is the NPR-C ligand rANP 4-23 [Des18-22] (SEQ ID NO: 1) tagged with fluorophore Alexa Fluor 488. Ab-1 and Ab-2 binding is detected by a fluorescently tagged secondary antibody, targeting the primary antibodies. * indicates that p < 0.05, and ** indicates that p < 0.01 in Fisher’s Least Significant Difference test. “ns” indicates that there is no significant difference.

[0058] FIGs. 11A-11B show that the internalization of NPR-C ligands occurs in a NPR-C dependent manner as measured by flow cytometry in an example embodiment of the disclosure. POL-1-1 and POL-1-15 show minimal internalization in parental HEK293 cells (FIG.11A) and increased internalization in HEK293 cells overexpressing NPR-C (FIG.11B). Increasing concentrations of peptide ligands POL-1-1 and POL-1-15 show increased internalization in HEK293 cells overexpressing NPR-C until a plateau is reached (FIG.11B).

[0059] FIG. 12 shows that NPR-C ligands POL-1-1 and POL-1-15 undergo rapid internalization in NPR-C overexpressing cells as measured by flow cytometry in an example embodiment of the disclosure.

[0060] FIG.13 shows the % intact peptide over time for NPR-C ligands incubated in mouse plasma in an example embodiment of the disclosure. POL-1-8-2 comprises the NPR-C ligand rANP 4-23 [Des18-22], a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-9-2 comprises the NPR-C ligand Musc23, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-10-2 comprises the NPR-C ligand Musc23, a His-sponge, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-16 to POL-1-33 all comprise a NPR-C binding domain, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-39 comprises a NPR-C binding domain, an endosomal escape domain, a linker, and a crosslinker 6-azidohexanoic acid at the N-terminus.

[0061] FIG.14 shows binding affinities of constructs comprising NPR-C ligands conjugated to an siRNA targeting GAPDH using a fluorescence polarization competition assay in an example embodiment of the disclosure. POL-1-4 comprises the D-enantiomer of rANP 4-23 [Des18-22]. POL-1-6 comprises the NPR-C ligand Musc23 (SEQ ID NO: 2). POL 1-7 and POL-1-8 each comprise the NPR-C ligand rANP 4-23 [Des18-22] and a linker, and are conjugated to an siRNA against the expression of GAPDH. POL-1-8 further comprises a his- sponge but POL-1-7 does not. POL-1-9 and POL-1-10 each comprise the NPR-C ligand Musc23 and a linker, and are conjugated to an siRNA against the expression of GAPDH. POL-1-10 further comprises a his-sponge but POL-1-9 does not.

[0062] FIG.15 shows that peptide-siRNA conjugates deliver functional siRNA into HEK293 cells overexpressing NPR-C using RT-qPCR in an example embodiment of the disclosure. The first two columns (Untreated; “naked” siRNA) represent negative controls, whereas the third (siRNA +Lipo) represents a positive control. POL-1-7 and POL-1-8 comprise the ligand rANP 4-23 [Des18-22], whereas POL-1-9 and POL-1-10 comprise the ligand Musc23. POL- 1-8 and POL-1-10 comprise the his-sponge, whereas POL-1-7 and POL-1-9 do not. “Lipo” is lipofectamine and “CQ” is chloroquine. ** that p < 0.01, and *** indicates that p <0.001 compared to “Untreated” in a one-way ANOVA with post-hoc Dunnett’s test for multiple comparisons. “ns” indicates that there is no significant difference.

[0063] FIGs. 16A-16B show that peptide-siRNA conjugate knockdown in HEK293 cells overexpressing NPR-C using RT-qPCR is stable over 48 hours in an example embodiment of the disclosure. FIG.16A shows siRNA knockdown in HEK293 cells overexpressing NPR- C in the absence of CQ, whereas FIG. 16B shows siRNA knockdown in HEK293 cells overexpressing NPR-C in the presence of CQ. “Lipo” is lipofectamine, “CQ” is chloroquine. ** indicates that p < 0.01, *** indicates that p < 0.001 and **** indicates that p < 0.0001 compared to “Untreated” in a one-way ANOVA with post-hoc Dunnett’s test for multiple comparisons. “ns” indicates that there is no significant difference.

[0064] FIGs.17A-17F show the localization of peptide-siRNA conjugates in mouse kidney 7 days post injection as measured by miRNAscope staining in an example embodiment of the disclosure. Mice were injected with 5 mg / kg unconjugated siRNA (FIG. 17A) or siRNA conjugated to NPR-C targeting peptides; POL-1-10-4 (FIG. 17B), POL-1-20-2 (FIG. 17C), POL-1-28-2 (FIG. 17D), POL-1-33-2 (FIG. 17E), POL-1-39-2 (FIG.17F) and miRNAscope staining in the kidney assessed 7 days post injection to assess the localization of siRNA conjugates. Glomeruli are outlined with a dashed line. siRNA conjugated to NPR-C targeting peptides show significantly more staining in the kidney, particularly the kidney cortex and proximal tubules relative to unconjugated siRNA. Peptides containing a linker and endosomal escape domain (POL-1-10-4, FIG. 17BA and POL-1-39-2 FIG.17F) show the greatest degrees of kidney staining.

[0065] FIGs. 18A-18B show the localization of peptide-siRNA conjugates in mouse kidney as measured by florescent imaging in an example embodiment of the disclosure. Fluorescently labeled peptide-siRNA conjugates POL-1-10-3, POL-1-78-2, and POL-1-80-2 and fluorescently labeled siRNA alone were subcutaneously injected into mice (5 mg / kg) and imaged 6 and 168 hours later (FIG. 18A). POL-1-10-3 and POL-1-80-2 show higher siRNA localization compared to siRNA alone and non-NPR-C binding peptide-siRNA conjugate POL-1-78-2. Quantification of Cy5.5 fluorescence in kidney cortex (FIG. 18B) showed a 6.6-fold increase in fluorescent signal for POL-1-10-3 and 8.6-fold increase in fluorescent signal for POL-1-80-2 over non-NPR-C binding peptide-siRNA conjugate POL-1- 78-2. POL-1-80-2 exhibited a 1.4-fold increase in fluorescent signal over POL-1-10-3.

[0066] Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, embodiments of the disclosure, aregiven by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole. Detailed Description of the Disclosure

[0067] The following is a detailed description provided to aid those skilled in the art in practicing the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[0068] Further, the definitions and embodiments described in particular sections are intended to be applicable to other embodiments herein described for which they are suitable as would be understood by a person skilled in the art. For example, in the following passages, different aspects of the disclosure are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature described herein may be combined with any other feature or features described herein. I. Definitions

[0069] As used herein, the following terms may have meanings ascribed to them below, unless specified otherwise. However, it should be understood that other meanings that are known or understood by those having ordinary skill in the art are also possible, and within the scope of the present disclosure. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0070] In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives.

[0071] The term “consisting” and its derivatives, as used herein, are intended to be closed ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or term “consisting essentially of”, as usedherein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps.

[0072] Further, terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least about ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0073] As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. Thus, for example, a composition containing “a compound” includes a mixture of two or more compounds.

[0074] The phrase "and / or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and / or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified.

[0075] As used herein, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of' or "exactly one of" or, when used in the claims, "consisting of" will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0076] As used herein, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of This definition also allows that elementsmay optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.

[0077] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the description. Ranges from any lower limit to any upper limit are contemplated. The upper and lower limits of these smaller ranges which may independently be included in the smaller ranges is also encompassed within the description, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the description. The recitation of numerical ranges by endpoints herein includes all numbers and fractions subsumed within that range (e.g.1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term "about."

[0078] The term “amino acid” includes all of the naturally occurring amino acids as well as modified L-amino acids, including non-canonical amino acids, as well as D-amino acids. For example, the term amino acid includes N(omega)-methyl-L-arginine, beta-Alanine, N-methyl- Glycine, trans-4-Hydroxy-D-proline, and 3-Cyclohexyl-L-Alanine. The atoms of the amino acid can for example include different isotopes. For example, the amino acids can comprise deuterium substituted for hydrogen, nitrogen-15 substituted for nitrogen-14, and carbon-13 substituted for carbon-12 and other similar changes.

[0079] A "conservative amino acid substitution" as used herein, is one in which one amino acid residue is replaced with another amino acid residue without abolishing the protein's desired properties. Suitable conservative amino acid substitutions can be made by substituting amino acids with similar hydrophobicity, polarity, and R-group size for one another. Examples of conservative amino acid substitution include: Conservative Substitutions Type of Amino Acid Substitutable Amino AcidsHydrophilic Ala, Pro, Gly, Gln, Asn, Ser, Thr Sulphydryl Cys Aliphatic Val, Ile, Leu, Met Basic Lys, Arg, His Acidic Glu, Asp Aromatic Phe, Tyr, Trp

[0080] The term “operably linked” as used herein refers to an arrangement of two or more components, wherein the components so described are in a relationship permitting them to function in a coordinated manner. For example, an NPR-C ligand and a linker are operably linked when they are joined together, for example they are fused to each other, in such an arrangement that each of the NPR-C ligand and the linker can function as intended.

[0081] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise.

[0082] Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, examples of methods and materials are now described. II. Polypeptides, Constructs and Conjugates

[0083] The inventors developed and validated ligand polypeptides and polypeptide constructs comprising these ligands that target cells expressing NPR-C for targeted payload delivery to these cells. These polypeptide constructs can be conjugated to a payload, and the conjugates are internalized into cells that express NPR-C, including cells in the kidney. These polypeptide constructs can be used for selective delivery of a payload to kidney cells for treating diseases or injury of the kidney.

[0084] Accordingly, in an aspect herein provided polypeptide comprising: # the amino acid sequence according to any one of SEQ ID NOs: 4-66 and 196- 245; # a polypeptide comprising an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 4-66 and 196-245; or # a polypeptide comprising a conservatively substituted amino acid sequence of any one of SEQ ID NOs: 4-66 and 196-245.

[0085] In another aspect, herein provided is a polypeptide construct for targeted delivery of a payload comprising a natriuretic peptide receptor C (NPR-C) ligand operably linked to a linker, wherein the NPR-C ligand comprises: a polypeptide comprising an amino acidsequence represented by: (Hydrophobic amino acid) X X (Hydrophobic amino acid) X0-1 X X(I / E14 / H16 / NLE) (D / B38 / d / I14) (I / H16 / E82 / E94) (SEQ ID NO: 391).

[0086] As used herein, uppercase letters are used to refer to L-enantiomers and lowercase letters are used to refer to D-enantiomers of an amino acid. Two or more amino acids separated by a slash “ / ” and located within parentheses indicate amino acids that are present at the given positionthe alternative. For example, (D / B38 / d / I14) is intended to refer to either the L- or D-enantiomer of aspartate, Homo-L-Cysteine, or alpha-methyl-L-aspartic acid present at the given position. Each instance of “X” is independently selected from any amino acid. Further, an amino acid characterized by superscriptm-nindicates that there are m-n instances of the underlying amino acid. For example, X0-1indicates that the sequence includes zero or one amino acid selected from any amino acid at the given position. Each instance of (Hydrophobic amino acid) represents an amino acid selected from any hydrophobic amino acid.

[0087] In some embodiments, the polypeptide comprises the amino acids represented by (I / E14 / H16 / NLE) (D / B38 / d / I14) (R / E80 / B33 / B48 / E66) and (I / H16 / E82 / E94) in SEQ ID NO: 391 as shown in the last four amino acids of any one sequence selected from Table 1. In some embodiments, the amino acids represented by (I / E14 / H16 / NLE) (D / B38 / d / I14) (R / E80 / B33 / B48 / E66) and (I / H16 / E82 / E94) in SEQ ID NO: 391 consist of the last four amino acids of any one sequence selected from Table 1.

[0088] In some embodiments, the polypeptide comprises an amino acid sequence represented by: (Hydrophobic amino acid) X X (Hydrophobic amino acid) X0-1X X (I / NLE / H16) (D / I14) E80 (I / H16 / E82) (SEQ ID NO: 392).

[0089] In another aspect, herein provided is a polypeptide construct for targeted delivery of a payload, comprising a natriuretic peptide receptor C (NPR-C) ligand operably linked to a linker, wherein the NPR-C ligand comprises a polypeptide comprising an amino acid sequence represented by: (F / f / c / s / E62 / H52 / D15 / y) (S / s / e / B50) (J92 / E26 / SAR / s) (A61 / A99 / F / B16 / C71 / E65) (s / SAR / D19 / G)0-1(B83 / G / bALA / SAR / J43 / G60 / G77) (A64 / G39 / SAR / H30 / E76 / C) (I / E14 / H16 / NLE) (D / B38 / d / I14) (R / E80 / B33 / B48 / E66) (I / H16 / E82 / E94) (SEQ ID NO:389).

[0090] In some embodiments the polypeptide comprises an amino acid sequence represented by: (f / c / s / E62 / H52 / D15 / y) (S / s / e) (J92 / E26 / SAR / s) (A61 / A99 / F / B16 / C71 / E65) (s / SAR / D19 / G)0-1(B83 / G / bALA / SAR / J43 / G60 / G77) (A64 / G39 / SAR / H30 / E76 / C) (I / E14 / H16 / NLE) (D / B38 / d / I14) (R / E80) (SEQ ID NO:385).

[0091] In some embodiments, the polypeptide construct comprises an amino acid sequence represented by: (F / f / c / s / E62 / H52 / D15 / y) (S / s / e / B50) (J92 / E26 / SAR / s) (A61 / A99 / F / B16 / C71 / E65) (s / SAR / D19 / G)0-1(B83 / G / bALA / SAR / J43 / G60 / G77) (A64 / G39 / SAR / H30 / E76 / C)(I / NLE / H16) (D / I14) E80 (I / H16 / E82) (SEQ ID NO: 393).

[0092] In another aspect, herein provided is a polypeptide construct for targeted delivery of a payload comprising a natriuretic peptide receptor C (NPR-C) ligand operably linked to a linker, wherein the NPR-C ligand comprises: # a polypeptide comprising the amino acid sequence according to any one of SEQ ID NOs: 1-66 and 196-245 or a functional fragment thereof; # a polypeptide comprising an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 1-66 and 196-245; or #a polypeptide comprising a conservatively substituted amino acid sequence ofany one of SEQ ID NOs: 1-66 and 196-245.

[0093] In an embodiment, the polypeptide comprises an amino acid sequence with at least about 75% sequence identity over its entire length to any one of SEQ ID NOs: 1-66 and 196- 245. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 80% sequence identity over its entire length to any one of SEQ ID NOs: 1-66 and 196- 245. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 85% sequence identity over its entire length to any one of SEQ ID NOs: 1-66 and 196- 245. In yet another embodiment, the polypeptide comprises an amino acid sequence with at least about 90% sequence identity over its entire length to any one of SEQ ID NOs: 1-66 and 196-245. In a further embodiment, the polypeptide comprises an amino acid sequence with at least about 95% sequence identity over its entire length to any one of SEQ ID NOs: 1-66 and 196-245.

[0094] In an embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 1. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 2. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 3. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 4. In another embodiment, the polypeptide comprises the amino acid according to SEQ ID NO: 5. In anotherembodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 6. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 7. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 8. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 9. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 10. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 11. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 12. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 13. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 14. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 15. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 16. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 17. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 18. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 19. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 20. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 21. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 22. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 23. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 24. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 25. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 26. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 27. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 28. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 29. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 30. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 31. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 32. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 33. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 34. In embodiment, the polypeptide comprisesthe amino acid sequence according to SEQ ID NO: 35. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 36. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 37. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 38. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 39. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 40. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 41. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 42. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 43. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 44. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 45. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 46. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 47. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 48. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 49. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 50. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 51. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 52. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 53. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 54. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 55. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 56. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 57. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 58. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 59. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 60. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 61. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 62. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 63. In another polypeptide comprises the amino acidsequence according to SEQ ID NO: 64. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 65. In another embodiment, thepolypeptide comprises the amino acid sequence according to SEQ ID NO: 66. In anotherembodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 196. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 197. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 198. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 199. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 200. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 201. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 202. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 203. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 204. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 205. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 206. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 207. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 208. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 209. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 210. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 211. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 212. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 213. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 214. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 215. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 216. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 217. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 218. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 219. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 220. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 221. In another embodiment, the the amino acid sequence accordingto SEQ ID NO: 222. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 223. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 224. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 225. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 226. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 227. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 228. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 229. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 230. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 231. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 232. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 233. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 234. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 235. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 236. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 237. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 238. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 239. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 240. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 241. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 242. In another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 243. In yet another embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 244. In a further embodiment, the polypeptide comprises the amino acid sequence according to SEQ ID NO: 245.

[0095] In an embodiment, the polypeptide comprises the amino acid sequence according to any one of SEQ ID NOs:4-66 and 196-245.

[0096] The inventors demonstrated that a construct comprising SEQ ID NOs: 2, 13, or 15 delivered siRNA to kidney cells in vivo. Accordingly, in an embodiment, the polypeptide comprises the amino acid sequence according to any one of SEQ ID NOs: 2, 13, and 15. In another embodiment, the polypeptide the amino acid sequence according to anyone of SEQ ID NOs: 2, 8, 13, 15, and 20. In another embodiment, the polypeptide comprises the amino acid sequence according to any one of SEQ ID NOs: 2, 8, 13, 15, 20, and 66.

[0097] The inventors demonstrated that constructs comprising SEQ ID NOs: 5, 11, 14, 15, 18, 20, and 22 have beneficial plasma stability. Accordingly, in an embodiment, the polypeptide comprises the amino acid sequence according to any one of SEQ ID NOs: 5, 11, 14, 15, 18, 20, and 22.

[0098] In some embodiments, the polypeptide comprises the amino acid sequence according to any one of SEQ ID NOs: 1, 2, 5, 8, 11-15, 18, 20, 22, 200, and 236. In some embodiments, the polypeptide comprises the amino acid sequence according to any one of SEQ ID NOs: 2, 5, 8, 11-15, 18, 20, 22, 200, and 236.

[0099] In some embodiments, the polypeptide comprises a sequence represented by:

[0100] In some embodiments, the polypeptide comprises a sequence represented by:

[0101] In some embodiments, the polypeptide comprises a sequence represented by:

[0102] In another embodiment, the polypeptide comprises the amino acid sequence according to any one of SEQ ID NOs: 8, 13, 15, 20, and 66.

