Stable peptides having renalase agonist activity

Abstract

To provide stable peptides that have renalase agonist activity and are useful for treating diseases such as AKI and AP, including those relating to SARS-CoV-2.SOLUTION: Provided is a peptide comprising R-X220-Ile221-Arg222-Phe223-Val234-Ser225-Ile226-Asp227-Asn228-Lys229-R', wherein the superscripts represent positions within the renalase A chain (1-342), R is selected from Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac-, Ac-Z, H-, H-Z, B-Z-, and B, wherein Z is selected from one or more of the amino acid residues at positions 205-219 of the renalase A chain, R' is selected from -NH2, Z'-NH2, -B, and Z'-B, wherein Z' is selected from one or more of the amino acid residues at positions 230-253 of the renalase A chain, B is PEG or bis-PEG, and X is the residue of an amino acid.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference of Sequence Listing Submitted via EFS-Web The contents of the ASCII text file of the sequence listing named "8712-0001WO SEQUENCE LISTING_seq_ST25" with a size of 70 kb, created on May 21, 2021 and electronically submitted simultaneously with the application via EFS-Web, are hereby incorporated by reference in their entirety.

[0002] Cross-reference of Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 032,055, filed May 29, 2020, which is hereby incorporated by reference in its entirety.

[0003] The present disclosure relates to stable peptides that exhibit tissue-protective activity and are useful for treating kidney or pancreatic diseases such as acute kidney injury or acute pancreatic injury, particularly kidney diseases or pancreatic injuries associated with or exacerbated by SARS-CoV-2.

Background Art

[0004] The following discussion is provided solely to assist the reader's understanding of the present disclosure and is not admitted to explain or constitute prior art thereof.

[0005] Renalase (RNLS) is secreted by the kidney and has multiple biological functions. See, for example, Patent Documents 1, 2, 3, 4, and 5 (International Patent Application No. US18 / 67608), which are hereby incorporated by reference in their entirety as if fully reproduced herein. Administration of recombinant or biologically isolated renalase has been shown to treat certain diseases and conditions, as described in Patent Documents 4 and Non-Patent Document 1 above. RNLS has been shown to prevent acute kidney injury independent of its oxidase function by the cell signaling mechanism (Non-Patent Document 1).

[0006] Acute kidney injury (AKI) and acute pancreatitis (AP) are each seen in at least 1 / 3 and 1 / 5 of hospitalized COVID-19 patients, respectively, and occur more frequently in severe disease. Renalase (RNLS) is an endogenous circulating protein that potently increases cell survival and reduces inflammation to treat kidney diseases such as AKI and / or AP.

[0007] However, the synthesis and administration of the entire Renalase chain A are cumbersome and expensive and can result in complex pharmacological properties due to both oxidase function and cell signaling function (Non-Patent Document 1). A stable synthetic peptide that exhibits Renalase agonist activity, particularly having a cell signaling tissue repair function, is highly desired. The present disclosure provides such a peptide.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Non-Patent Documents

[0009]

Non-Patent Document 1

Summary of the Invention

[0010] The present invention relates to a novel peptide derived from Renalase chain A (1-342) (SEQ ID NO: 1) shown in FIG. 1. The peptide is <Chemical Formula 1> [Chemical formula] and <Chemical formula 2> [Chemical formula] and at least containing residues 220 - 229 of renallase A(1 - 342) substituted by residues of amino acids selected from 220 Cys In Chemical formula 1, R 1 and R 2 are independently H, C1 - C8 n - alkyl optionally substituted by a hydroxyl group, C3 - C8 branched alkyl optionally substituted by a hydroxyl group, C4 - C8 dibranched alkyl optionally substituted by a hydroxyl group, C3 - C6 cycloalkyl optionally substituted by a hydroxyl group or a methyl group or both at one or more arbitrary positions and including all structurally realizable stereoisomers thereof, CH2 - C3 - C6 cycloalkyl optionally substituted by a hydroxyl group or a methyl group or both at one or more arbitrary positions, R 1 and R 2 are optionally (CH2) n linked to each other and may be substituted at any position by a methyl group or a hydroxyl group or both, n is 2, 3, 4 or 5, In Chemical formula 2, Y is (CH2) nThe carbon atom bonded to the amino group is optionally substituted at any one or more positions by a methyl group, a hydroxyl group, or both, provided that the carbon atom can be substituted only by a methyl group, and includes all diastereomeric forms that are structurally feasible, cis- or trans-1,2-cyclopropanediyl, cis- or trans-1,2-cyclobutanediyl, cis- or trans-1,3-cyclobutanediyl, cis- or trans-1,2-cyclopentanediyl, cis- or trans-1,3-cyclopentanediyl, cis- or trans-1,2-cyclohexanediyl, cis- or trans-1,3-cyclohexanediyl, or cis- or trans-1,4-cyclohexanediyl.