[0103] In some embodiments, the polypeptide comprises a sequence represented by: f (S / s) J92 A99 s0-1(G / G77) A64 (I / H16) (D / I14) E80 I (SEQ ID NO: 388)

[0104] In an embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 1. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 2. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 3. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% identity over its entire length to SEQ IDNO: 4. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 5. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 6. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 7. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 8. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 9. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 10. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 11. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 12. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 13. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 14. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 15. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 16. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 17. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 18. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 19. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 20. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 21. In another embodiment, the comprises an amino acid sequence with atleast about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 22. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 23. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 24. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 25. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 26. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 27. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 28. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 29. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 30. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 31. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 32. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 33. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 34. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 35. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 36. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 37. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 38. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% identity over its entire length to SEQ IDNO: 39. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 40. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 41. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 42. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 43. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 44. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 45. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 46. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 47. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 48. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 49. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 50. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 51. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 52. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 53. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 54. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 55. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 56. In another embodiment, the comprises an amino acid sequence with atleast about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 57. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 58. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 59. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 60. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 61. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 62. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 63. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 64. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 65. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ IDNO: 66. In another embodiment, the polypeptide comprises an amino acid sequence with atleast about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 196. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 197. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 198. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 199. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 200. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 201. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 202. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or identity over its entire length to SEQID NO: 203. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 204. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 205. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 206. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 207. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 208. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 209. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQID NO: 210. In another embodiment, the polypeptide comprises an amino acid sequence withat least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 211. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 212. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 213. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 214. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 215. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 216. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 217. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 218. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 219. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 220. In another embodiment, the comprises an amino acid sequence withat least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 221. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 222. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 223. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 224. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQID NO: 225. In another embodiment, the polypeptide comprises an amino acid sequence withat least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 226. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 227. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 228. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 229. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 230. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 231. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 232. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 233. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 234. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 235. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 236. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 237. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or identity over its entire length to SEQID NO: 238. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 239. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQID NO: 240. In another embodiment, the polypeptide comprises an amino acid sequence withat least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 241. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 242. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 243. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 244. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to SEQ ID NO: 245.

[0105] In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 4-66. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 8, 13, 15, 20, and 66. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 2, 13, and 15. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 5, 11, 14, 15, 18, 20, and 22. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 2, 8, 13, 15, and 20. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 2, 8, 13, 15, 20, and 66. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 1, 2, 5, 8, 11-15, 18, 20, 22, 200, and 236. In another embodiment, the polypeptide comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 2, 5, 8, 11-15, 18, 20, 22, 200, and 236.

[0106] In another embodiment, the polypeptide comprises an amino acid sequence with at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs:1-66 and 196-245, wherein the polypeptide comprises the last 4 amino acids as defined the any one of SEQ ID NOs:1-66 and 196-245.

[0107] In yet another embodiment, the polypeptide comprises an amino acid sequence selected from Table 1.

[0108] In an embodiment, the NPR-C ligand selectively binds NPR-C.

[0109] The “natriuretic peptide receptor C” or “NPR-C” can be from any organism, optionally human, and optionally as shown in GenBank accession number P17342. NPR-C is also known as natriuretic peptide receptor 3 (NPR3).

[0110] The term “linker” as used herein refers to one or more amino acid residues inserted between the NPR-C ligand of a polypeptide construct and the location of payload conjugation, in order to provide sufficient mobility for the polypeptide construct, when conjugated to a payload, to bind to an NPR-C. The linker can, for example, be a protease resistant linker. Protease resistance can be conferred by use of N-methylated amino acids, for example N-methyl-glycine (sarcosine) or N-methyl-beta-Alanine, D-enantiomers, for example D-Histidine, and amino acids with extended backbones, for example beta-Alanine or 6-aminohexanoic acid. The linker can, for example, increase efficiency of endosome escape. The linker can, for example, increase solubility of the polypeptide construct. The linker can further comprise an albumin binding domain.

[0111] The term “albumin binding” as used herein refers to the ability of a molecule to bind albumin proteins, for example during in vivo circulation after injection. Accordingly, the term “albumin binding domain” refers to an amino acid sequence in a polypeptide construct or a conjugate herein disclosed that permits albumin protein binding. An albumin binding domain can comprise, for example, a fatty acid, a small molecule albumin binder, and / or an amino acid sequence.

[0112] The albumin binding domain can be located on either the N-terminus side of the NPR-C ligand or on the C-terminus side of the NPR-C ligand. The albumin binding domain can be located in between the linker domain and the endosomal escape domain or between the endosomal escape domain and the NPR-C ligand. The albumin binding domain can also be located on the sidechain of an amino acid in the sequence.

[0113] In an embodiment, the linker resistant linker.

[0114] In an embodiment the linker comprises a plurality of N-methylated amino acid residues. In another embodiment, the plurality of N-methylated amino acid residues comprises at least one sarcosine residue. In another embodiment, the plurality of N- methylated amino acid residues comprises at least two sarcosine residues. In another embodiment, the plurality of N-methylated amino acid residues comprises at least three sarcosine residues. In yet another embodiment, the plurality of N-methylated amino acid residues comprises at least four sarcosine residues. In another further embodiment, the linker comprises an amino acid sequence according to any one of SEQ ID NOs: 67-76. In another embodiment, linker comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 67-76. In yet another embodiment, the linker comprises amino acid sequence SEQ ID NO: 67. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:68. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:69. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:70. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:71. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:72. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:73. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:74. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:75. In a further embodiment, the linker comprises amino acid sequence SEQ ID NO:76.

[0115] In an embodiment, the linker is a flexible linker. In another embodiment, the linker is cleavable. In yet another embodiment the linker is non-cleavable.

[0116] In an embodiment, the albumin binding domain is on the N-terminus side of the NPR-C ligand. In another embodiment, the albumin binding domain is on the C-terminus side of the NPR-C ligand.

[0117] In an embodiment, the polypeptide construct further comprises an endosomal escape motif operably linked to the NPR-C ligand.

[0118] The term “endosomal escape” as used herein refers to the ability of a molecule to escape the endosomal compartment of a cell, for example following receptor-mediated endocytosis. Accordingly, the term “endosomal escape motif” refers to an amino acid sequence in a polypeptide construct or a conjugate herein disclosed that permits escape from endosomes into the cytoplasm. An endosomal escape motif can comprise, for example, a proton sponge, membrane active peptides, pH sensitive peptides, cell penetrating peptides, and hydrophobic regions.

[0119] A proton sponge is an amino acid sequence comprising a sufficient number of proton acceptor sites such that when the proton sponge is introduced into an endosome within a living cell, endosomal protons associate with the proton sponge such that the endosomal pH rises, the endosomal proton pump is activated to lower the pH by introducing more protons, which in turn causes additional ions and water to enter the endosome until the osmotic pressure within the endosome rises to a point that bursts the endosome. A proton sponge can comprise any suitably charged amino acid residues, such as aspartic acid, glutamic acid, and non-canonical variants capable of accepting a proton. A proton sponge can also comprise amino acid residues that are neutral at physiological pH, but become protonated and charged in acidic environments, such as within endosomes and lysosomes, such as histidine.

[0120] The term “membrane active peptide” as used herein refers to a peptide that interacts with biological lipid membranes through binding, insertion, disruption, or fusion with the lipid membrane, for example antimicrobial peptides and cell penetrating peptides.

[0121] A his-sponge is a proton sponge comprising one or more histidine residues. In an embodiment, the endosomal escape motif comprises a proton sponge, a membrane active peptide, a pH sensitive peptide, a cell penetrating peptide, a hydrophobic region, or a combination thereof. In another embodiment, the endosomal escape motif comprises a proton sponge. In another embodiment, the endosomal escape motif comprises a membrane active peptide. In another embodiment, the endosomal escape motif comprises a pH sensitive peptide. In another embodiment, the endosomal escape motif comprises a cell penetrating peptide. In yet another embodiment, the endosomal escape motif comprises a hydrophobic region. In a further embodiment, the endosomal escape motif comprises a his- sponge. In yet another embodiment, the his-sponge comprises two or more histidine residues.

[0122] In an embodiment, the endosomal escape motif comprises an amino acid sequence selected from SEQ ID NOs:77-92. In another embodiment, the endosomal escape motif comprises an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95% sequence identity over its entire length to any one of SEQ ID NOs: 77-92. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 77. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 78. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 79. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 80. In embodiment, the endosomal escape motifcomprises amino acid sequence SEQ ID NO: 81. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 82. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 83. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 84. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 85. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 86. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 87. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 88. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 89. In another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 90. In yet another embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 91. In a further embodiment, the endosomal escape motif comprises amino acid sequence SEQ ID NO: 92.The endosomal escape motif can be located on either the N-terminus side of the NPR-C ligand or on the C-terminus side of the NPR-C ligand. The endosomal escape motif can also be located on a sidechain of an amino acid in a polypeptide construct or conjugate herein disclosed.

[0123] In an embodiment, the endosomal escape motif is located on either the N- terminus side or the C-terminus side of the NPR-C ligand. In another embodiment, the endosomal escape motif is located on the N-terminus side of the NPR-C ligand. In yet another embodiment, the endosomal escape motif is located on the C-terminus side of the NPR-C ligand. In a further embodiment, the endosomal escape motif is located on a sidechain of an amino acid in a polypeptide construct or conjugate herein disclosed.

[0124] A linker and / or endosomal escape motif and / or albumin binding domain herein disclosed in a polypeptide construct or conjugate herein disclosed may have a reversed amino acid sequence. For example, the endosomal escape motif comprising sequence his- his-his-his-his-his-gly-gly-his-his-his-his (SEQ ID NO: 77) may be comprised in the construct or conjugate such that the sequence, when read from N-terminus to C-terminus is his-his- his-his-gly-gly- his-his-his-his-his-his.

[0125] In an embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 93-192 and 246-384. In another embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 93, 94, 99-118, 123-155, 162-171 and 246-295. In another embodiment, the polypeptide construct comprises an sequence according to any one of SEQID NOs: 93-96. In yet another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 93 or 94. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 95 or 96. In another embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NO: 103, 110, 115, 121, and 160. In another embodiment, the polypeptideconstruct comprises an amino acid sequence according to any one of SEQ ID NO: 100, 103,106, 107, 108, 109, 110, 115, 117, and 160.

[0126] The inventors demonstrated that a construct comprising SEQ ID NOs: 96, 103, 110, 115, 121, and 160 delivered siRNA to kidney cells in vivo. In an embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 96, 121, and 160. In another embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 103, 110, and 115. In yet another embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 96, 103, 110, 115, 121, and 160.

[0127] The inventors have also demonstrated that constructs comprising SEQ ID NOs: 100, 106, 109, 110, 113, 115, and 117 have beneficial plasma stability. In an embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 100, 106, 109, 110, 113, 115, and 117.

[0128] The inventors have further demonstrated that including an endosomal escape motif increases plasma stability of the constructs. Accordingly, in an embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 95-98, 119-122, 156-161, 172-192 and 296-384. In another embodiment, the polypeptide construct comprises an amino acid sequence according to any one of SEQ ID NOs: 96, 120, 121, and 122.

[0129] In an embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 93. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 94. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 95. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 96. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 97. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 98. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 99. In another the polypeptide construct comprisesan amino acid sequence according to SEQ ID NO: 100. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 101. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 102. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 103. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 104. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 105. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 106. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 107. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 108. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 109. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 110. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 111. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 112. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 113. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 114. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 115. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 116. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 117. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 118. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 119. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 120. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 121. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 122. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 123. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 124. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 125. In another embodiment, the polypeptide comprises an amino acid sequenceaccording to SEQ ID NO: 126. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 127. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 128. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 129. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 130. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 131. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 132. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 133. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 134. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 135. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 136. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 137. In yet another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 138. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 139. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 140. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 141. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 142. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 143. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 144. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 145. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 146. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 147. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 148. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 149. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 150. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 151. In a further embodiment, the polypeptide construct comprises an amino according to SEQ ID NO: 152. Ina further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 153. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 154. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 155. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 156. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 157. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 158. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 159. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 160. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 161. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 162. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 163. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 164. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 165. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 166. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 167. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 168. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 169. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 170. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 171. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 172. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 173. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 174. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 175. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 176. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 177. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to NO: 178. In a further embodiment, thepolypeptide construct comprises an amino acid sequence according to SEQ ID NO: 179. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 180. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 181. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 182. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 183. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 184. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 185. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 186. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 187. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 188. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 189. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 190. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 191. In a further embodiment, the polypeptide construct comprises an amino acid sequenceaccording to SEQ ID NO: 192. In another embodiment, the polypeptide construct comprisesan amino acid sequence according to SEQ ID NO: 246. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 247. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 248. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 249. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 250. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 251. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 252. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 253. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 254. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 255. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 256. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 257. In another the polypeptide construct comprisesan amino acid sequence according to SEQ ID NO: 258. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 259. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 260. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 261. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 262. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 263. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 264. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 265. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 266. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 267. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 268. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 269. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 270. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 271. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 272. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 273. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 274. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 275. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 276. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 277. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 278. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 279. In another embodiment, thepolypeptide construct comprises an amino acid sequence according to SEQ ID NO: 280. Inanother embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 281. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 282. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 283. In another embodiment, the polypeptide comprises an amino acid sequenceaccording to SEQ ID NO: 284. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 285. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 286. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 287. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 288. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 289. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 290. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 291. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 292. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 293. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 294. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 295. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 296. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 297. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 298. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 299. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 300. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 301. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 302. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 303. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 304. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 305. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 306. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 307. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 308. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 309. In another embodiment, thepolypeptide construct comprises an amino according to SEQ ID NO: 310. Inanother embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 311. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 312. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 313. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 314. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 315. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 316. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 317. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 318. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 319. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 320. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 321. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 322. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 323. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 324. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 325. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 326. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 327. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 328. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 329. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 330. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 331. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 332. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 333. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 334. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 335. In another embodiment, the polypeptide construct comprises an amino acid sequence according to NO: 336. In another embodiment, thepolypeptide construct comprises an amino acid sequence according to SEQ ID NO: 337. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 338. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 339. In another embodiment, thepolypeptide construct comprises an amino acid sequence according to SEQ ID NO: 340. Inanother embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 341. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 342. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 343. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 344. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 345. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 346. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 347. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 348. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 349. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 350. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 351. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 352. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 353. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 354. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 355. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 356. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 357. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 358. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 359. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 360. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 361. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 362. In another the polypeptide construct comprisesan amino acid sequence according to SEQ ID NO: 363. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 364. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 365. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 366. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 367. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 368. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 369. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 370. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 371. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 372. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 373. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 374. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 375. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 376. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 377. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 378. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 379. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 380. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 381. In another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 382. In yet another embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 383. In a further embodiment, the polypeptide construct comprises an amino acid sequence according to SEQ ID NO: 384.

[0130] In an embodiment, the polypeptide construct comprises an amino acid sequence selected from Table 1, Table 2, and / or Table 3.

[0131] In another embodiment, the linker is operably linked to the payload. In an embodiment, the linker is conjugated to the payload.

[0132] The term “payload” as used herein refers to a peptide, a polypeptide (e.g., a bispecific polypeptide), a protein, a nucleic acid, a small molecule, or a radioisotope that can effect change in a cell expressing NPR-C. The “payload” can, for example, be a small interfering RNA (siRNA), for example a light-activated siRNA or a synthetic siRNA, anantisense oligonucleotide (ASO), or a microRNA (miRNA). The “payload” can, for example,also be a hybrid of two or more of the above, for example a CRISPR / siRNA hybrid. The payload can, for example, target any gene, transcript, or protein, in a pathway in an NPR-C expressing cell, for example to activate, silence, increase, or decrease the activity of a protein in the cell, either directly, or indirectly.

[0133] In an embodiment, the payload comprises an siRNA, an ASO, an miRNA, a small molecule, or a radioisotope. In another embodiment, the payload comprises an siRNA. In another embodiment, the payload comprises a light-activated siRNA. In another embodiment, the payload comprises a synthetic siRNA. In another embodiment In another embodiment, the payload comprises a CRISPR / siRNA hybrid. In another embodiment, the payload comprises an ASO. In another embodiment, the payload comprises an miRNA. In yet another embodiment, the payload comprises a small molecule. In a further embodiment, the payload comprises a radioisotope.

[0134] In some embodiments, the payload targets expression of a target gene. In some embodiments, the target gene has increased transcription, a gain-of-function mutation or is duplicated. In some embodiments, the payload targets a gene upstream of the target gene that has increased transcription or a gain-of-function mutation or that is duplicated. In some embodiments, the payload reduces expression of a target gene that has increased transcription or a gain-of-function mutation or that is duplicated. In some embodiments, the payload increases expression of a target gene that has increased transcription or a gain-of- function mutation or that is duplicated. In some embodiments the payload corrects a splicing error. In some embodiments, the payload targets expression of a gene upstream of a target protein. In some embodiments, the payload targets activity of a target protein. In some embodiments the payload activates, inhibits, increases, or decreases a protein function. In some embodiments, the payload targets expression of a gene and / or activity of a protein. In other embodiments, the payload targets expression of a gene and / or activity of a protein upstream and / or downstream of a target protein.

[0135] In some embodiments, the gene that is targeted is transient receptor potassium channel 6 (TRPC6), apolipoprotein A1 (APOL1), alpha actinin-4 (ACTN4), solute carrier family 5 member 2 (SGLT2), solute family 22 member 2 (SLC22A2 / OCT2) orsodium-dependent neutral amino acid transporter B(0)AT1. In some embodiments, the gene that is targeted is TRPC6, APOL1, or ACTN4. In another embodiment, the payload targets expression of TRPC6. In another embodiment, the payload targets expression of APOL1. In yet another embodiment, the payload targets expression of ACTN4. In some embodiments, the payload targets expression of (SGLT2, SLC22A2 / OCT2 or B(0)AT1. In another embodiment, the payload targets expression of SGLT2. In another embodiment, the payload targets expression SLC22A2 / OCT2. In yet another embodiment, the payload targets expression of sodium-dependent neutral amino acid transporter B(0)AT1.

[0136] In another aspect, herein provided is a conjugate for targeted delivery of a payload comprising a polypeptide construct herein disclosed conjugated to a payload herein disclosed.

[0137] In an embodiment, the linker in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by a crosslinker, an amide bond, or an ester bond, a hydrazone bond, a carbonate bond, an oxime bond, a disulphide bond, a triazole linkage, or a thioether linkage. In an embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by a crosslinker. In another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by an amide bond. In another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by an ester bond. In another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by a hydrazone bond. In another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by a carbonate bond. In another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by an oxime bond. In another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by a disulphide bond. In yet another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by a triazole linkage. In yet another embodiment, in the polypeptide construct herein disclosed or the conjugate herein disclosed is conjugated to a payload by a thioether linkage.

[0138] The term “crosslinker” as used herein refers to a reagent or set of reagents that can chemically link two molecules, for example a polypeptide and a nucleic acid, by one or more covalent bonds. Crosslinking reagents contain two or more reactive ends that are capable of attaching to specific functional (e.g., primary amines, sulfhydryls, azides,alkynes, maleimides, etc.) on polypeptides or other molecules. A crosslinker can be, for example, a cleavable or a non-cleavable crosslinker.

[0139] In an embodiment, the crosslinker is cleavable. In another embodiment, the crosslinker is non-cleavable.

[0140] In an embodiment, the crosslinker comprises succinimidyl 3-(2- pyridyldithio)propionate (SPDP) and a thiol, an azide (e.g. 6-azidohexanoic acid, 6- azidonorleucine, 6-azidolysine, azide-PEG4-amine or azide-PEG4-COOH) and terminal alkyne or strained alkyne, a thiol and a thiol, a thiol and a maleimide, an amine and a maleimide, or an alcohol and a carbonate group. In another embodiment, the crosslinker comprises succinimidyl 3-(2-pyridyldithio)propionate (SPDP). In another embodiment, the crosslinker comprises succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and a thiol. In another embodiment, the crosslinker comprises an azide (e.g. 6-azidohexanoic acid or 6- azidonorleucine, 6-azidolysine, azide-PEG4-amine or azide-PEG4-COOH). In some embodiments, the crosslinker comprises an azide (e.g. 6-azidohexanoic acid or 6- azidonorleucine, 6-azidolysine, azide-PEG4-amine or azide-PEG4-COOH) and a terminal alkyne or strained alkyne. In another embodiment, the crosslinker comprises a thiol. In some embodiments, the crosslinker comprises a thiol and a thiol, or a thiol and a maleimide. In another embodiment, the crosslinker comprises an amine. In some embodiments, the crosslinker comprises an amine and a maleimide. In a further embodiment, the crosslinker comprises an alcohol. In some embodiments, the crosslinker comprises an alcohol and a carbonate group.

[0141] The construct or conjugate disclosed herein can be stable, such that it is resistant to breakdown in blood, for example, resistant to cleavage by plasma proteases. For instance, a construct or conjugate can be resistant to cleavage by plasma proteases when it has a half-life in plasma of, for example, at least about 15 minutes, at least about 30 minutes, at least about 60 minutes. In an embodiment, the construct or the conjugate herein disclosed is stable in blood. In some embodiments, the construct or the conjugate herein disclosed is stable in plasma.

[0142] In an embodiment, the construct or the conjugate herein increases the solubility of the entire molecule (construct + conjugate + payload). In another embodiment, the construct or the conjugate herein disclosed delivers the payload to cells expressing NPR- C. In another embodiment, the construct or the conjugate herein disclosed selectively delivers the payload to cells expressing NPR-C. In another embodiment, the construct or the conjugate herein disclosed delivers the to cells expressing NPR-C via receptor-mediated endocytosis. In yet another embodiment, the construct or the conjugate herein disclosed escapes an endosome of the cells expressing NPR-C. In a further embodiment, the construct or the conjugate herein disclosed delivers the payload to the cytosol of cells expressing NPR-C. III. Compositions

[0143] In another aspect, herein provided is a composition comprising a polypeptide construct herein disclosed or a conjugate herein disclosed and a pharmaceutically acceptable carrier or diluent.

[0144] The term “pharmaceutically acceptable” refers to the compatibility of a carrier or diluent with use in a subject, in particular, humans. Each carrier or buffer should also be compatible with the other ingredients of the composition.

[0145] Suitable buffers and carriers are described, for example, in Remington's Pharmaceutical Sciences, 22nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at the University of the Sciences, 2012). On this basis, the compositions include, albeit not exclusively, solutions of a polypeptide construct or a conjugate herein disclosed in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with physiological fluids.

[0146] In another aspect, herein provided is a polypeptide, a construct, a conjugate, or a composition herein disclosed, wherein the polypeptide, construct, the conjugate, or the composition is suitable for use in a subject. IV. Kits

[0147] In yet another aspect, herein provided is a kit comprising a polypeptide construct herein disclosed and a crosslinker.

[0148] In an embodiment, the polypeptide construct and / or the crosslinker is composed in a pharmaceutically acceptable carrier herein disclosed.

[0149] In an embodiment, the kit further includes instructions for use. V. Methods and Uses

[0150] The polypeptides, polypeptide constructs, and conjugates herein disclosed target cells expressing NPR-C for selective delivery of a payload for treating diseases or injury of the kidney in a subject in need thereof.

[0151] Accordingly, in an aspect, herein provided is a method of treating a disease or injury of NPR-C expressing cells in a subject in need thereof comprising administering to the subject a construct, conjugate, or composition herein disclosed.

[0152] In another aspect, herein provided is a use of a construct, conjugate, or composition herein disclosed for treating a disease or injury of NPR-C expressing cells in a subject in need thereof.

[0153] In yet another aspect, herein provided is a use of a construct, conjugate, or composition herein disclosed in the manufacture of a medicament for treating a disease or injury of NPR-C expressing cells in a subject in need thereof.

[0154] In a further aspect, herein provided is a construct, conjugate, or composition herein disclosed for use in treating a disease or injury of NPR-C expressing cells in a subject in need thereof.

[0155] In some embodiments, the administering or the use comprises a therapeutically effective amount of the construct, conjugate, or composition herein disclosed.

[0156] NPR-C is highly expressed in specialized kidney cells such as podocytes and proximal tubule cells, which play key roles in filtering blood within the Bowman’s capsule and reabsorption within proximal tubules. Injury, detachment, or loss of these cells is a common feature across various forms of kidney disease and can serve as a marker of late-stage disease.

[0157] Accordingly, in an embodiment, the disease or injury of NPR-C expressing cells is a disease or injury of the kidney.

[0158] The term "disease or injury of the kidney” as used herein refers to any disease of the kidney or nephropathy, including primary kidney diseases and secondary kidney diseases. The term “disease or injury of the kidney” as used herein also refers to injury to the kidney that can occur independent of a disease, for example due to environmental factors. Kidney diseases can include, for example, glomerulopathies, podocytopathies, proximal tubular disorders, renal amyloidosis, vascular disorders, and / or acute or chronic kidney diseases. Specific kidney diseases can include, for example, membranous nephropathy (MN), diabetic nephropathy, focal segmental glomerulosclerosis (FGSF), thin basement membrane disease (TBMN), light-chain deposition disease (LCDD), HIV nephropathy, Alport syndrome, drug-induced glomerulopathies, minimal-change disease (MCD), lupus nephritis,anti-glomerular basement membrane disease, IgA nephropathy (Berger’s Disease), membranoproliferative Glomerulonephritis (MPGN) or combinations thereof.

[0159] Accordingly, in an embodiment, the disease or injury of the kidney comprises a glomerulopathy, a podocytopathy, a proximal tubular disorder, a renal amyloidosis, a vascular disorder, an acute or chronic kidney disease, or a combination thereof.

[0160] In an embodiment, the disease or injury of the kidney comprises a glomerulopathy. In another embodiment, the disease or injury of the kidney comprises a podocytopathy. In another embodiment, the disease or injury of the kidney comprises a proximal tubular disorder. In another embodiment, the disease or injury of the kidney comprises a renal amyloidosis. In another embodiment, the disease or injury of the kidney comprises a vascular disorder. In a further embodiment, the disease or injury of the kidney comprises an acute or chronic kidney disease.

[0161] In an embodiment, the disease or injury of the kidney comprises membranous nephropathy (MN), diabetic nephropathy, focal segmental glomerulosclerosis (FGSF), thin basement membrane disease (TBMN), light-chain deposition disease (LCDD), HIV nephropathy, Alport syndrome, drug-induced glomerulopathies, minimal-change disease (MCD), lupus nephritis, anti-glomerular basement membrane disease, IgA nephropathy (Berger’s Disease), membranoproliferative Glomerulonephritis (MPGN), or a combination thereof. In another embodiment, the disease or injury of the kidney comprises focal segmental glomerulosclerosis (FSGS) and / or diabetic nephropathy.

[0162] In an embodiment, the disease or injury of the kidney comprises membranous nephropathy (MN). In another embodiment, the disease or injury of the kidney comprises diabetic nephropathy. In another embodiment, the disease or injury of the kidney comprises focal segmental glomerulosclerosis (FGSF). In another embodiment, the disease or injury of the kidney comprises thin basement membrane disease (TBMN). In another embodiment, the disease or injury of the kidney comprises light-chain deposition disease (LCDD). In another embodiment, the disease or injury of the kidney comprises HIV nephropathy. In another embodiment, the disease or injury of the kidney comprises Alport syndrome. In another embodiment, the disease or injury of the kidney comprises drug-induced glomerulopathies. In another embodiment, the disease or injury of the kidney comprises minimal-change disease (MCD). In another embodiment, the disease or injury of the kidney comprises lupus nephritis. In another embodiment, the disease or injury of the kidney comprises anti-glomerular basement membrane disease. In yet another embodiment, the disease or injury of the kidney comprises (Berger’s Disease). In a furtherembodiment, the disease or injury of the kidney comprises membranoproliferative Glomerulonephritis (MPGN).

[0163] In some embodiments, the disease or injury of the kidney comprises disease or injury of proximal tubules, podocytes, mesangial cells and / or endothelial cells. In another embodiment, the disease or injury of the kidney comprises disease or injury of proximal tubules. In another embodiment, the disease or injury of the kidney comprises disease or injury of podocytes. In another embodiment, the disease or injury of the kidney comprises disease or injury of mesangial cells. In a further embodiment, the disease or injury of the kidney comprises disease or injury of endothelial cells.

[0164] In some embodiments, the disease or injury of the NPR-C expressing cells comprises a disease or injury of peripheral organ systems due to renal malfunction. In some embodiments, the disease or injury of peripheral organ systems comprises metabolic acidosis, mineral and bone disorders, anemia, and / or cardiorenal syndrome. In another embodiment, the disease or injury of peripheral organ systems comprises metabolic acidosis. In another embodiment, the disease or injury of peripheral organ systems comprises, mineral and bone disorders. In another embodiment, the disease or injury of peripheral organ systems comprises anemia. In yet another embodiment, the disease or injury of peripheral organ systems comprises cardiorenal syndrome.

[0165] The term “administering” or “administration” as used herein refers to the placement of a construct, conjugate or composition as disclosed herein into a subject by a method or route which results in at least partial delivery to a desired site. The construct, conjugate or composition disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject, and can be for example by intravenous injection or intramuscularly.

[0166] In an embodiment, the construct, conjugate, or composition is administered intravenously, orally, through slow-release deposits, through subcutaneous injection, through intra-arterial administration or through intraperitoneal injection. In another embodiment, the construct, conjugate, or composition is for use intravenously, orally, through subcutaneous injection, through intra-arterial administration or through intraperitoneal injection.

[0167] In an embodiment, the construct, conjugate, or composition is administered or for use intravenously. In another embodiment, the construct, conjugate, or composition is administered or for use orally. In another embodiment, the construct, conjugate, or composition is administered or for slow release deposits. In anotherembodiment, the construct, conjugate, or composition is administered or for use through subcutaneous injection. In yet another embodiment, the construct, conjugate, or composition is administered or for use through intra-arterial administration. In yet another embodiment, the construct, conjugate, or composition is administered or for use through injection to a renal artery. In yet another embodiment, the construct, conjugate, or composition is administered or for use through intraperitoneal injection.

[0168] The term “treating”, “treatment”, and the like, as used herein, and as is well understood in the art, refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, arresting development of disease, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, including regression of the disease, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” may also refer to prolonging survival as compared to expected survival if not receiving treatment.

[0169] In an embodiment, the construct, conjugate, or composition is administered or for use in a single dose. In another embodiment, the conjugate is administered or for use in repeated doses.

[0170] The term "subject" or "patient" or synonym thereto, as used herein includes all members of the animal kingdom, for example mammals, including human.

[0171] In an embodiment, the subject is a human. In another embodiment, the subject is a domesticated animal. In an embodiment, the subject is a dog, a cat, or a horse. In yet another embodiment, the subject is a rodent. In an embodiment, rodent is a mouse or a rat. In yet another embodiment, the subject is a non-human primate. In an embodiment, the non- human primate is a monkey.

[0172] In an embodiment, a polypeptide construct, a conjugate, a composition, or a kit herein disclosed is for use in an assay. Examples

[0173] The following non-limiting Examples are illustrative of the present disclosure: Example 1

[0174] Given that systemic administration of therapeutic agents can lead to undesirable side effects and can interfere efficacy of in vivo treatments, the Inventorsdeveloped constructs and conjugates that target NPR-C expressing cells for targeted delivery of a therapeutic agent. NPR-C receptors are highly expressed in the vascular endothelium, the heart, the kidney, and smooth muscle cells. There are several known ligands to these receptors, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C- type natriuretic peptide (CNP), wherein binding affinity of these ligands to NPR-C is according to ANP > CNP > BNP. Once bound to its ligand, the complex can be internalized through receptor-mediated internalization. Methods Construct and Conjugate

[0175] Several NPR-C ligands were selected for use in these polypeptide constructs in order to target cells expressing NPR-C. Some ligands comprise variants of ANP. ANP is a small polypeptide which consists of 28 amino acids in both human and in rat. Though human and rat ANP are not identical, the amino acids are highly conserved between the two. For example, one ligand was a truncated version of full-length rat ANP (SEQ ID NO: 3), comprising amino acids 4-23 [Des18-22], wherein residues 18-23 in the native numbering are missing (rANP 4-23 [Des18-22]; SEQ ID NO:1; Maack et al., 1987). Another ligand was a synthetic ANP variant here called Musc23 (SEQ ID NO: 2; Nishizawa et al., 2017). The NPR-C ligands are set out in Table 1. Table 1: Amino acid sequences of NPR-C Ligands SEQ ID NO: Amino Acid Sequence 1 ARG-SER-SER-CYS-PHE-GLY-GLY-ARG-ILE-ASP-ARG-ILE-GLY-ALA-CYS 2 phe-SER-hyp-CHA-ser-GLY-HYP-ILE-ASP-ARG(Me)-ILE 3 SER-LEU-ARG-ARG-SER-SER-CYS-PHE-GLY-GLY-ARG-ILE-ASP-ARG-ILE- GLY-ALA-GLN-SER-GLY-LEU-GLY-CYS-ASN-SER-PHE-ARG-TYR 4 A64-E80-ile-J92-C71-ser-asp-PHE-GLY-ile-SER 5 phe-ser-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 6 phe-I18-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 7 phe-SER-J92-A61-ser-GLY-A64-ILE-ASP-E80-ILE 8 phe-SER-J92-A99-G77-A64-ILE-ASP-E80-ILE 9 phe-SER-J92-A99-G78-A64-ILE-ASP-E80-ILE 10 phe-SER-J92-A99-ser-GLY-E66-ILE-ASP-E80-ILE 11 phe-SER-J92-A99-ser-GLY-E76-ILE-ASP-E80-ILE 12phe-SER-J92-A99-ser-GLY-A64-NLE-ASP-E80-ILE 13 phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 14cys-SER-J92-A99-ser-B38-A64-ILE-ASP-E80-ILE 15phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80-ILE 16 phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-H16 17phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-E69SEQ ID NO: Amino Acid Sequence 18phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-E82 19 phe-SER-J92-A99-ser-SAR-A64-ILE-ASP-E80-ILE 20phe-SER-J92-A99-ser-GLY-A64-ILE-I14-E80-ILE 21phe-ser-J92-A61-ser-GLY-A64-ILE-ASP-E80-ILE 22 phe-SER-J92-A99-G77-A64-ILE-ASP-E80-E82 23cys-SER-J92-A61-ser-B38-A64-ILE-ASP-E80-ILE 24 ser-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 25E62-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 26 E62-SER-J92-A99-ser-GLY-A64-ILE-ASP-ARG-ILE 27 H52-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 28D15-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 29 phe-glu-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 30 phe-B50-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 31 phe-SER-E26-A99-ser-GLY-A64-ILE-ASP-E80-ILE 32 phe-SER-SAR-A99-ser-GLY-A64-ILE-ASP-E80-ILE 33phe-SER-ser-A99-ser-GLY-A64-ILE-ASP-E80-ILE 34 phe-SER-J92-PHE-ser-GLY-A64-ILE-ASP-E80-ILE 35phe-SER-J92-B16-ser-GLY-A64-ILE-ASP-E80-ILE 36phe-SER-J92-C71-ser-GLY-A64-ILE-ASP-E80-ILE 37 phe-SER-J92-E65-ser-GLY-A64-ILE-ASP-E80-ILE 38phe-SER-J92-A99-SAR-GLY-A64-ILE-ASP-E80-ILE 39 phe-SER-J92-A99-D19-GLY-A64-ILE-ASP-E80-ILE 40 phe-SER-J92-A99-GLY-bALA-A64-ILE-ASP-E80-ILE 41phe-SER-J92-A99-G60-A64-ILE-ASP-E80-ILE 42 phe-SER-J92-A99-J43-A64-ILE-ASP-E80-ILE 43phe-SER-J92-A99-ser-GLY-G39-ILE-ASP-E80-ILE 44 phe-SER-J92-A99-ser-GLY-SAR-ILE-ASP-E80-ILE 45 phe-SER-J92-A99-ser-GLY-H30-ILE-ASP-E80-ILE 46phe-SER-J92-A99-ser-GLY-A64-E14-ASP-E80-ILE 47 phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-E94 48phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE-bALA 49phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE-SAR 50 phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE-I74 51phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE-H34 52 tyr-SER-J92-A61-ser-GLY-E76-ILE-ASP-E80-ILE 53 phe-SER-J92-A99-ser-GLY-CYS-ILE-B38-E80-ILE 54 phe-SER-J92-A99-ser-GLY-A64-ILE-asp-E80-ILE 55 H52-SER-J92-A99-ser-SAR-A64-ILE-ASP-E80-H16 56phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80-H16 57 ASP-ALA-GLY-ALA-ARG-SER-ALA-SER-ALA-GLY-ALA58 phe-SER-J92-A99-G77-A64-H16-ASP-E80-ILE59 phe-SER-J92-A99-G77-A64-ILE-I14-E80-ILE60 phe-ser-J92-A99-G77-A64-ILE-ASP-E80-ILE61 phe-SER-J92-A99-G77-A64-ILE-ASP-E80-E8262 phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80-E82SEQ ID NO: Amino Acid Sequence 63 phe-ser-J92-A99-ser-GLY-A64-ILE-ASP-E80-E8264 phe-SER-J92-A99-ser-GLY-A64-ILE-I14-E80-E8265 phe-ser-J92-A99-ser-GLY-A64-H16-ASP-E80-ILE66 phe-ser-J92-A99-ser-GLY-A64-ILE-I14-E80-ILE196 phe-ser-J92-A99-ser-GLY-E76-ILE-ASP-E80-ILE197 phe-ser-J92-A99-ser-GLY-A64-NLE-ASP-E80-ILE198 cys-ser-J92-A99-ser-B38-A64-ILE-ASP-E80-ILE199 phe-ser-J92-A99-G77-A64-ILE-ASP-E80-E82200 phe-ser-J92-A99-ser-GLY-A64-H16-I14-E80-ILE201 phe-ser-J92-A99-ser-GLY-A64-H16-ASP-E80-E82202 cys-ser-J92-A99-ser-B38-E76-ILE-ASP-E80-ILE203 phe-ser-J92-A99-ser-GLY-E76-H16-ASP-E80-ILE204 phe-ser-J92-A99-ser-GLY-E76-ILE-ASP-E80-E82205 phe-ser-J92-A99-ser-GLY-E76-ILE-I14-E80-ILE206 phe-ser-J92-A99-ser-GLY-A64-H16-I14-E80-E82207 phe-SER-J92-A99-G77-E76-ILE-ASP-E80-ILE208 phe-SER-J92-A99-G77-A64-NLE-ASP-E80-ILE209 phe-SER-J92-A99-G77-A64-ILE-ASP-E80-E82210 phe-SER-J92-A99-G77-A64-H16-ASP-E80-E82211 phe-SER-J92-A99-G77-A64-H16-I14-E80-ILE212 phe-SER-J92-A99-G77-A64-H16-I14-E80-E82213 phe-SER-J92-A99-ser-GLY-E76-NLE-ASP-E80-ILE214 cys-SER-J92-A99-ser-B38-E76-ILE-ASP-E80-ILE215 phe-SER-J92-A99-ser-GLY-E76-H16-ASP-E80-ILE216 phe-SER-J92-A99-ser-GLY-E76-ILE-ASP-E80-E82217 phe-SER-J92-A99-ser-GLY-E76-ILE-I14-E80-ILE218 phe-SER-J92-A99-G77-E76-ILE-ASP-E80-E82219 phe-SER-J92-A99-ser-GLY-E76-H16-I14-E80-ILE220 phe-SER-J92-A99-ser-GLY-E76-H16-ASP-E80-E82221 phe-SER-J92-A99-ser-GLY-E76-H16-I14-E80-E82222 cys-SER-J92-A99-ser-GLY-B38-NLE-ASP-E80-ILE223 phe-SER-J92-A99-ser-GLY-A64-NLE-ASP-E80-E82224 phe-SER-J92-A99-ser-GLY-A64-NLE-I14-E80-ILE225 phe-SER-J92-A99-G77-A64-NLE-ASP-E80-E82226 phe-ser-J92-A99-ser-GLY-A64-NLE-ASP-E80-E82227 phe-ser-J92-A99-ser-GLY-A64-NLE-I14-E80-ILE228 phe-SER-J92-A99-ser-GLY-A64-NLE-I14-E80-ILE229 phe-ser-J92-A99-ser-GLY-A64-NLE-I14-E80-E82230 cys-SER-J92-A99-ser-B38-A64-H16-ASP-E80-ILE231 cys-SER-J92-A99-ser-B38- E80-E82SEQ ID NO: Amino Acid Sequence 232 cys-SER-J92-A99-ser-B38-A64-ILE-I14-E80-ILE233 cys-SER-J92-A99-ser-B38-A64-H16-ASP-E80-E82234 cys-SER-J92-A99-ser-B38-A64-H16-I14-E80-ILE235 cys-SER-J92-A99-ser-B38-A64-H16-I14-E80-E82236 phe-SER-J92-A99-ser-GLY-A64-H16-I14-E80-ILE237 phe-SER-J92-A99-G77-A64-H16-ASP-E80-E82238 phe-SER-J92-A99-ser-GLY-A64-H16-I14-E80-E82239 phe-ser-J92-A99-ser-GLY-A64-H16-I14-E80-E82240 phe-ser-J92-A99-ser-GLY-E76-H16-I14-E80-E82241 phe-ser-J92-A99-G77-E76-H16-I14-E80-E82242 phe-SER-J92-A99-G77-A64-ILE-I14-E80-E82243 phe-ser-J92-A99-G77-A64-ILE-I14-E80-E82244 phe-SER-J92-A99-G77-A64-H16-I14-E80-E82245 phe-ser-J92-A99-G77-A64-H16-I14-E80-E82