[0011] This modification improves the biological potency of the peptides and stabilizes them by potential in situ dimerization and / or oligomerization. Preferably, X 220 is selected from Ser, Ala, Leu, Val, Ile, Nle, β-Ala, Aib, cyclopropyl-glycine, and (cyclopropylmethyl)-glycine.

[0012] Additional amino acid residues may be added to the NH2-terminus of X corresponding to some or all of the amino acid residues in positions 205 - 219 of the sequence of lenarase A shown at the corresponding position in Figure 1, or to the COOH-terminus of Lys corresponding to some or all of the amino acid residues in positions 230 - 253 of the sequence of lenarase A shown at the corresponding position in Figure 1. Further, a long chain of poly(ethylene) glycol [PEG] or bis-poly(ethylene) glycol (bis-PEG) with a varying average molecular weight (e.g., 5000 - 20000 amu), or a similar polymer known in the art (as described below), may be attached to the NH2-terminus of X or the NH2-terminus of the long fragment side, or to the COOH-terminus of Lys 220 or the COOH-terminus of the long fragment side. 229 220 229

[0013] ​​​The expression "corresponding to some or all of the amino acid residues in the sequence from positions 205 to 219 of renalarase A" means that the added amino acid residues can be included from position 219 in the sequence, from positions 218 and 219, from positions 217 to 219, from positions 216 to 219, etc., up to positions 205 to 219. Similarly, the expression "corresponding to some or all of the amino acid residues in the sequence from positions 230 to 253 of renalarase A" means that the added amino acid residues can be included from position 230 in the sequence, from positions 230 - 231, from positions 230 to 232, etc., up to positions 230 to 253.

[0014] The present disclosure also provides methods for treating kidney diseases including AKI, AP, and kidney diseases caused by SARS-CoV-2.

Brief Description of the Drawings

[0015]

Figure 1

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Mode for Carrying Out the Invention

[0016] Synthetic peptides, pharmaceutical compositions containing peptides, and methods for treating human diseases using synthetic peptides and pharmaceutical compositions are provided by the present disclosure.

[0017] The inventors discovered that specific peptide fragments within the sequence of renallase chain A exhibit renallase agonist activity. However, they also discovered that these peptides are unstable and thus not suitable for use as therapeutic agents. The inventors discovered that the instability of the peptide fragments can be eliminated by substituting the cysteine residue at position 220 of renallase chain A (1-342) with appropriately selected different amino acids. Furthermore, the modified peptide fragments increased in potency compared to the unmodified fragments.

[0018] The amino acid at position 220 is <Chemical Formula 3>

Chem.

Chem.

[0019] The peptide of the present invention has positions 220 to 229 having X as described above 220 and includes a fragment of renin A containing additional amino acids at appropriate positions of renin A on one or both sides of positions 220 to 229, and the peptide generally varies in length from about 49 amino acids to about 20 amino acid residues and may be longer as needed.