[0176] The linkers used included N-methylated amino acids (e.g. N-methyl-Glycine and N-methyl-beta-Alanine), D-enantiomer amino acids, and amino acids with elongated backbones (e.g. beta-Alanine and 6-aminohexanoic acid). The linkers used in the present constructs and conjugates were as defined in SEQ ID NOs: 67 to 76.

[0177] Further, peptides were used for endosomal escape. The peptide sequences used for endosomal escape in the present constructs and conjugates were as defined in SEQ ID NOs: 77-92. The linkers and endosomal escape motifs are set out in Table 2, below. Table 2: Amino acid sequences of other components of NPR-C-targeting constructs SEQ ID NO:Description Amino Acid Sequence67 Linker bALA-SAR-SAR-SAR-SAR 68 Linker bALA-SAR-SAR-SAR-SAR-bALA-bALA 69Linker + Albuminbinding domain bALA-SAR-SAR-SAR-SAR-J86 70Linker + Albuminbinding domain bALA-SAR-SAR-SAR-SAR-bALA-bALA-J86 71Linker + Albuminbinding domain J86-bALA-SAR-SAR-SAR-SAR 72Linker + Albuminbinding domain J86-bALA-SAR-SAR-SAR-SAR-bALA-bALA 73Linker + Albuminbinding domain bALA-SAR-SAR-SAR-SAR-ALBSEQ ID NO:Description Amino Acid Sequence74Linker + Albuminbinding domain bALA-SAR-SAR-SAR-SAR-bALA-bALA-ALB75Linker + Albuminbinding domain ALB-bALA-SAR-SAR-SAR-SAR 76Linker + Albuminbinding domain ALB-bALA-SAR-SAR-SAR-SAR-bALA-bALA 77Endosomal escapemotif his-his-his-his-his-his-gly-gly-his-his-his-his 78Endosomal escapemotif his-his-K02-K02-his-his-K02-K02-his-his-K02-K02 79Endosomal escapemotif leu-leu-K02-K02-leu-leu-K02-K02-leu-leu-K02-K02 80Endosomal escapeG78-G78-K02-K02-G78-G78-K02-K02-G78-G78-K02- motif K02 81Endosomal escapemotif leu-leu-C27-C27-leu-leu-C27-C27-leu-leu-C27-C27 82Endosomal escapeK02-K02-bALA-bALA-K02-K02-bALA-bALA-K02-K02- motif bALA-bALA 83Endosomal escapemotif his-his-his-his-his-his-gly-gly-his-his-his-his-bAla-bAla 84Endosomal escapehis-his-K02-K02-his-his-K02-K02-his-his-K02-K02-bALA- motif bALA 85Endosomal escapeleu-leu-K02-K02-leu-leu-K02-K02-leu-leu-K02-K02-bALA- motif bALA 86Endosomal escapebAla-bAla-leu-leu-K02-K02-leu-leu-K02-K02-leu-leu-K02- motif K02 87Endosomal escapeG78-G78-K02-K02-G78-G78-K02-K02-G78-G78-K02- motif K02-bALA-bALA 88Endosomal escapebAla-bAla-G78-G78-K02-K02-G78-G78-K02-K02-G78- motif G78-K02-K02 89Endosomal escapeleu-leu-C27-C27-leu-leu-C27-C27-leu-leu-C27-C27- motif bALA-bALA 90Endosomal escapebAla-bAla-leu-leu-C27-C27-leu-leu-C27-C27-leu-leu- motif C27-C27 91Endosomal escapebALA-bALA-K02-K02-bALA-bALA-K02-K02-bALA-bALA- motif K02-K02-bALA-bALA 92Endosomal escapebAla-bAla-K02-K02-bALA-bALA-K02-K02-bALA-bALA- motif K02-K02SEQ ID NO:Description Amino Acid SequenceWherein: uppercase = L-enantiomers; lowercase = D-enantiomers; and bALA beta-Alanine NCCC(=O)O SAR N-methyl-Glycine N(C)CC(=O)O K02 L-Aminopimelic acid C(CCC(=O)O)C[C@@H](C(=O)O)N G78 6-aminohexanoic acid C(CCC(=O)O)CCN C27 (2S)-2-Aminohexanedioic acid N[C@@H](CCCC(=O)O)C(=O)O 6&6RL#6&X&3EN&1&6RL&#+&# Ic1ccc(CCCC(=O)[N+H2]CCCC[C@]([O-])( ALB I& Iodophenyl)butyric acid)) [N+H2]C(=O)C([N+H3])CCC(=O)[N+H2]CC CCC([N+H3])C(=O)[O-])C(=O)[O-])cc1 OC([C@@H](N)CCCCNC(COCCOCCNC( J86 6&6RL#.22.>&.22.>&6&X&3EN& COCCOCCNC(CC[C@@H](NC(CCCCCC C18diacid) CCCCCCCCCCC(O)=O)=O)C(O)=O)=O)= O)=O)=O