[0020] Furthermore, as is known in the pharmaceutical art, poly(ethylene) glycol (PEG) or bis-poly(ethylene) glycol (bis-PEG) of various average molecular weights (e.g., 500 - 20,000 amu) can be attached to either end of a peptide to promote the long-term activity of the peptide. Poly(ethylene) glycol is an amphiphilic polymer consisting of repeating units of ethylene oxide that can associate into linear or branched structures to give various PEGs with different configurations and molecular weights. PEG needs to be activated to be covalently attached to the appropriate sites of biopharmaceutical compounds (including peptides and proteins) to thereby improve their pharmacological and pharmaceutical properties. In addition to improving solubility, conjugation with PEG protects biopharmaceutical compounds from the host immune system, thereby reducing immunogenicity and antigenicity and extending the biological half-life. The resulting PEGylated pharmaceuticals can be used at reduced doses and frequencies without sacrificing efficacy. PEG is available in various average molecular weights and can be functionalized at one end (the other end is usually protected as methoxy). Alternatively, both ends of the polymer can be functionalized to yield homo- or hetero-bifunctional derivatives that can be used to link two moieties. A review of first- and second-generation PEG derivatives with more diverse and efficient functional groups for conjugation to peptides and proteins is described in Roberts, Adv. Drug Deliv. Rev. 54, 459 (2002). Third-generation PEGylation agents with branched polymers have been developed and may offer additional advantages of protecting proteins from proteolysis and further reducing immunogenicity and antigenicity. [PEG] is commonly used for conjugation to peptides and proteins, but other appropriately functionalized polymers with suitable flexibility, including but not limited to those containing carbohydrate moieties, can also be used and have been reviewed by Sola and Griebenow, J. Pharm. Sci. 98, 1223 (2009) and Witteloostuijn, Pedersen, and Jensen, ChemMedChem, 11, 4 (2016), both of which are incorporated herein by reference.

[0021] The amino acids selected for substitution at position 220 of the peptide of the present invention include glycine, serine, alanine, leucine, valine, isoleucine, norleucine, beta-alanine, cyclopropyl-glycine, (cyclopropylmethyl)-glycine and other hydrophobic amino acids, as well as the D-amino acid enantiomers of the amino acids described. Furthermore, Lys 229 may be substituted with its D-isomer to provide additional stability. Lys 205 , Arg 222 , Lys 230 and / or Arg 231 Other amino acids containing may also be substituted with the corresponding D-amino acids for a similar enhancement of stability against enzymatic degradation.

[0022] In one embodiment, a peptide containing R-X 220 -Ile 221 -Arg 222 -Phe 223 -Val 234 -Ser 225 -Ile 226 -Asp 227 -Asn 228 -Lys 229 -R', where the superscript represents the position within the renin A chain (1-342), R is selected from Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac-, Ac-Z, H-, H-Z, B-Z- and B, Z is selected from one or more of the amino acid residues at positions 205-219 of the renin A chain, R' is selected from -NH2, Z'-NH2, -B and Z'-B, Z' is selected from one or more of the amino acid residues at positions 230-253 of the renin A chain, B is PEG or bis-PEG, and X is, <Chemical formula 5>

Chemical formula

Chemical formula

[0023] In another embodiment, the sequence R-Lys 205 -Ile 206 -Asp 207 -Val 208 -Pro 209 -Trp 210 -Ala 211 -Gly 212 -Gln 213 -Tyr 214 -Ile 215 -Thr216 -Ser 217 -Asn 218 -Pro 219 -X 220 -Ile 221 -Arg 222 -Phe 223 -Val 234 -Ser 225 -Ile 226 -Asp 227 -Asn 228 -Lys 229 -Lys 230 -Arg 231 -Asn 232 -Ile 233 -Glu 234 -Ser 235 -Ser 236 -Glu 237 -Ile 238 -Gly 239 -Pro 240 -Ser 241 -Leu 242 -Val 243 -Ile 244 -His 245 -Thr 246 -Thr 247 -Val 248 -Pro 249 -Phe 250 -Gly 251 -Val 252 -Thr 253 A peptide having -R’ is provided, wherein R is selected from Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac-, H- and PEG, and R’ is selected from -Tyr-Leu-Glu-NH2, Tyr-Leu-NH2, -Tyr-NH2, -NH2, -OH and PEG, and X 220 is selected from Gly, Ser, Ala, Leu, Val, Ile, Nle, β-Ala, cyclopropyl-Gyl, (cyclopropylmethyl)-Gly and Aib.

[0024] Thus, the peptide of the present invention is [X 220 -Ac-renalase A(205~240)-NH2 (SEQ ID NO: 2), [X 220-Ac-renallase A(214~253)-NH2(SEQ ID NO: 3), [X 220 -Ac-renallase A(214~240)-NH2(SEQ ID NO: 4) and [X 220 -Ac-renallase A(205~253)-NH2(SEQ ID NO: 5), wherein X is selected from glycine, serine, alanine, leucine, valine, isoleucine, norleucine, cyclopropyl-glycine, (cyclopropylmethyl)-glycine and beta-alanine.