[0178] The specific polypeptide constructs used herein included the amino acid sequences laid out in Table 3, below, and are further defined according to Table 4, below. Table 3: Amino acid sequences of NPR-C-targeting constructs SEQ ID NO: Amino Acid Sequence 93 bALA-SAR-SAR-SAR-SAR-ARG-SER-SER-CYS-PHE-GLY-GLY-ARG-ILE- ASP-ARG-ILE-GLY-ALA-CYS 94 bALA-SAR-SAR-SAR-SAR-phe-SER-hyp-CHA-ser-GLY-HYP-ILE-ASP- ARG(Me)-ILE bAla-SAR-SAR-SAR-SAR-his-his-his-his-his-his-gly-gly-his-his-his-his-bAla- 95 bAla-ARG-SER-SER-CYS-PHE-GLY-GLY-ARG-ILE-ASP-ARG-ILE-GLY- ALA-CYS 96 bAla-SAR-SAR-SAR-SAR-his-his-his-his-his-his-gly-gly-his-his-his-his-bAla- bAla-phe-SER-hyp-CHA-ser-GLY-HYP-ILE-ASP-ARG(Me)-ILE bALA-SAR-SAR-SAR-SAR-ARG-SER-SER-CYS-PHE-GLY-GLY-ARG-ILE- 97 ASP-ARG-ILE-GLY-ALA-CYS-bALA-bALA-his-his-his-his-his-his-gly-gly-his- his-his-his 98 bALA-SAR-SAR-SAR-SAR-phe-SER-hyp-CHA-ser-GLY-HYP-ILE-ASP- ARG(Me)-ILE-bAla-bALA-his-his-his-his-his-his-gly-gly-his-his-his-his 99 bALA-SAR-SAR-SAR-SAR-A64-E80-ile-J92-C71-ser-asp-PHE-GLY-ile-SER 100 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-ILE- ASP-E80-ILE 101 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-I18-J92-A99-ser-GLY-A64-ILE- ASP-E80-ILE 102 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A61-ser-GLY-A64- ILE-ASP-E80-ILE 103 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE- ASP-E80-ILESEQ ID NO: Amino Acid Sequence 104 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G78-A64-ILE- ASP-E80-ILE 105 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E66- ILE-ASP-E80-ILE 106 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- ILE-ASP-E80-ILE 107 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- NLE-ASP-E80-ILE 108 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILE 109 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-ILE- ASP-E80-ILE 110 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- H16-ASP-E80-ILE 111 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-H16 112 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-E69 113 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-E82 114 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-SAR-A64- ILE-ASP-E80-ILE 115 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-I14-E80-ILE 116 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A61-ser-GLY-A64-ILE- ASP-E80-ILE 117 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE- ASP-E80-E82 118 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A61-ser-B38-A64-ILE- ASP-E80-ILE 119 bALA-SAR-SAR-SAR-SAR-his-his-K02-K02-his-his-K02-K02-his-his-K02- K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 120 bALA-SAR-SAR-SAR-SAR-leu-leu-K02-K02-leu-leu-K02-K02-leu-leu-K02- K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 121 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- 122 ILE-ASP-E80-ILE-bALA-bALA-leu-leu-K02-K02-leu-leu-K02-K02-leu-leu- K02-K02 123 bALA-SAR-SAR-SAR-SAR-bALA-bALA-ser-SER-J92-A99-ser-GLY-A64-ILE- ASP-E80-ILE 124 bALA-SAR-SAR-SAR-SAR-bALA-bALA-E62-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILE 125 bALA-SAR-SAR-SAR-SAR-bALA-bALA-E62-SER-J92-A99-ser-GLY-A64- ILE-ASP-ARG-ILE 126 bALA-SAR-SAR-SAR-SAR-bALA-bALA-H52-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILE 127 bALA-SAR-SAR-SAR-SAR-bALA-bALA-D15-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILESEQ ID NO: Amino Acid Sequence 128 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-glu-J92-A99-ser-GLY-A64-ILE- ASP-E80-ILE 129 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-B50-J92-A99-ser-GLY-A64-ILE- ASP-E80-ILE 130 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-E26-A99-ser-GLY-A64- ILE-ASP-E80-ILE 131 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-SAR-A99-ser-GLY-A64- ILE-ASP-E80-ILE 132 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-ser-A99-ser-GLY-A64-ILE- ASP-E80-ILE 133 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-PHE-ser-GLY-A64- ILE-ASP-E80-ILE 134 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-B16-ser-GLY-A64- ILE-ASP-E80-ILE 135 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-C71-ser-GLY-A64- ILE-ASP-E80-ILE 136 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-E65-ser-GLY-A64- ILE-ASP-E80-ILE 137 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-SAR-GLY-A64- ILE-ASP-E80-ILE 138 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-D19-GLY-A64- ILE-ASP-E80-ILE 139 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-GLY-bALA-A64- ILE-ASP-E80-ILE 140 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G60-A64-ILE- ASP-E80-ILE 141 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-J43-A64-ILE- ASP-E80-ILE 142 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-G39- ILE-ASP-E80-ILE 143 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-SAR- ILE-ASP-E80-ILE 144 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-H30- ILE-ASP-E80-ILE 145 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- E14-ASP-E80-ILE 146 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-E94 147 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILE-bALA 148 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILE-SAR 149 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILE-I74 150 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-ASP-E80-ILE-H34 151 bALA-SAR-SAR-SAR-SAR-bALA-bALA-tyr-SER-J92-A61-ser-GLY-E76-ILE- ASP-E80-ILESEQ ID NO: Amino Acid Sequence 152 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-CYS- ILE-B38-E80-ILE 153 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-asp-E80-ILE 154 bALA-SAR-SAR-SAR-SAR-bALA-bALA-H52-SER-J92-A99-ser-SAR-A64- ILE-ASP-E80-H16 155 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- H16-ASP-E80-H16 156 bALA-SAR-SAR-SAR-SAR-leu-leu-C27-C27-leu-leu-C27-C27-leu-leu-C27- C27-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE bALA-SAR-SAR-SAR-SAR-bALA-bALA-K02-K02-bALA-bALA-K02-K02- 157 bALA-bALA-K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP- E80-ILE bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- 158 K02-K02-bALA-bALA-ASP-ALA-GLY-ALA-ARG-SER-ALA-SER-ALA-GLY- ALA 159 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE-ASP-E80-ILE 160 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80-ILE 161 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-I14-E80-ILE 162 bALA-SAR-SAR-SAR-SAR-bALA-bALA-ASP-ALA-GLY-ALA-ARG-SER-ALA- SER-ALA-GLY-ALA 163 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-H16- ASP-E80-ILE 164 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE- I14-E80-ILE 165 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-G77-A64-ILE-ASP- E80-ILE 166 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE- ASP-E80-E82 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- 167 H16-ASP-E80-E82 168 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-ILE- ASP-E80-E82 169 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- ILE-I14-E80-E82 170 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16- ASP-E80-ILE 171 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-ILE- I14-E80-ILE 172 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-H16-ASP-E80-ILE 173 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE-I14-E80-ILE 174 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-G77-A64-ILE-ASP-E80-ILESEQ ID NO: Amino Acid Sequence 175 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE-ASP-E80-E82 176 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80-E82 177 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-ILE-ASP-E80-E82 178 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-I14-E80-E82 179 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16-ASP-E80-ILE 180 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-ILE-I14-E80-ILE 181 bALA-SAR-SAR-SAR-SAR-J86-his-his-his-his-his-his-GLY-GLY-his-his-his- his-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 182 J86-bALA-SAR-SAR-SAR-SAR-his-his-his-his-his-his-GLY-GLY-his-his-his- his-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 183 bALA-SAR-SAR-SAR-SAR-ALB-his-his-his-his-his-his-GLY-GLY-his-his-his- his-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 184 ALB-bALA-SAR-SAR-SAR-SAR-his-his-his-his-his-his-GLY-GLY-his-his-his- his-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE bALA-SAR-SAR-SAR-SAR-J86-G78-G78-K02-K02-G78-G78-K02-K02-G78- 185 G78-K02-K02-bALA-bALA-ASP-ALA-GLY-ALA-ARG-SER-ALA-SER-ALA- GLY-ALA J86-bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78- 186 G78-K02-K02-bALA-bALA-ASP-ALA-GLY-ALA-ARG-SER-ALA-SER-ALA- GLY-ALA bALA-SAR-SAR-SAR-SAR-ALB-G78-G78-K02-K02-G78-G78-K02-K02-G78- 187 G78-K02-K02-bALA-bALA-ASP-ALA-GLY-ALA-ARG-SER-ALA-SER-ALA- GLY-ALA ALB-bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78- 188 G78-K02-K02-bALA-bALA-ASP-ALA-GLY-ALA-ARG-SER-ALA-SER-ALA- GLY-ALA bALA-SAR-SAR-SAR-SAR-J86-G78-G78-K02-K02-G78-G78-K02-K02-G78- 189 G78-K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80- ILE J86-bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78- 190 G78-K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80- ILE bALA-SAR-SAR-SAR-SAR-ALB-G78-G78-K02-K02-G78-G78-K02-K02-G78- 191 G78-K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80- ILE ALB-bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78- 192 G78-K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80- ILE 246 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-ILE- ASP-E80-ILE 247 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE- ASP-E80-ILESEQ ID NO: Amino Acid Sequence 248 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-ser-J92-A99-ser-B38-A64-ILE- ASP-E80-ILE 249 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-G77-A64-ILE-ASP- E80-E82 250 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16- I14-E80-ILE 251 bALA-SAR-SAR-SAR-SAR-bALA-bALAphe-ser-J92-A99-ser-GLY-A64-H16- ASP-E80-E82 252 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-ser-J92-A99-ser-B38-E76-ILE- ASP-E80-ILE 253 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-H16- ASP-E80-ILE 254 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-ILE- ASP-E80-E82 255 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-ILE- I14-E80-ILE 256 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16- I14-E80-E82 257 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-E76-ILE- ASP-E80-ILE 258 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-NLE- ASP-E80-ILE 259 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE- ASP-E80-E82 260 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-H16- ASP-E80-E82 261 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-H16- I14-E80-ILE 262 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-H16- I14-E80-E82 263 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- NLE-ASP-E80-ILE 264 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-E76-ILE- ASP-E80-ILE 265 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- H16-ASP-E80-ILE 266 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- ILE-ASP-E80-E82 267 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- ILE-I14-E80-ILE 268 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-E76-ILE- ASP-E80-E82 269 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- H16-I14-E80-ILE 270 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- H16-ASP-E80-E82 271 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76- H16-I14-E80-E82SEQ ID NO: Amino Acid Sequence 272 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-GLY-B38- NLE-ASP-E80-ILE 273 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- NLE-ASP-E80-E82 274 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- NLE-I14-E80-ILE 275 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-NLE- ASP-E80-E82 276 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE- ASP-E80-E82 277 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE- I14-E80-ILE 278 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- NLE-I14-E80-ILE 279 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE- I14-E80-E82 280 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-A64- H16-ASP-E80-ILE 281 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-ILE- ASP-E80-E82 282 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-ILE- I14-E80-ILE 283 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-A64- H16-ASP-E80-E82 284 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-A64- H16-I14-E80-ILE 285 bALA-SAR-SAR-SAR-SAR-bALA-bALA-cys-SER-J92-A99-ser-B38-A64- H16-I14-E80-E82 286 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- H16-I14-E80-ILE 287 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-H16- ASP-E80-E82 288 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64- H16-I14-E80-E82 289 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16- I14-E80-E82 290 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-H16- I14-E80-E82 291 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-G77-E76-H16-I14- E80-E82 292 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE- I14-E80-E82 293 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-G77-A64-ILE-I14- E80-E82 294 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-SER-J92-A99-G77-A64-H16- I14-E80-E82 295 bALA-SAR-SAR-SAR-SAR-bALA-bALA-phe-ser-J92-A99-G77-A64-H16-I14- E80-E82SEQ ID NO: Amino Acid Sequence 296 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 297 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE-ASP-E80-ILE 298 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-ILE-ASP-E80-ILE 299 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-NLE-ASP-E80-ILE 300 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-ILE-ASP-E80-ILE 301 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-E82 302 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-ILE-ASP-E80-ILE bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G303 78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE-ASP-E80-ILE 304 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-ser-J92-A99-ser-B38-A64-ILE-ASP-E80-ILE 305 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-G77-A64-ILE-ASP-E80-E82 306 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16-I14-E80-ILE 307 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16-ASP-E80-E82 308 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-ser-J92-A99-ser-B38-E76-ILE-ASP-E80-ILE 309 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-H16-ASP-E80-ILE 310 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-ILE-ASP-E80-E82 311 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-ILE-I14-E80-ILE 312 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16-I14-E80-E82 313 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-E76-ILE-ASP-E80-ILE 314 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-NLE-ASP-E80-ILE 315 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE-ASP-E80-E82 316 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-H16-ASP-E80-E82 317 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-H16-I14-E80-ILE 318 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-H16-I14-E80-E82 319 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-NLE-ASP-E80-ILESEQ ID NO: Amino Acid Sequence 320 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-E76-ILE-ASP-E80-ILE 321 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-H16-ASP-E80-ILE 322 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-ILE-ASP-E80-E82 323 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-ILE-I14-E80-ILE 324 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-E76-ILE-ASP-E80-E82 325 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-H16-I14-E80-ILE 326 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-H16-ASP-E80-E82 327 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-E76-H16-I14-E80-E82 328 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-GLY-B38-NLE-ASP-E80-ILE 329 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-NLE-ASP-E80-E82 330 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-NLE-I14-E80-ILE 331 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-NLE-ASP-E80-E82 332 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE-ASP-E80-E82 333 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE-I14-E80-ILE 334 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-NLE-I14-E80-ILE 335 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-NLE-I14-E80-E82 336 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-H16-ASP-E80-ILE 337 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-ILE-ASP-E80-E82 338 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-ILE-I14-E80-ILE 339 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-H16-ASP-E80-E82 340 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-H16-I14-E80-ILE 341 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-cys-SER-J92-A99-ser-B38-A64-H16-I14-E80-E82 342 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-I14-E80-ILE 343 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-H16-ASP-E80-E82SEQ ID NO: Amino Acid Sequence 344 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-I14-E80-E82 345 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-A64-H16-I14-E80-E82 346 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-ser-GLY-E76-H16-I14-E80-E82 347 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-G77-E76-H16-I14-E80-E82 348 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-ILE-I14-E80-E82 349 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-G77-A64-ILE-I14-E80-E82 350 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G77-A64-H16-I14-E80-E82 351 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-ser-J92-A99-G77-A64-H16-I14-E80-E82 352 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-ser-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 353 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-E62-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 354 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-E62-SER-J92-A99-ser-GLY-A64-ILE-ASP-ARG-ILE 355 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-H52-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 356 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-D15-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 357 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-glu-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 358 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-B50-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE 359 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-E26-A99-ser-GLY-A64-ILE-ASP-E80-ILE 360 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-SAR-A99-ser-GLY-A64-ILE-ASP-E80-ILE 361 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-ser-A99-ser-GLY-A64-ILE-ASP-E80-ILE 362 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-PHE-ser-GLY-A64-ILE-ASP-E80-ILE 363 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-B16-ser-GLY-A64-ILE-ASP-E80-ILE 364 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-C71-ser-GLY-A64-ILE-ASP-E80-ILE 365 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-E65-ser-GLY-A64-ILE-ASP-E80-ILE 366 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-SAR-GLY-A64-ILE-ASP-E80-ILE 367 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-D19-GLY-A64-ILE-ASP-E80-ILESEQ ID NO: Amino Acid Sequence 368 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-GLY-bALA-A64-ILE-ASP-E80-ILE 369 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-G60-A64-ILE-ASP-E80-ILE 370 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-J43-A64-ILE-ASP-E80-ILE 371 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-G39-ILE-ASP-E80-ILE 372 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-SAR-ILE-ASP-E80-ILE 373 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-H30-ILE-ASP-E80-ILE 374 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-E14-ASP-E80-ILE 375 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-E94 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- 376 K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE- bALA bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- 377 K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE- SAR 378 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE-I74 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- 379 K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-ASP-E80-ILE- H34 380 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-tyr-SER-J92-A61-ser-GLY-E76-ILE-ASP-E80-ILE 381 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-CYS-ILE-B38-E80-ILE 382 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-ILE-asp-E80-ILE 383 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-H52-SER-J92-A99-ser-SAR-A64-ILE-ASP-E80-H16 384 bALA-SAR-SAR-SAR-SAR-G78-G78-K02-K02-G78-G78-K02-K02-G78-G78- K02-K02-bALA-bALA-phe-SER-J92-A99-ser-GLY-A64-H16-ASP-E80-H16 Wherein: uppercase = L-enantiomers; lowercase = D-enantiomers; and bALA beta-Alanine NCCC(=O)O SAR N-methyl-Glycine N(C)CC(=O)O E80 N(omega)-methyl-L-arginine CN=C(N)NCCC[C@@H](C(=O)O)N (Arg(Me)) J92 (HYP) trans-4-Hydroxy-D-proline C1[C@@H](CN[C@H]1C(=O)O)OA99 3-Cyclohexyl-L-Alanine N[C@@H](CC1CCCCC1)C(=O)O (CHA) A64 trans-4-Hydroxy-L-proline O=C(O)[C@@H]1C[C@@H](O)CN1 C27 (2S)-2-Aminohexanedioic acid N[C@@H](CCCC(=O)O)C(=O)OSEQ ID NO: Amino Acid Sequence C71 3-Cyclohexyl-D-Alanine N[C@H](CC1CCCCC1)C(=O)O G77 5-aminovaleric acid C(CCN)CC(=O)O G78 6-aminohexanoic acid C(CCC(=O)O)CCN E62 4-Chloro-D-Phenylalanine N[C@H](Cc1ccc(Cl)cc1)C(=O)O E65 Cyclohexyl-Homo-L-Alanine N[C@@H](CCC1CCCCC1)C(=O)O E66 N2-Methyl-L-Arginine N(C)[C@@H](CCCNC(=N)N)C(=O)O E69 L-Beta-Homoleucine N[C@@H](CC(C)C)CC(=O)O E76 N-Methyl-L-Serine N(C)[C@@H](CO)C(=O)O NLE L-Norleucine N[C@@H](CCCC)C(=O)O B38 Homo-L-Cysteine N[C@@H](CCS)C(=O)O H16 N-Methyl-L-Isoleucine N(C)[C@@H]([C@H](CC)C)C(=O)O E82 L-Beta-Leucine N[C@@H](C(C)C)CC(=O)O I14 alpha-methyl-L-aspartic acid C[C@](CC(=O)O)(C(=O)O)N K02 L-Aminopimelic acid C(CCC(=O)O)C[C@@H](C(=O)O)N H52 4-fluoro-D-phenylalanine C1=CC(=CC=C1C[C@H](C(=O)O)N)F D15 Homo-D-Phenylalanine N[C@H](CCc1ccccc1)C(=O)O B50 Homo-L-serine N[C@@H](CCO)C(=O)O E26 N-Methyl-D-Glutamic acid N(C)[C@H](CCC(=O)O)C(=O)O B16 L-Cyclohexylglycine N[C@@H](C1CCCCC1)C(=O)O D19 Homo-D-Serine N[C@H](CCO)C(=O)O G60 gamma-aminobutyric-acid NCCCC(O)=O J43 2-(2-aminoethoxy)acetic Acid C(COCC(=O)O)N G39 L-Pipecolic acid C1CCN[C@@H](C1)C(=O)O H30 1- C1CCC(C1)(C(=O)O)N Aminocyclopentanecarboxylic acid E14 N-Methyl-L-Norleucine N(C)[C@@H](CCCC)C(=O)O E94 N-Methyl-L-Leucine N(C)[C@@H](CC(C)C)C(=O)O I74 N-methyl-beta-Alanine CNCCC(=O)O H34 2-[2-(2- C(COCCOCC(=O)O)N aminoethoxy)ethoxy]acetic acid A61 4-Fluoro-L-Phenylalanine N[C@@H](Cc1ccc(F)cc1)C(=O)O ALB 6&6RL#6&X&3EN&1&6RL&#+&#I& Ic1ccc(CCCC(=O)[N+H2]CCCC[C@]([O Iodophenyl)butyric acid)) -])([N+H2]C(=O)C([N+H3])CCC(=O)[N+ H2]CCCCC([N+H3])C(=O)[O-])C(=O)[O- ])cc1 J86 6&6RL#.22.>&.22.>&6&X&3EN& OC([C@@H](N)CCCCNC(COCCOCCN C18diacid) C(COCCOCCNC(CC[C@@H](NC(CCC CCCCCCCCCCCCCC(O)=O)=O)C(O)= O)=O)=O)=O)=O I18 alpha-methyl-L-serine C[C@](CO)(C(=O)O)NTable 4: Peptide constructs and conjugates used throughout the Examples Construct Descri Molecular (Conjugate) ption Weight POL-1-1 rANP 4-23 [Des18-23] (SEQ ID NO: 1) with Alexa Fluor 488 at N-terminus and NH2at C-terminus 2,112.00 POL-1-2 rANP 4-23 [Des18-23] (SEQ ID NO: 1) with NH2at both N- and C-terminus 1,594.83 POL-1-3 D-enantiomer of rANP 4-23 [Des18-23] (SEQ ID NO: 1) + Alexa Fluor 488 at N-terminus and NH 2,112.00 2 at C-terminus POL-1-4 D-enantiomer of rANP 4-23 [Des18-23] (SEQ ID NO: 1) with NH2at both N- and C-terminus 1,594.83 POL-1-5 rANP 1-28 (SEQ ID NO: 3) with NH2 at N-terminus and COOH at C-terminus 3,062.41 POL-1-6 Musc23 (SEQ ID NO: 2) with Hydroxyacetyl (HOCH2CO) at 1,358.70 N-terminus and methylamide (NHCH3) at C-terminus POL-1-7 Linker + rANP 4-23 [Des18-23] (SEQ ID NO: 93) with NH2at (Conjugate) C-terminus and crosslinked at the N-terminus (via SPDP) to 17,668.96 siRNA against expression of GAPDH POL-1-8 Linker + his-sponge + rANP 4-23 [Des18-23] (SEQ ID NO: (Conjugate) 95) with NH2 at C-terminus and crosslinked at the N-terminus 19,296.64 (via SPDP) to siRNA against expression of GAPDH POL-1-9 Linker + Musc23 (SEQ ID NO: 94) with methylamide (Conjugate) (NHCH3) at C-terminus and crosslinked at the N-terminus 17,374.29 (via SPDP) to siRNA against expression of GAPDH Linker + his-sponge + Musc23 (SEQ ID NO: 96) with POL-1-10 methylamide (NHCH3) at C-terminus and crosslinked at the (Conjugate) N-terminus (via SPDP) to siRNA against expression of 19,002.33 GAPDH POL-1-11 Linker + his-sponge + rANP 4-23 [Des18-23] (SEQ ID NO: 95) with acetyl at N-terminus and NH2at C-terminus 3,619.91 POL-1-12 Linker + rANP 4-23 [Des18-23] + his-sponge (SEQ ID NO:97) with acetyl at N-terminus and NH 3,619.91 2 at C-terminus POL-1-13 Linker + his-sponge + Musc23 (SEQ ID NO: 96) with acetyl at N-terminus and methylamide (NHCH3) at C-terminus 3,324.53 POL-1-14 Linker + Musc23 + his-sponge (SEQ ID NO: 98) with acetyl at N-terminus and methylamide (NHCH3) at C-terminus 3,324.53 POL-1-15 Musc23 (SEQ ID NO: 2) with Alexa Fluor 488 at N-terminus and methylamide (NHCH3) at C-terminus 1,816.98 Linker + rANP 4-23 [Des18-23] (SEQ ID NO: 93) with NH2 at POL-1-7-2 C-terminus and crosslinker 6-azidohexanoic acid at the N- 2,089.39 terminus Linker + his-sponge + rANP 4-23 [Des18-23] (SEQ ID NO: POL-1-8-2 95) with NH2 at C-terminus and crosslinker 6-azidohexanoic 3,759.08 acid at the N-terminus Linker + Musc23 (SEQ ID NO: 94) with methylamide POL-1-9-2 (NHCH3) at C-terminus and crosslinker 6-azidohexanoic acid 1,796.40 at the N-terminus POL-1-10-2 Linker + his-sponge + Musc23 (SEQ ID NO: 96) with 3,424.04Construct jugate) Descri Molecular (Con ption Weight methylamide (NHCH3) at C-terminus and crosslinker 6- azidohexanoic acid at the N-terminus Linker + his-sponge + Musc23 (SEQ ID NO: 96) with POL-1-10-3 methylamide (NHCH3) at C-terminus and crosslinked at the (Conjugate) N-terminus (via BCN-azide) to Cy5.5 labeled siRNA against 19,115.22 expression of GAPDH POL-1-10-4 Linker + his-sponge + Musc23 (SEQ ID NO: 96) with (Conjugate) methylamide (NHCH3) at C-terminus and crosslinked at the U N-terminus (via azide-click) to an unspecified siRNA Linker + his-sponge + Musc23 (SEQ ID NO: 96) with POL-1-10-5 methylamide (NHCH3) at C-terminus and crosslinker Azide- U PEG4-amine at the N-terminus POL-1-16 SEQ ID NO:99 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,796.40 POL-1-17 SEQ ID NO:100 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,938.8 POL-1-18 SEQ ID NO:101 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-19 SEQ ID NO:102 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-20 SEQ ID NO:103 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,893.95 SEQ ID NO:103 with methylamide (NHCH3) at C-terminus POL-1-20-2 and crosslinked at the N-terminus (via azide-click) to an U unspecified siRNA POL-1-21 SEQ ID NO:104 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-22 SEQ ID NO:105 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-23 SEQ ID NO:106 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,926.79 POL-1-24 SEQ ID NO:107 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,938.00 POL-1-25 SEQ ID NO:108 with crosslinker 6-azidohexanoic acid at N- terminus and butylamine (0GA) at C-terminus U POL-1-26 SEQ ID NO:108 with crosslinker 6-azidohexanoic acid at N- terminus and N-cyclopropane at C-terminus U POL-1-27 SEQ ID NO:109 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,952.10 POL-1-28 SEQ ID NO:110 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,952.10 SEQ ID NO:110 with methylamide (NHCH3) at C-terminus POL-1-28-2 and crosslinked at the N-terminus (via azide-click) to an U unspecified siRNAConstruct njugate) Descri Molecular (Co ption Weight POL-1-29 SEQ ID NO:111 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-30 SEQ ID NO:112 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-31 SEQ ID NO:113 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,938.8 POL-1-32 SEQ ID NO:114 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-33 SEQ ID NO:115 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,952.8 SEQ ID NO:115 with methylamide (NHCH3) at C-terminus POL-1-33-2 and crosslinked at the N-terminus (via azide-click) to an U unspecified siRNA POL-1-34 SEQ ID NO:116 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-35 SEQ ID NO:117 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 1,893.3 POL-1-36 SEQ ID NO:118 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-37 SEQ ID NO:119 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-38 SEQ ID NO:120 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 3,452.60 POL-1-39 SEQ ID NO:121 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 3,560.1 SEQ ID NO:121 with methylamide (NHCH3) at C-terminus POL-1-39-2 and crosslinked at the N-terminus (via azide-click) to an U unspecified siRNA POL-1-40 SEQ ID NO:122 with crosslinker 6-azidohexanoic acid at N- terminus and NH2 at C-terminus 3,720.1 POL-1-41 SEQ ID NO:31 with Alexa Fluor 488 at N-terminus and methylamide (NHCH3) at C-terminus 1,816.98 POL-1-42 SEQ ID NO:123 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-43 SEQ ID NO:124 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-44 SEQ ID NO:125 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-45 SEQ ID NO:126 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-46 SEQ ID NO:127 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide at C-terminus UConstruct jugate) Descri Molecular (Con ption Weight POL-1-47 SEQ ID NO:128 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-48 SEQ ID NO:129 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-49 SEQ ID NO:130 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-50 SEQ ID NO:131 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-51 SEQ ID NO:132 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-52 SEQ ID NO:133 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-53 SEQ ID NO:134 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-54 SEQ ID NO:135 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-55 SEQ ID NO:136 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-56 SEQ ID NO:137 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-57 SEQ ID NO:138 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-58 SEQ ID NO:139 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-59 SEQ ID NO:140 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-60 SEQ ID NO:141 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-61 SEQ ID NO:142 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-62 SEQ ID NO:143 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-63 SEQ ID NO:144 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-64 SEQ ID NO:145 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-65 SEQ ID NO:146 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-66 SEQ ID NO:147 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-67 SEQ ID NO:148 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide at C-terminus UConstruct jugate) Descri Molecular (Con ption Weight POL-1-68 SEQ ID NO:149 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-69 SEQ ID NO:150 with crosslinker 6-azidohexanoic acid at N- terminus and PEG2H34-NH2 at C-terminus U POL-1-71 SEQ ID NO:151 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-72 SEQ ID NO:152 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-73 SEQ ID NO:153 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-74 SEQ ID NO:154 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-75 SEQ ID NO:155 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-76 SEQ ID NO:156 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-77 SEQ ID NO:157 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-78 SEQ ID NO:158 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 3,204.77 SEQ ID NO:158 with methylamide (NHCH3) at C-terminus POL-1-78-2 and crosslinked at the N-terminus (via BCN-azide) to Cy5.5 18,894.13 labeled siRNA against expression of GAPDH POL-1-78-3 SEQ ID NO:158 with crosslinker Azide-PEG4-amine at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-79 SEQ ID NO:159 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-80 SEQ ID NO:160 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus 3,576.00 SEQ ID NO:160 with methylamide (NHCH3) at C-terminus POL-1-80-2 and crosslinked at the N-terminus (via BCN-azide) to Cy5.5 19,265.69 labeled siRNA against expression of GAPDH POL-1-80-3 SEQ ID NO:160 with crosslinker Azide-PEG4-amine at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-81 SEQ ID NO:161 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-82 SEQ ID NO:162 with crosslinker 6-azidohexanoic acid at N- terminus and methylamide (NHCH3) at C-terminus U POL-1-83 SEQ ID NO:163 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-84 SEQ ID NO:164 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide at C-terminusConstruct jugate) Descri Molecular (Con ption Weight POL-1-85 SEQ ID NO:165 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-86 SEQ ID NO:166 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-87 SEQ ID NO:167 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-88 SEQ ID NO:168 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-89 SEQ ID NO:169 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-90 SEQ ID NO:170 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-91 SEQ ID NO:171 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-92 SEQ ID NO:172 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-93 SEQ ID NO:173 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-94 SEQ ID NO:174 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-95 SEQ ID NO:175 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-96 SEQ ID NO:176 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-97 SEQ ID NO:177 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-98 SEQ ID NO:178 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-99 SEQ ID NO:179 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-100 SEQ ID NO:180 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-101 SEQ ID NO:181 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-101-2 SEQ ID NO:181 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-102 SEQ ID NO:182 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-102-2 SEQ ID NO:182 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-103 SEQ ID NO:183 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide at C-terminusConstruct onjugate) Descr Molecular (C iption Weight POL-1-103-2 SEQ ID NO:183 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-104 SEQ ID NO:184 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-104-2 SEQ ID NO:184 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-105 SEQ ID NO:185 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-105-2 SEQ ID NO:185 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-106 SEQ ID NO:186 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-106-2 SEQ ID NO:186 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-107 SEQ ID NO:187 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-107-2 SEQ ID NO:187 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-108 SEQ ID NO:188 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-108-2 SEQ ID NO:188 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-109 SEQ ID NO:189 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-109-2 SEQ ID NO:189 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-110 SEQ ID NO:190 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-110-2 SEQ ID NO:190 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-111 SEQ ID NO:191 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-111-2 SEQ ID NO:191 with crosslinker Azido-PEG4-amine at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-112 SEQ ID NO:192 with crosslinker 6-azidohexanoic acid at N- U terminus and methylamide (NHCH3) at C-terminus POL-1-112-2 SEQ ID NO:192 with crosslinker Azido-PEG4-amine at N- terminus and methylamide (NHCH3) at C-terminus U Wherein: 6-azidohexanoic acid C(CCC(=O)O)CCN=[N+]=[N-] 0GA (Butylamine) CCCCN[H]Construct Descrip Molecular (Conjugate) tion Weight methylamide NHCH3 azido-PEG4-Acid C(COCCOCCOCCOCCN=[N+]=[N-])C(=O)O Cy5.5 CCN\1C2=C(C3=CC=CC=C3C=C2)C( / C1=C\C=C\C=C\C4=[N+](C5=C(C4(C)C)C6=CC= CC=C6C=C5)CC)(C)C.[I-]