[0025] Representative compounds of the present invention include, without limitation, [Ala 220 -Ac-renallase A(205~240)-NH2(SEQ ID NO: 6), [Ala 220 -Ac-renallase A(214~253)-NH2(SEQ ID NO: 7), [Ala 220 -Ac-renallase A(214~240)-NH2(SEQ ID NO: 8), [Ala 220 -Ac-renallase A(205~253)-NH2(SEQ ID NO: 9), [Val 220 -Ac-renallase A(214~240)-NH2(SEQ ID NO: 10), [Ser 220 -Ac-renallase A(214~253)-NH2(SEQ ID NO: 11), [Ala 220 ,D-Lys 229 -Ac-renallase A(205~240)-NH2(SEQ ID NO: 12), [Ser 220 -Ac-renallase A(205~240)-NH2(SEQ ID NO: 13), [Ala 220 -Ac-renallase A(214~234)-NH2(SEQ ID NO: 14), [Ala 220 -Ac-renallase A(220~239)-NH2(SEQ ID NO: 15), [Gly 220 -Ac-renallase A(205~240)-NH2(SEQ ID NO: 16), [Gly 220 -Ac-Renalase A(214 - 253)-NH2 (SEQ ID NO: 17), [Cyclopropyl-Gly 220 -Ac-Renalase A(205 - 253)-NH2 (SEQ ID NO: 18), [(Cyclopropylmethyl)-Gly 220 -Ac-Renalase A(214 - 240)-NH2 (SEQ ID NO: 19) is included.

[0026] A typical example of the PEGylated peptide of the present invention is [Bis-PEG 5000 -Lys 205 -Ile 206 -Asp 207 -Val 208 -Pro 209 -Trp 210 -Ala 211 -Gly 212 -Gln 213 -Tyr 214 -Ile 215 -Thr 216 -Ser 217 -Asn 218 -Pro 219 -Ala 220 -Ile 221 -Arg 222 -Phe 223 -Val 234 -Ser 225 -Ile 226 -Asp 227 -Asn 228 -Lys 229 -Lys 230 -Arg 231 -Asn 232 -Ile 233 -Glu 234 -Ser 235 -Ser 236 -Glu 237 -Ile 238 -Gly 239 -Pro 240 -NH2 (SEQ ID NO: 20).

[0027] Peptides are generally prepared using solid-phase synthesis as described by Merrifield, J. Am. Chem. Soc. 85, 2149 (1963), although other equivalent chemical syntheses, including solution-phase synthesis or biological production using recombinant techniques, well known to those skilled in the art, may be used. Solid-phase synthesis is initiated from the C-terminus of the peptide by coupling an NH2-protected amino acid to a suitable resin. The starting material is N アルファ The COOH terminus of an N-9-fluorenylmethoxycarbonyl (Fmoc) amino acid is prepared by attaching it to a commercially available 4,4'-dimethoxybenzhydryl-amine, (Mbh)-handle linked to the solid-phase resin. Solid-phase synthesis and coupling with Fmoc-amino acids (including appropriately protected side chains for trifunctional amino acids) proceeded by stepwise elongation of the desired peptide chain using a reaction mediated by carbodiimide / HOBt. Final cleavage of the side-chain protecting groups and liberation of the C-terminal amide moiety were achieved by treatment with trifluoroacetic acid in the presence of scavengers. The peptide was purified by preparative high-performance liquid chromatography (purity ≥ 95%) and characterized by amino acid analysis and mass spectrometry. Specific details regarding the synthesis of this peptide are provided below.

[0028] As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. "Consisting essentially of" is used to define compositions and methods and is intended to mean excluding any other elements that are essential to the composition or method. "Consisting of" is intended to mean excluding other materials in excess of trace amounts of the claimed composition and substantial steps of the method. Embodiments defined by each of these transitional terms are within the scope of this disclosure. Thus, the methods and compositions may include additional steps and components (comprising), or alternatively, may include non-essential steps and components (consisting essentially of), or alternatively, may be intended to include only the recited steps of the method or composition (consisting of).

[0029] As used herein, "about" means ±10%.

[0030] As used herein, "optional" or "optionally" means that the subsequently described event or situation may or may not occur, and the description includes examples where the above-described event or situation occurs and examples where it does not occur.

[0031] As used herein, the terms "individual", "patient" or "subject" can be an individual organism, a vertebrate, a mammal (e.g., a cow, a dog, a cat or a horse) or a human. In a preferred embodiment, the individual, patient or subject is a human.