[0179] The siRNA against expression of GAPDH used in the constructs and throughout this Example comprised the sequences in Table 1. Table 5: siRNA used within Example 1 SEQ ID NO: Nucleic Acid Sequence Experiments 193 A*a*GgUcAuCCAuGaCaAcUuU (Sense Strand) In vitro 194 a*A*aGuUgUcAuggAuGaCcUu*g*g (Antisense Strand) In vitro 193 [BCN] [amino-C6] A*a*GgUcAuCCAuGaCaAcUuU [Cy5.5] [C3] (Sense Strand) In vivo 195 (VPmA)*A*aGuUgUcAuggAuGaCcUu*g*g (Antisense Strand) In vivo Wherein: * phosphorothioate linkage (PS bond) Lower case 2’-OMe Upper case 2’-F(VPmA) 5’-(E)-vinyl phosphonate 2’-OMe A Cy5.5 Cyanine 5.5 BCN (1R,8S,9s)-Bicyclo[6.1.0]non-4-yn-9-ylmethyl Succinimidyl Carbonate Amino-C6 hexyl amine Immunohistochemistry Staining of NPR-C

[0180] All staining procedures performed using the Leica Bond RX automated stainer (Leica Microsystems) and standard procedures with fully automated workflow. Samples wereIKH>@LL@?% @F=@??@? DG I<K<AADG% <G? L@>MDHG@? <M +YF' :ED?@L P@K@ ?@P<Q@? NLDGB QRE@G@and alcohol based dewaxing solutions. Epitope retrieval was performed by heat-induced epitope retrieval (HIER) of the formalin-fixed, paraffin-embedded tissue using citrate based pH 6 solution (Leica Microsystems, AR9961) for 20 mins at 100°C. Tissues were first incubated with peroxide block buffer (Leica Microsystems), followed by incubation with DAKO Protein Block (X0909) for 15 mins. This was then followed by incubation with the Natriuretic Peptide Receptor C Antibody (Novus Biologicals, NBP1-31365) at a 1:2,000 dilution for 30 mins, followed by DAB rabbit secondary polymer, DAB refine and hematoxylin(Bond Polymer Refine Detection Kit, Leica Microsystems) according to the manufacturer's protocol. The slides were dried, cover slipped (TissueTek-Prisma Coverslipper) and visualized using a Leica Aperio AT2 slide scanner (Leica Microsystems) at 40X. Fluorescence Polarization Direct Binding Assay

[0181] A fluorescently labelled polypeptide construct comprising an NPR-C ligand (e.g., POL-1-1) in PBS buffer pH 7.4 with 0.05% tween-20 was added at a fixed concentration to increasing concentrations of NPR-C in PBS buffer pH 7.4 with 0.05% tween-20 and allowed to equilibrate for 15 minutes. Samples were excited and fluorescence polarization was measured using a fluorescent plate reader. Fluorescence polarization values were normalized and plotted for each concentration of NPR-C. Fluorescence polarization data was fitted (e.g. one site - specific binding) to produce a binding curve from which affinity values (Kd) were derived. The higher the polarization value, the more the polypeptide construct is bound to its binding partner (NPR-C). A plateau is reached once all available NPR-C receptors are bound. The more left shifted the fitted curve, the higher the affinity of the polypeptide for the NPR-C receptor.

[0182] The fluorescence polarization direct binding assay was repeated with varied pH (e.g.7.5, 6.0, 4.5) to assess pH dependency of polypeptide binding to NPR-C receptor. Briefly, fluorescently labelled polypeptide POL-1-1 or POL-1-15 in PBS buffer pH 7.4 with 0.05% tween-20 was added at a fixed concentration to increasing concentrations of NPR-C in PBS buffer pH 7.4 with 0.05% tween-20 and allowed to equilibrate for 15 minutes at 5X the final assay concentration. The polypeptide + NPR-C receptor sample was then diluted into a phosphate citrate buffer with 0.05% tween-20 at pH 7.5 or 6.0 or 4.5 and allowed to equilibrate for 15 minutes. Binding affinity was measured from fluorescence polarization values as above. Fluorescence Polarization Competition Assay

[0183] Unlabeled polypeptide constructs comprising an NPR-C ligand (e.g. POL-1-2, POL-1-4) in PBS buffer pH 7.4 with 0.05% tween were added at increasing concentrations to a fixed concentration of NPR-C receptor in PBS buffer pH 7.4 with 0.05% tween and allowed to equilibrate for 15 minutes (in parallel experiments, each using only one unlabeled polypeptide construct). A fluorescently labeled polypeptide construct comprising an NPR-C ligand (e.g. POL-1-1) in PBS buffer pH 7.4 with 0.05% tween was then added at a fixed concentration to the solution of unlabeled polypeptide and NPR-C receptor in PBS buffer pH 7.4 with 0.05% tween and allowed to for 15 minutes. Samples were excited andfluorescence polarization was measured for each concentration of unlabeled polypeptide using a fluorescent plate reader. Fluorescence polarization values were normalized and plotted to produce a graph demonstrating “Fraction Probe Bound” for each concentration of NPR-C, where “probe” refers to the fluorescently labelled polypeptide. Fraction Probe Bound data was fitted (e.g. dose response inhibition curve) to produce an inhibitory curve from which half maximal inhibitory concentration values (IC50) were derived. The lower the fraction probe bound value, the more the polypeptide construct is outcompeting the fluorescent polypeptide or probe for binding to NPR-C. A plateau is reached once all fluorescent polypeptide or probe is unbound from available NPR-C receptors. The more left shifted the fitted curve, the higher the affinity of the polypeptide for the NPR-C receptor. Binding Assay Using HEK293 cells

[0184] HEK293 cells were transfected with NPR-C to produce HEK293 cells overexpressing NPR-C, according to the following methods. Briefly, HEK293 cells were transiently transfected with plasmid encoding human NPR-C receptor using Lipofectamine2000 (Invitrogen, cat # 11668027). Transfected HEK293 cells were allowed to express the NPR-C receptor for 24 hours prior to binding assays.

[0185] HEK293 cells that either did or did not overexpress NPR-C were rinsed in cold PBS buffer pH 7.4 with 0.5% BSA and incubated with either a fluorescently labeled polypeptide construct comprising an NPR-C ligand (e.g., POL-1-1), a commercially available rabbit NPR3 polyclonal antibody from Invitrogen (cat # PA5-120508) targeting the extracellular region of NPR-C receptor (AB-1), or a commercially available mouse NPR3 monoclonal antibody from Origene (cat # TA501021) targeting a non-surface exposed epitope on the NPR-C receptor (AB-2) at 4& for 20 minutes. HEK293 cells were then washed twice with cold PBS buffer pH 7.4 with 0.5% BSA. The HEK293 cells were further labeledPDMC +V%,&?D<FD?DGH&*&IC@GREDG?HE@ #1.85% / DHE@B@G?% ><M " +**-()$ MH LM<DG MC@ >@EE GN>E@D DGcold PBS buffer pH 7.4 with 0.5% BSA at 4& for 20 minutes. HEK293 cells bound by primary NPR3 antibodies were additionally stained with fluorescently labeled anti-mouse (FITC anti- mouse IgG2b Antibody from Biolegend, cat # 406705) or anti-rabbit (FITC Donkey anti-rabbit IgG (minimal x-reactivity) Antibody from Biolegend, cat # 406403) secondary antibodies in cold PBS pH 7.4 with 0.5% BSA at 4& for 20 minutes. HEK293 cells were then washed twice with cold PBS buffer pH 7.4 with 0.5% BSA and kept at 4&. Fluorescence intensity was measured using a flow cytometer and 2-3 replicates per sample. For each replicate, the median fluorescence intensity value was obtained and used as a normalized measure of fluorescence intensity.Peptide Internalization Assay Using HEK293 Cells and HEK293 Cells Stably Expressing NPR-C

[0186] HEK293 cells stably expressing NPR-C were generated by transfecting HEK293 cells with plasmid encoding human NPR-C receptor using Lipofectamine2000 (Invitrogen, cat # 11668027) and growing under selective pressure. Stably expressing NPR- C HEK293 cells were expanded and validated for NPR-C expression by western blot and flow cytometry.

[0187] HEK293 cells or HEK293 cells stably overexpressing NPR-C were initially incubated at 4°C with fluorescently labelled peptides (POL-1-1 and POL-1-15) at concentrations up to 1 µM in PBS buffer pH 7.4 with 0.5% BSA. The cells were incubated at 37°C for various timepoints up to 60 minutes to allow for NPR-C internalization. The cells were then moved back to 4°C to prevent further internalization. After several washes with the buffer, the cells were incubated in 50 mM glycine pH 3, 150 mM NaCl buffer to remove any peptides bound to the cell surface. The cells were analyzed on a flow cytometer. The internalized MFI (median fluorescence intensity) was calculated by subtracting the MFI measured from cells that were incubated at 37°C by the MFI measured from cells that were incubated only at 4°C. Peptide plasma stability

[0188] Stability of the peptides in mouse and cynomolgus monkey plasma was measured over time. Briefly, 2 µM peptide was incubated in heparin-treated mouse and cynomolgus monkey plasma for up to 24 hours at 37&. Samples were collected at timepoints 0, 0.5, 4, 8, 12 and 24hr. Collected samples were centrifuged and treated with organic solvent to stop the reaction and precipitate proteins. Supernatant was then quantified by liquid chromatography and mass spectrometry (LC / MS) with use of an internal standard. The amount of the peptide remaining at each timepoint was evaluated against the amount of the peptide in plasma at 0 minutes, which provides the fraction remaining at each of the later time points. These experiments are performed in triplicates. In vitro plasma half-life (t1 / 2) is calculated by fitting a one phase exponential decay curve and using the formula t1 / 2 = Ln(2) / K, wherein K is the slope in the linear fit of the natural logarithm of the fraction remaining of the construct or conjugate as a function of incubation time. Pharmacokinetic study

[0189] Pharmacokinetic stability of peptides in mice was assessed over time. Briefly, mice were injected with 1 mg / kg of peptide in 25 mM histidine pH 710% sucrose0.02% tween-80 in the tail vein. Blood was collected via saphenous vein in tubes containing 0.5 M EDTA-K2 as anti-coagulant at time points 0.083, 0.5, 1, 2, 4 and 12 hours. Collected samples were centrifuged and treated with organic solvent to stop the reaction and precipitate proteins. Supernatant was then quantified by liquid chromatography and mass spectrometry (LC / MS) with use of an internal standard. Samples were analysed to determine the amount of peptide remaining in each sample and calculate the T1 / 2 (h), Vdss (L / kg), and Cl(mL / min / kg). RT-qPCR Functional Assay in HEK293 cells

[0190] HEK293 cells were transiently transfected with a plasmid encoding human NPR-C receptor using Lipofectamine2000 (Invitrogen, cat # 11668027). Transfected HEK293 cells were cultured in Dulbecco's Modified Eagle Medium (DMEM from Wisent, cat # 319- 005-CL) supplemented with 10% fetal bovine serum (FBS from Wisent, cat # 080-150) and 1% Penicillin-Streptomycin (Wisent, cat # 450-200-EL). Cells were seeded in 96 well plates and either left untreated for 24 or 48 hours (untreated control groups), or were treated with one of several different siRNAs, or polypeptide constructs conjugated to a siRNA, and / or one or more small molecule compounds to promote endosomal escape (e.g. chloroquine) suspended in Opti-MEM media (ThermoFisher, cat # 31985062). Three or more biological replicates, each comprised of two technical replicates were tested, as further described below. Positive controls included siRNA and polypeptide constructs conjugated to siRNA transfected into HEK293 cells using Lipofectamine RNAimax Transfection Reagent (Invitrogen, cat # 13778075). Negative controls included untreated HEK293 cells and HEK293 cells treated with Lipofectamine RNAimax Transfection Reagent (Invitrogen, cat # 13778075) alone and HEK293 cells treated with “naked” siRNA in Opti-MEM media (ThermoFisher, cat # 31985062).

[0191] Following 24 or 48 hours, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA expression was measured according to the following methods. Briefly, the TaqMan Gene Expression Cells-to-CT Kit (ThermoFisher, cat # AM1729) was used to lyse HEK293 cells, generate cDNA, and run RT-qPCR. TaqMan kit Human GAPD (GAPDH) Endogenous Control (VIC™ / MGB probe, Applied Biosystems, cat # 4326317E) and TaqMan kit Human ACTB (Beta Actin) Endogenous Control (FAM™ / MGB probe, Applied Biosystems, cat # 4333762T) were used to measure the mRNA levels of GAPDH and housekeeping gene.0; / ' ;C@ >HFI<K<MDO@ JN<GMDAD><MDHG F@MCH? #*&WW0;$ P<L NL@? MH GHKF<EDS@ 3.814mRNA levels to housekeeping gene ACTB and to normalize across samples. TaqMan kitHuman NPR-C (VIC™ / MGB probe, Applied Biosystems, cat # 4448489) was used to confirm NPR-C expression in transfected HEK293 cells.

[0192] The treatments comprised one of the following siRNAs or siRNA-conjugates either alone or in combination with one or more of the following drugs: “naked” siRNA: siRNA comprising the nucleotide sequence according to SEQ ID NOs: 140 and 141, which is an siRNA against expression of GAPDH. “naked” siRNA was in Opti- MEM buffer (ThermoFisher, cat # 31985062) and was added to HEK293 cells at time 0 (T0; start of the 24h or 48h experiment) in a concentration of 20 nM. Any one of conjugates POL-1-7 to POL-1-10: a conjugate comprising a targeting polypeptide construct conjugated to the siRNA comprising the nucleotide sequence according to SEQ ID NOs: 140 and 141 in Opti-MEM buffer (ThermoFisher, cat # 31985062), which is an siRNA against expression of GAPDH was added to the HEK293 cells at T0 in a concentration of 10 µM. Lipo: Lipofectamine Transfection Reagent (Invitrogen, cat # 13778075) is a transfection agent that contains lipid subunits that can form liposomes. Lipofectamine was diluted in Opti-MEM buffer (ThermoFisher, cat # 31985062) and added to the siRNA or the conjugate in Opti-MEM buffer (ThermoFisher, cat # 31985062), and incubated for five minutes at room temperature. Complexed lipofectamine / siRNA (or conjugate) was added to the cell culture at T0 at a concentration of 20 nM for siRNA and 10 µM for polypeptide constructs conjugated to the siRNA . CQ: chloroquine is a drug that passively diffuses into endosomes and results in endosome rupture, and cytoplasmic release of the endosome’s cargo. Chloroquine was diluted in Dulbecco's Modified Eagle Medium (DMEM from Wisent, cat # 319-005-CL) supplemented with 10% fetal bovine serum (FBS from Wisent, cat # 080-150) and 1% Penicillin-Streptomycin (Wisent, cat # 450-200-EL) and was added to HEK293 cells at T0 at a concentration of 60 µM. miRNAscope staining of siRNA & siRNA-peptide conjugates in mouse kidney tissue

[0193] Mice were injected subcutaneously with 5 mg / kg of unconjugated siRNA (sequence disclosed) and peptide-siRNA conjugates (POL-1-10-4, POL-1-20-2, POL-1-28- 2, POL-1-33-2, POL-1-39-2; conjugated to an undisclosed siRNA sequence) formulated in PBS. Mice were sacrificed after 7 days and kidneys were extracted, sectioned, fixed with formalin and embedded with paraffin. Unconjugated siRNA and siRNA-peptide conjugates were detected using a miRNAscope probe to the siRNA (pink in figure).Fluorescence imaging of siRNA & siRNA-peptide conjugates

[0194] Mice were injected subcutaneously with 5 mg / kg of Cy5.5-labeled GAPDH siRNA (SEQ ID NO:195) or Cy5.5-labeled siRNA-peptide conjugates (POL-1-10-3, POL-1- 78-2, POL-1-80-2) formulated in PBS. After 6 and 168 hours, the mice were sacrificed and the fluorescence intensity was measured in the whole kidney. The kidney was then sectioned for tissue fluorescence imaging. Cy5.5 fluorescent intensity was quantified in the whole kidney and kidney cortex.

[0195] In repeat dosing experiments, mice were injected subcutaneously with 5 mg / kg of Cy5.5-labeled GAPDH siRNA (SEQ ID NO:195) or Cy5.5-labeled siRNA-peptide conjugates (POL-1-10-3, POL-1-78-2, POL-1-80-2) formulated in PBS in multiple intervals (every day and every 3 days). RT-qPCR mouse kidney tissue

[0196] Mice were injected subcutaneously with 5 mg / kg of unconjugated Cy5.5- labeled GAPDH siRNA (SEQ ID NO:195) or Cy5.5-labeled GAPDH siRNA-peptide conjugates (POL-1-10-3, POL-1-78-2, POL-1-80-2) formulated in PBS. After 7 days, mice were sacrificed and tissue punches taken from the kidney cortex, heart, liver, and bone for extraction of mRNA for GAPDH transcript level analysis using RT-qPCR. The comparativeJN<GMDAD><MDHG F@MCH? #*&WW0;$ P<L NL@? MH GHKF<EDS@ 3.814 F97. E@O@EL MHhousekeeping gene ACTB and to normalize across samples.

[0197] In repeat dosing experiments, mice were injected subcutaneously with 5 mg / kg of Cy5.5-labeled GAPDH siRNA (SEQ ID NO:195) or Cy5.5-labeled siRNA-peptide conjugates (POL-1-10-3, POL-1-78-2, POL-1-80-2) formulated in PBS in multiple intervals (every day and every 3 days). Statistical analyses

[0198] Statistical analyses were performed using GraphPad Prism. For pairwise comparisons, student t tests were used. One-way and two-way ANOVAs were also used as appropriate, and multiple comparisons were evaluated using the Dunnett’s post-hoc test for multiple comparisons. A p < 0.05 was considered to be significantly different. Results Immunohistochemistry staining of NPR-C in human and mouse kidney

[0199] NPR-C expression was assessed in human and mouse kidney tissues. In human kidney tissue, NPR-C staining in proximal tubules and mildly in theglomerulus, evident from the intensity of staining (FIG.1). In mouse kidney, strong NPR-C expression is observed in the cortex region and to a lesser degree in the medulla region of a coronal kidney slice (FIG.2A), with high intensity in proximal tubules and milder presence in the glomerulus (FIG.2B). Ligands Bind to NPR-C in a pH-Dependent Manner

[0200] Binding of fluorescently labelled ligands rANP 4-23 [des18-22] (POL-1-1) and Musc23 (POL-1-15) to human NPR-C was evaluated using a fluorescence polarization assay at different pH values. Binding of both rANP 4-23 [des18-22] and Musc23 to NPR-C was pH- dependent, wherein the more acidic the environment, the less affinity the ligand had for NPR- C (FIG.3, Table 6). Endosomes have a pH of roughly 5.0-6.5, and lysosomes have a pH of roughly 4.5-5.0. It is therefore likely that once the ligand binds NPR-C, and the NPR-C complex undergoes receptor-mediated endocytosis into an endosome, the ligand will begin to dissociate from NPR-C. Table 6 – Ligand binding at different pH pH Value POL-1-1POL-1-15 rANP 4-23 Musc23 [des18-22] 7.5 30.6 nM 27.6 nM6.0 90.4 nM 69.4 nM4.5 > 1 µM > 1 µMrANP 4-23 [des18-22] Is Selective for NPR-C and is Cross-Reactive with Mouse NPR-C

[0201] Binding of fluorescently labeled rANP 4-23 [des18-22] (POL-1-1) and its D- enantiomer (POL-1-3) to human NPR-C and natriuretic peptide receptor A (NPR-A) was evaluated using a fluorescence polarization assay. POL-1-1 was 140x more selective for NPR-C than NPR-A (FIG.4). The D-enantiomer (POL-1-3) did not significantly bind to either NPR-C or NPR-A.

[0202] Next, the binding of rANP 4-23 [des18-22] and its D-enantiomer with mouse NPR-C was assessed and compared to binding between these same peptides and human NPR-C. As seen in FIG.5, rANP 4-23 [des18-22] is cross-reactive to mouse NPR-C (17.66 nM vs 55.17 nM, with human and mouse NPR-C, respectively). The D-enantiomer did not notably bind with either the human or the mouse NPR-C. Inclusion of His-Sponge and Linker Does Not Interfere with NPR-C Binding Affinity

[0203] It was next assessed whether addition of the linker and the endosomal escape motif into a construct comprising the ligand would impact binding between the ligand and NPR-C. It was also examined whether placement of the endosomal escape motif (either on the N-terminus side or C-terminus side of the ligand) would impact binding of the ligand to NPR-C. Inclusion of the linker and the endosomal escape motif did not negatively impact binding between either rANP 4-23 [des18-22] or Musc23 and NPR-C (FIG.6). Further, the placement of the endosomal escape motif had no impact on ligand binding. The D- enantiomer of the rANP 4-23 [des18-22] ligand (POL-1-4) was used as a negative control, and the rANP 4-23 [des18-22] ligand-alone (POL-1-6) was used as a positive control. Novel Peptide Variants Exhibit a Range in Affinity for Human and Mouse NPR-C

[0204] Novel peptide variants were developed from the Musc23 parent peptide (SEQ ID NO: 2), incorporating point mutations, deletions, and side chain cyclizations. Select variants also included novel endosomal escape domains. Peptide candidates were evaluated for binding to human and mouse NPR-C, as shown in FIG.7, FIG.8, and Table 7. For human NPR-C, the peptides displayed a range of IC50 values. Variants POL-1-17, POL-1-20, POL- 1-24, POL-1-28, and POL-1-33 retained high binding affinity, comparable to the parent peptide POL-1-9-2, indicating that the introduced sequence changes did not negatively impact binding to human NPR-C and identifying these sequences as potential candidates for in vivo payload delivery to cells via NPR-C binding. Notably, POL-1-28 and POL-1-33 demonstrated the highest affinity (~15 nM), each carrying a single point mutation in the core sequence. In contrast, POL-1-23 and POL-1-31 showed moderate reductions in affinity. POL- 1-27 and POL-1-35 exhibited substantial decreases in binding, suggesting these particular sequence modifications were detrimental to human NPR-C binding.

[0205] Addition of novel endosomal escape domains to the Musc23 parent peptide was also assessed. Peptides POL-1-38, POL-1-39 each contained a novel endosomal escape motif located on the N-terminus of the core sequence. POL-1-40 contained the same endosomal escape domain as POL-1-38, but positioned on the C-terminus of the core sequence. POL-1-38 and POL-1-40 did not bind human NPR-C at concentrations up to 2500 nM, indicating this particular endosomal escape domain prevented binding of the core sequence to human NPR-C. Notably, POL-1-38 and POL-1-40 exhibited lower solubility than POL-1-10-2 and POL-1-39. However, POL-1-39 exhibited binding to human NPR-C with an IC50 of 222 nM, corresponding to a 16-fold decrease in affinity compared to the His-sponge- containing variant POL-1-10-2.

[0206] Binding affinity to mouse NPR-C showed a similar pattern. Peptides POL-1- 17, POL-1-20, POL-1-28, and POL-1-33 maintained strong binding, consistent with the human NPR-C results. POL-1-23 and POL-1-31 showed moderate reductions in affinity, while POL-1-27 displayed a significant decrease. Peptides not assessed for mouse NPR-C binding are denoted as "nt" in Table 7. POL-1-39, which includes a novel endosomal escape domain, bound mouse NPR-C with an IC50 of 18.2 nM, a 5-fold reduction in binding relative to POL-1-10-2.

[0207] To evaluate the combined impact of a novel endosomal escape and a core sequence change, the endosomal escape domain present in POL-1-39 was combined with the point mutation from POL-1-28 to generate POL-1-80. This construct was tested alongside POL-1-78, a control lacking NPR-C binding, and the reference sequence POL-1-10-2 (Musc23 with His-sponge), as shown in FIG.9 and Table 7. POL-1-78 exhibited no binding to human NPR-C up to 5000 nM, indicating that the novel endosomal escape domain alone does not contribute to NPR-C binding. POL-1-80 demonstrated an IC50 of 79.1 nM for human NPR-C, only a 6-fold reduction in affinity compared to POL-1-10-2, identifying POL-1-80 as a potential candidate for payload delivery to cells via NPR-C binding. Table 7 - Peptide Ligand Binding to Human and Mouse NPR-C Internal ID Human IC50 Mouse IC50 (nM) (nM) POL-1-9-2 14.6 2.4 POL-1-10-2 13.9 3.6 POL-1-16 >10000 7608.0 POL-1-17 16.7 5.0 POL-1-20 17.3 3.1 POL-1-23 45.7 12.8 POL-1-24 17.8 nt POL-1-27 838.7 208.3 POL-1-28 15.5 4.3 POL-1-31 39.5 13.1 POL-1-33 15.4 5.5 POL-1-35 469.5 nt POL-1-38 >2500 nt POL-1-39 221.7 18.2 POL-1-40 >4500 ntPOL-1-78 >5000 ntPOL-1-80 79.1 nt Peptide Ligands Bind and Internalize in Cells Expressing NPR-C

[0208] Whether rANP 4-23 [des18-22] could bind NPR-C cells present on the cellular membranes of HEK293 cells was assessed using the fluorescently tagged rANP 4-23 [des18- 22] ligand (POL-1-1, SEQ ID NO:1 with Alexa Fluor 488 at N-terminus and NH2 at C- terminus). As can be seen in the comparison of the top left and right panel of FIG.10A, rANP 4-23 [des18-22] (POL-1-1, SEQ ID NO:1 with Alexa Fluor 488 at N-terminus and NH2 at C- terminus) bound HEK293 cells in a manner dependent on the amount of NPR-C expressed on the surface of HEK293 cells (FIG.10A, top left and right panels). This pattern was similar to that observed for rabbit NPR3 polyclonal antibody from Invitrogen (cat # PA5-120508) (Ab1; FIG.10A, bottom left and right panels). These results are quantified in FIG.10B. Note that no such NPR-C-driven increase in binding was seen for Ab2, a mouse NPR3 monoclonal antibody from Origene (cat # TA501021) targeting a non-surface exposed epitope on the NPR-C receptor. These initial results demonstrated that the NPR-C receptor is amenable to payload delivery via receptor-mediated endocytosis, and highlighted the NPR-C binding ligand POL-1-1 as a viable candidate for targeted delivery to NPR-C–expressing cells.

[0209] To further characterize NPR-C–mediated internalization of bound peptide ligands, both the internalization capacity and rate were assessed in HEK293 cells stably overexpressing NPR-C (FIG.11, FIG.12). Increasing concentrations of NPR-C ligands POL- 1-1 (SEQ ID NO: 1 with Alexa Fluor 488 at the N-terminus and NH# at the C-terminus) and POL-1-15 (SEQ ID NO: 2 with Alexa Fluor 488 at the N-terminus and a methylamide group at the C-terminus) showed minimal internalization in parental HEK293 cells (FIG. 11A). In contrast, both peptides showed robust, concentration-dependent internalization in NPR-C overexpressing cells, with uptake reaching a plateau at approximately 333 nM (FIG.11B). A non-NPR-C binding peptide (Unrelated peptide) was used as a negative control and showed no significant internalization. These results confirm that internalization of POL-1-1 and POL- 1-15 is mediated specifically by NPR-C and occurs in a saturable manner, supporting the use of NPR-C binders for targeted payload delivery to NPR-C–expressing cells.

[0210] In a time-course study, internalization of POL-1-1 and POL-1-15 was monitored in NPR-C–expressing HEK293 cells over 60 minutes (FIG. 12). Both ligands exhibited rapid internalization, reaching a plateau by approximately 30 minutes. The non- binding control peptide again showed no internalization. These findings furtherdemonstrate that NPR-C binding ligands enable efficient and time-dependent cellular uptake, reinforcing their potential for delivering therapeutic payloads to NPR-C expressing cells. Peptide Stability in Mouse and Cynomolgus Monkey Plasma

[0211] NPR-C ligands were assessed for plasma stability in both mouse and cynomolgus plasma over time. Table 8 lists the % intact peptide after 30 minutes, 4 hours, and 24 hours incubation in mouse plasma at 37&. Peptides contain a NPR-C binding sequence, linker domain, optionally an endosomal escape domain, and a crosslinker 6- azidohexanoic acid at N-terminus and either NH2 or methylamide (NHCH3) at C-terminus. Peptides containing rANP 4-23 [des18-22] core sequence (SEQ ID NO:1) including both POL-1-7-2 and POL-1-8-2 exhibit poorer plasma stability than peptides containing Musc23 core sequence (SEQ ID NO:2) including POL-1-9-2 and POL-1-10-2. These results identified the Musc23 core sequence as the likely better candidate for in vivo studies.

[0212] Musc23 based peptides POL-1-10-2 (SEQ ID NO:96), POL-1-38 (SEQ ID NO:120), POL-1-39 (SEQ ID NO:121), POL-1-40 (SEQ ID NO:122) all contain an endosomal escape domain and show enhanced mouse plasma stability over Musc23 based peptide POL-1-9-2 which lacks an endosomal escape domain (SEQ ID NO:94), indicating the presence of the endosomal escape domain improves mouse plasma stability of Musc23 based peptides.

[0213] Musc23 based peptides lacking an endosomal escape domain show a range in plasma stability dependent on the sequence. Notably, peptides POL-1-17 (SEQ ID NO:100), POL-1-23 (SEQ ID NO:106), POL-1-27 (SEQ ID NO:109), POL-1-28 (SEQ ID NO:110), POL-1-31 (SEQ ID NO:113), POL-1-33 (SEQ ID NO:115), POL-1-35 (SEQ ID NO:117) all show enhanced mouse plasma stability compared to POL-1-9-2 indicating these specific sequence changes improve mouse plasma stability of Musc23 based peptides. POL- 1-20 and POL-1-24 showed decreased mouse plasma stability relative to POL-1-9-2 indicating these specific sequence changes are detrimental to mouse plasma stability and likely should be avoided for in vivo studies. Table 8 - Peptide stability in mouse plasma Mouse % Mouse % Mouse % Internal ID intact 30 min intact 4 hrs intact 24 hrs POL-1-7-2 17.6 0 0 POL-1-8-2 0 0 0 POL-1-9-2 98.4 94.1 71.6POL-1-10-2 123.5 108.6 92.7POL-1-16 82 45.8 22.2POL-1-17 102.6 112.8 91.5 POL-1-20 87.7 91.7 67POL-1-23 112.9 105.8 77.2POL-1-24 101.3 96.9 66.4 POL-1-27 100.5 100.7 86.1 POL-1-28 100.3 105.6 91.7 POL-1-31 101.4 105.7 103.9 POL-1-33 88.5 114.1 95.7 POL-1-35 104.1 99.1 92.3 POL-1-38 102.6 107.4 97.4 POL-1-39 95.7 97.7 101 POL-1-40 105.6 96.2 98.4

[0214] Table 9 lists the % intact peptide after 30 minutes, 4 hours, and 24 hours incubation in cynomolgus monkey plasma at 37&. All peptides in Table 9 contain the same NPR-C binding sequence, and vary in linker domain and endosomal escape domain. All peptides contain the crosslinker 6-azidohexanoic acid at N-terminus and methylamide (NHCH3) at C-terminus.

[0215] POL-1-10-2 (SEQ ID NO:96), POL-1-38 / 40 (SEQ ID NOs: 120 and 122 respectively), and POL-1-39 (SEQ ID NO:121) all contain different endosomal escape domains. The endosomal escape domain in sequence POL-1-39 (the endosomal escape domain of SEQ ID NO: 87) imparts a significantly higher plasma stability relative to the other endosomal escape domains.

[0216] POL-1-38 and POL-1-40 contain the same endosomal escape domain but located to different termini of the sequence. Minimal impact of endosomal escape domain position on SEQ ID NO: 78) with methylamide (NHCH3) at C-terminus and crosslinker 6- azidohexanoic acid at the N-terminus plasma stability is observed. Table 9 - Peptide stability in cynomolgus monkey plasma Cyno % intact Cyno % Cyno % Internal ID 30 min intact 4 hrs intact 24 hrsPOL-1-10-2 117.6 98.4 40.8POL-1-38 109.7 102.2 58.4POL-1-39 121.9 127.6 85.2POL-1-40 112.1 108.4 60.2

[0217] FIG.13 depicts the % intact peptide over time in mouse plasma for a selection of peptides from Table 8. POL-1-8-2 comprises SEQ ID NO: 77 with NH2 at C-terminus and crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-9-2 comprises the SEQ ID NO: 76 with methylamide (NHCH3) at C-terminus and crosslinker 6-azidohexanoic acid at the N- terminus. POL-1-10-2 comprises SEQ ID NO: 78 with methylamide (NHCH3) at C-terminus and crosslinker 6-azidohexanoic acid at the N-terminus. POL-1-16 to POL-1-33 all comprise a NPR-C binding domain, a linker, and a crosslinker 6-azidohexanoic acid at N-terminus and methylamide (NHCH3) at C-terminus. POL-1-39 comprises a NPR-C binding domain, an endosomal escape domain, a linker, and a crosslinker 6-azidohexanoic acid at N-terminus and methylamide (NHCH3) at C-terminus. POL-1-8-2 and POL-1-16 are significantly less stable than the other peptides. Peptide Pharmacokinetic stability in mice

[0218] Table 10 lists the quantity of POL-1-9-2 and POL-1-10-2 remaining in circulation at 0.083, 0.5, 1, 2, 4 and 12 hours post 1mg / kg tail vein injection in mice as measured by liquid chromatography and mass spectrometry (LC / MS). Table 10 lists the Initial Plasma Concentration (C0, ng / mL) Elimination Half-Life (T1 / 2, min), Volume of Distribution at Steady State (Vdss, L / kg), Clearance (Cl, mL / min / kg), Time of Last Quantifiable Concentration (Tlast, min), Area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-last, ng.h / mL), and Mean Residence Time up to the last quantifiable time point (MRT0-last, min) of POL-1-9-2 and POL-1-10-2. POL-1-10-2 contains an endosomal escape domain, whereas POL-1-9-2 does not. POL-1-9-2 showed a higher initial plasma concentration (C" = 7212 ng / mL) than POL-1-10-2 (2116 ng / mL), indicating greater immediate systemic exposure. However, POL-1-9-2 had a significantly shorter half-life (9.8 min vs. 19 min), lower volume of distribution (0.26 vs. 0.55 L / kg), and shorter terminal exposure (Tlast = 1 h vs.2 h), suggesting faster clearance and limited tissue distribution compared to POL-1-10-2. Despite a higher AUC"-last (1364 vs. 630 ng·h / mL), POL-1-9-2's exposure was driven by its high C", whereas POL-1-10-2 exhibited longer mean residence times (MRT"-last = 0.33 h vs. 0.20 h), indicating more sustained systemic presence. These findings suggest that inclusion of the endosomal escape domain improved pharmacokinetic elimination half-life, terminal exposure window, and mean residence time, which promotes longer retention in vivo. Table 10 - Peptide pharmacokinetic micePK Parameters POL-1-9-2 POL-1-10-2 C0 (ng / mL) 7212 2116 T1 / 2 (min) 9.8 19.0 Vdss (L / kg) 0.26 0.55 Cl(mL / min / kg) 20.2 26.2 Tlast (min) 60 120 AUC0-last (ng.h / mL) 1364 630 MRT0-last (min) 12 19.8 NPR-C Binding Persists with Addition of siRNA Payload

[0219] Next, it was assessed whether conjugating the constructs to an siRNA payload would impact binding between the ligand and NPR-C. When the constructs comprised both a linker and an endosomal escape motif positioned between the ligand and the siRNA payload, the binding of the ligand was comparable to the rANP 4-23 [des18-22] ligand-alone, for both rANP 4-23 [des18-22] (POL-1-8) and Musc23 (POL-1- 10; FIG.14). However, when the constructs comprised only a linker and no endosomal escape motif between the siRNA payload and the ligand, there was reduced binding between the ligand and NPR-C for both rANP 4-23 [des18-22] (POL-1-7) and Musc23 (POL-1-9; FIG.14), though binding persisted for both. Targeting Polypeptide Conjugates Are Internalized, Payloads Are Functional and Persist 24 and 48 Hours

[0220] Conjugates comprising a targeting polypeptide construct and a payload are significantly larger than the constructs-alone. For example, POL-1-11, which included a linker, an endosomal escape motif, and rANP 4-23 [des18-22] had a molecular weight of 3.6K g / mol, whereas the conjugate comprising the same construct and an siRNA payload had a molecular weight of 19.3K g / mol. It was therefore next assessed whether the conjugates comprising the targeting polypeptide constructs and the siRNA payload could be internalized in HEK293 cells overexpressing NPR-C, through receptor-mediated endocytosis. As can be observed FIG.15 and FIG.16A (at 24 hours and 48 hours, respectively), each of conjugates POL-1-7 to POL-1-10 resulted in decreased expression of GAPDH, the polypeptide whose expression was targeted by the siRNA in these constructs. This reduction varied between roughly 20% and roughly 40%, depending on the conjugate and the time point. This resultwas not seen when only the siRNA against GAPDH expression (“naked” siRNA”) was added to the cell culture, indicating that the constructs were likely internalized into the HEK293 cells.

[0221] Further, when the HEK293 cells were treated with chloroquine to rupture the endosomes, there was further knockdown of GAPDH expression for each of conjugates POL- 1-7 to POL-1-10 after 24 hours and 48 hours (FIG.15 and FIG.16B, respectively), indicating that the conjugates were present in HEK293 endosomes. The knockdown was by roughly 60% at 24 hours when chloroquine was added as compared to untreated HEK293 cells.

[0222] As a positive control, lipofectamine complexed to conjugates or siRNA was added to HEK293 cell cultures. Lipofectamine can introduce the conjugates or siRNA into the cell independent of NPR-C binding and receptor-mediated endocytosis. As can be seen in FIG. 15, this resulted in further reduction of GAPDH expression at 24 hours, but a comparable reduction of GAPDH expression at 48 hours when compared to use of the conjugates and chloroquine (FIG.16A and 16B). These results indicate that the conjugation of the polypeptide and linker and / or endosomal escape domain to the siRNA does not negatively impact the siRNA function within the cytoplasm of the cell. Peptide-siRNA Conjugates Exhibit Significant Uptake in Mouse Kidney After 6 Hours and 7 days

[0223] To evaluate in vivo uptake of peptide–siRNA conjugates in mouse kidney, peptides that demonstrated high plasma stability and strong NPR-C binding were conjugated to a non-disclosed siRNA sequence. Localization was assessed using miRNAscope staining with a probe complementary to the siRNA sequence, performed on tissue slices taken after seven days post subcutaneous administration. Mice received 5 mg / kg of either unconjugated siRNA (FIG.17A) or siRNA conjugated to NPR-C-targeting peptides: POL-1-10-4 (FIG.17B), POL-1-20-2 (FIG. 17C), POL-1-28-2 (FIG. 17D), POL-1-33-2 (FIG. 17E), and POL-1-39-2 (FIG.17F). Compared to the unconjugated control, all peptide–siRNA conjugates exhibited enhanced kidney staining, particularly within the cortex and proximal tubules. Glomeruli are indicated by dashed outlines. Notably, peptides incorporating both a linker and an endosomal escape domain, POL-1-10-4 (FIG. 17B) and POL-1-39-2 (FIG. 17F), showed the highest degree of staining intensity in the kidney. These results demonstrated that NPR-C binding peptides substantially increased siRNA delivery to kidney proximal tubule cells compared to unconjugated siRNA. Furthermore, the inclusion of an endosomal escape domain promoted increased kidney uptake in vivo relative to peptide-siRNA conjugates lacking an endosomal escape domain..

[0224] To enable quantitative assessment of kidney localization, two of the top NPR- C binding peptides incorporating endosomal escape domains, along with a non-binding control, were conjugated to a Cy5.5-labeled GAPDH-targeting siRNA (SEQ ID NO: 195). Mice were administered 5 mg / kg of either unconjugated siRNA, POL-1-10-3, POL-1-78-2, or POL-1-80-2 via subcutaneous injection. Kidney tissues were harvested and imaged for Cy5.5 fluorescence at 6 and 168 hours (7 days) post-injection (FIG.18A). Conjugate uptake was concentrated in the kidney cortex, with pronounced signal in proximal tubule cells. Peptide- siRNA conjugates POL-1-10-3 and POL-1-80-2 exhibited significantly greater kidney accumulation relative to both the unconjugated siRNA and the non-NPR-C-binding conjugate, POL-1-78-2.

[0225] Quantitative analysis of fluorescence intensity in the kidney cortex (FIG.18B) revealed a 866-fold increase for POL-1-10-3 and a 1131-fold increase for POL-1-80-2 compared to unconjugated siRNA after 7 days. Relative to POL-1-78-2, POL-1-10-3 showed a 6.6-fold increase, while POL-1-80-2 achieved an 8.6-fold increase in kidney signal after 7 days. Notably, POL-1-80-2 displayed a 1.4-fold enhancement in signal over POL-1-10-3, indicating the combination of novel endosomal escape domain and core sequence change in POL-1-80-2 improved kidney targeting and delivery in vivo. Overall these findings demonstrate that NPR-C-targeting peptide-siRNA conjugates enable selective, and prolonged uptake and delivery to kidney proximal tubule cells following systemic administration, with POL-1-80-2 showing the best overall kidney delivery.

[0226] Repeat dosing experiments, show increased uptake of Cy5.5-labeled siRNA- peptide conjugates (POL-1-10-3 and POL-1-80-2) in the glomerulus relative to Cy5.5-labeled siRNA alone and non-NPR-C binding peptide-siRNA conjugate POL-1-78-2.

[0227] Peptide-siRNA conjugates containing an albumin binding domain exhibit increased uptake in the glomerulus relative to Cy5.5-labeled siRNA alone and non-NPR-C binding peptide-siRNA conjugate POL-1-78-2. Peptide-siRNA Conjugates Promote Knockdown of GAPDH Transcripts in Mouse Kidney

[0228] Ability of Cy5.5-labeled siRNA-peptide conjugates to deliver functional siRNA to mouse kidney in vivo was assessed 7 days post subcutaneous injection of 5 mg / kg conjugate. NPR-C binding peptide-siRNA conjugates containing a linker and endosomal escape domain, POL-1-10-3 and POL-1-80-2, show significant knockdown of GAPDH mRNA transcript in kidney relative to non-NPR-C binding peptide-siRNA conjugate POL-1-78-3 and Cy5.5-labeled siRNA alone.

[0229] Repeat dosing experiments, Cy5.5-labeled siRNA-peptide conjugates (POL-1- 10-3 and POL-1-80-2) show increased knockdown of GAPDH transcripts in mouse kidney after 7 days relative to Cy5.5-labeled siRNA alone and non-NPR-C binding peptide-siRNA conjugate POL-1-78-2.

[0230] Peptide-siRNA conjugates containing an albumin binding domain exhibit increased knockdown of GAPDH transcripts in mouse kidney after 7 days relative to Cy5.5- labeled siRNA alone and non-NPR-C binding peptide-siRNA conjugate POL-1-78-2.

[0231] While the present disclosure has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

[0232] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present description is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.CITATIONS FOR REFERENCES REFERRED TO IN THE SPECIFICATION Maack T, Suzuki M, Almeida FA, et al., Physiological role of silent receptors of atrial natriuretic factor, Science (1987), 238(4827):675-8. Nishizawa N, Nakamura G, Noguchi Y et al., A potent and selective natriuretic peptide receptor-3 blocker 11-mer peptide created by hybridization of musclin and atrial natriuretic peptide, Bioorg Med Chem Lett (2017), 27(15):3542-3545. Remington's Pharmaceutical Sciences, 22nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at the University of the Sciences, 2012).

Claims

Claims:

1. A polypeptide construct for targeted delivery of a payload comprising a natriuretic peptide receptor C (NPR-C) ligand operably linked to a linker, wherein the NPR-C ligand comprises a polypeptide comprising an amino acid sequence represented by: (F / f / c / s / E62 / H52 / D15 / y) (S / s / e / B50) (J92 / E26 / SAR / s) (A61 / A99 / F / B16 / C71 / E65) (s / SAR / D19 / G)0-1(B83 / G / bALA / SAR / J43 / G60 / G77) (A64 / G39 / SAR / H30 / E76 / C) (I / E14 / H16 / NLE) (D / B38 / d / I14) (R / E80 / B33 / B48 / E66) (I / H16 / E82 / E94) (SEQ ID NO:389).

2. A polypeptide construct for targeted delivery of a payload comprising a natriuretic peptide receptor C (NPR-C) ligand operably linked to a linker, wherein the NPR-C ligand comprises: 1 a polypeptide comprising the amino acid sequence according to any one of SEQ ID NOs: 15, 1-14, 16-66 and 196-245; 1 a polypeptide comprising an amino acid sequence with at least about 75%, 80%, 85%, 90%, or 95%, sequence identity over its entire length to any one of SEQ ID NOs: 15, 1-14, 16-66 and 196-245; or 1 a polypeptide comprising a conservatively substituted amino acid sequence of any one of SEQ ID NOs: 15, 1-14, 16-66 and 196-245.

3. The polypeptide construct of claim 1 or 2, wherein the NPR-C ligand comprises a polypeptide comprising an amino acid sequence represented by: (F / f / c) (S / s) J92 A99 s0-1(G / A64 / B38 / G77) (A64 / E76) (I / NLE / H16) (D / I14) E80 (I / H16 / E82) (SEQ ID NO: 390).

4. The polypeptide construct of any one of claims 1 to 3, wherein the linker comprises a plurality of N-methylated amino acid residues.

5. The polypeptide construct of claim 4, wherein the plurality of N-methylated amino acid residues comprises at least one sarcosine residue.

6. The polypeptide construct of any one of claims 1 to 5, wherein the linker comprises amino acid sequence SEQ ID NO: 67-76.

7. The polypeptide construct of any one of claims 1 to 6, wherein the linker is a flexible linker.

8. The polypeptide construct of any one of claims 1 to 7, comprising an amino acid sequence according to any one of SEQ ID NOs: 93, 94, 99-118, 123-155, 162-171 and 246-295.

9. The polypeptide construct of any one of claims 1 to 7, further comprising an endosomal escape motif operably linked to the NPR-C ligand.

10. The polypeptide construct of claim 9, wherein the endosomal escape motif comprises a proton sponge, a membrane active peptide, a pH sensitive peptide, a cell penetrating peptide, a hydrophobic region, or a combination thereof.

11. The polypeptide construct of claim 10, wherein the proton sponge is a his-sponge, optionally comprising two or more histidine residues.

12. The polypeptide construct of claim 9 or 11, wherein the endosomal escape motif comprises an amino acid sequence selected from SEQ ID NOs: 77-92.

13. The polypeptide construct of any one of claims 9 to 12, wherein the endosomal escape motif is located on the N-terminus side or the C-terminus side of the NPR-C ligand.

14. The polypeptide construct of any one of claims 9 to 13, comprising an amino acid sequence according to any one of SEQ ID NOs: 95-98, 119-122, 156-161, 172-192 and 296-384.

15. The polypeptide construct of any one of claims 1 to 14, wherein the linker is conjugated to the payload.

16. The polypeptide construct of claim 15, wherein the linker is conjugated to the payload by a crosslinker, an amide bond, an ester bond, a hydrazone bond, a carbonate bond, an oxime bond, a disulphide bond, a triazole linkage, or a thioether linkage.

17. The polypeptide construct of claim 16, wherein the crosslinker comprises succinimidyl 3-(2-pyridyldithio)propionate and a thiol, an azide and terminal alkyneor strained alkyne, a thiol and a thiol, a thiol and a maleimide, an amine and a maleimide, or an alcohol and a carbonate group.

18. The polypeptide construct of any one of claims 15 to 17, wherein the payload comprises a small interfering RNA (siRNA), an antisense oligonucleotide (ASO), a microRNA (miRNA), a small molecule, a polypeptide or a radioisotope.

19. The polypeptide construct of claim 18, wherein the payload comprises the siRNA.

20. A conjugate comprising the polypeptide construct as defined in any one of claims 1 to 14 conjugated to the payload as defined in claim 18 or 19.

21. A composition comprising the polypeptide construct of any one of claims 15 to 19 or the conjugate of claim 20 and a pharmaceutically acceptable carrier.

22. A kit comprising the polypeptide construct of any one of claims 1 to 14 and a crosslinker.

23. A method of treating a disease or injury of NPR-C expressing cells in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the polypeptide construct as defined in any one of claims 15-19, the conjugate as defined in claim 20, or the composition as defined is claim 21.

24. The method of claim 23, wherein the payload targets expression of a target gene and / or activity of a target protein.

25. The method of claim 23, wherein the payload targets expression of a gene and / or activity of a protein upstream and / or downstream of a target protein.

26. The method of claim 24 or 25, wherein the target gene has increased transcription, a gain-of-function mutation or is duplicated.

27. The method of any one of claims 23 to 26, wherein the disease or injury of NPR-C expressing cells comprises a disease or injury of the kidney.

28. The method of claim 27, wherein the disease or injury of the kidney comprises a glomerulopathy, a podocytopathy, a proximal tubular disorder, a renal amyloidosis, a vascular disorder, an acute or chronic kidney disease, or a combination thereof.

29. The method of claim 27 or 28, wherein the disease or injury of the kidney comprises membranous nephropathy (MN), diabetic nephropathy, focal segmental glomerulosclerosis (FGSF), thin basement membrane disease (TBMN), light-chain deposition disease (LCDD), HIV nephropathy, Alport syndrome, drug-induced glomerulopathies, minimal-change disease (MCD), lupus nephritis, anti-glomerular basement membrane disease, IgA nephropathy (Berger’s Disease), membranoproliferative Glomerulonephritis (MPGN), Polycystic Kidney Disease (PKD), Phenylketonuria (PKU) or a combination thereof.

30. The method of claim 27 or 28, wherein the disease or injury of the kidney comprises focal segmental glomerulosclerosis (FSGS) and / or diabetic nephropathy.

31. The method of any one of claims 27 to 30, wherein the disease or injury of the kidney comprises disease or injury of proximal tubules, podocytes, mesangial and / or endothelial cells.

32. The method of any one of claims 23 to 26, wherein the disease or injury of the NPR- C expressing cells comprises a disease or injury of peripheral organ systems due to renal malfunction.

33. The method of claim 32, wherein the disease or injury of peripheral organ systems comprises metabolic acidosis, mineral and bone disorders, anemia, and / or cardiorenal syndrome.

34. The method of any one of claims 23 to 33, wherein the polypeptide construct or conjugate is administered intravenously, through subcutaneous injection, or through intra- arterial administration.

35. The method of any one of claims 23 to 34, wherein the polypeptide construct or conjugate is administered in a single dose.

36. The method of any one of claims 23 to 34, wherein the polypeptide construct or conjugate is administered in repeat doses.

37. The method of any one of claims 23 to 36, wherein the subject is a human.

38. The method of any one of claims 23 to 37, wherein the payload targets expression and / or the activity of transient receptor potassium channel 6 (TRPC6), apolipoprotein A1 (APOL1), alpha actinin-4 (ACTN4), solute carrier family 22 member 2 (SLC22A2 / OCT2), solute carrier family 5 member 2 (SGLT2) or sodium-dependent neutral amino acid transporter B(0)AT1.

39. The method of any one of claims 23 to 38, wherein the polypeptide construct or the conjugate is comprised in a pharmaceutical composition, optionally further comprising a pharmaceutically acceptable carrier or diluent.

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