[0032] As used herein, the phrases "therapeutically effective amount" and "therapeutic level" each mean the peptide dosage or plasma concentration in a subject that provides a particular pharmacological effect when the peptide is administered to a subject in need of such treatment, i.e., a treatment that reduces, alleviates or eliminates the effects or symptoms of a renal disease. It is emphasized that the therapeutically effective amount or therapeutic level of a drug is not always effective for the treatment of the conditions / diseases described herein, even if such dosage is considered by those skilled in the art to be a therapeutically effective amount. The therapeutically effective amount can vary based on, among other factors, the route and form of administration, the age and weight of the subject, and / or the condition of the subject, including the type and stage of amyloidosis at the time treatment is initiated.

[0033] As used herein in connection with renal disease, the terms "treatment" or "treating" refer to reducing, alleviating or eliminating one or more symptoms or effects of a disease or condition.

[0034] "Therapeutic response" means an improvement in at least one measure of a renal disease.

[0035] As used herein, the term "pharmaceutically acceptable carrier" means a material for admixture with a pharmaceutical compound (e.g., a chimeric peptide) for administration to a patient, as described, for example, in the 10th edition (2014) of "Ansel’s Pharmaceutical Dosage Forms and Delivery Systems".

[0036] Abbreviations The following abbreviations are used herein: "Ac" is acetyl, -NH2 is amide (-CO -NH 2), AKI is acute kidney injury, AP is acute pancreatitis, PMCA4b is plasma membrane ATPase 4b, and RNLS is renalase.

[0037] Amino acids are represented as follows by the abbreviations of the IUPAC: alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C), glutamine (Gln; Q), glutamic acid (Glu; E), glycine (Gly; G), histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), valine (Val; V), norleucine (Nle), and 2-aminobutyric acid (Aib).

[0038] The expression "[X 220 -Ac-renalase A(205~240)-NH2" means a peptide containing the amino acids at positions 205 to 240 of renalase A, the amino acid "X" at position 220, the acyl group at the NH2 terminus of the peptide, and the amide group at the COOH terminus. Thus, this peptide is Ac-Lys 205 -Ile 206 -Asp 207 -Val 208 -Pro 209 -Trp 210 -Ala 211 -Gly 212 -Gln213 -Tyr 214 -Ile 215 -Thr 216 -Ser 217 -Asn 218 -Pro 219 -X 220 -Ile 221 -Arg 222 -Phe 223 -Val 234 -Ser 225 -Ile 226 -Asp 227 -Asn 228 -Lys 229 -Lys 230 -Arg 231 -Asn 232 -Ile 233 -Glu 234 -Ser 235 -Ser 236 -Glu 237 -Ile 238 -Gly 239 -Pro 240 -NH2 (SEQ ID NO: 6). When X is Ala, this compound is sometimes referred to herein as "peptide 10" or "BP-1002".

[0039] Similar expressions for other peptides of the present invention have corresponding meanings.

[0040] Pharmaceutical formulations A pharmaceutical composition suitable for use in the methods described herein may contain one or more of the disclosed peptides and a pharmaceutically acceptable carrier or diluent.

[0041] The composition can be formulated for intravenous, subcutaneous, intraperitoneal, intramuscular, topical, oral, buccal, nasal, pulmonary or inhalation, intraocular, vaginal or rectal administration. In certain embodiments, the peptide is formulated for intravenous, subcutaneous, intraperitoneal, intramuscular administration, or for targeted tissue delivery in solutions, suspensions, emulsions, liposome formulations, etc. The pharmaceutical composition can be formulated using techniques known in the art to be an immediate release composition, a sustained release composition, a delayed release composition, etc.

[0042] Pharmacologically acceptable carriers for various dosage forms are known in the art. For example, excipients, lubricants, binders, and disintegrants for solid preparations are known, and solvents, solubilizers, suspending agents, isotonic agents, buffering agents, and soothing agents for liquid preparations are known. In certain embodiments, the pharmaceutical composition includes one or more additional components such as one or more preservatives, antioxidants, stabilizers, and the like.

[0043] Furthermore, the disclosed pharmaceutical composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentrations. The carrier can be a solvent or a dispersion medium including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. In certain embodiments, it is preferred that the composition includes an isotonic agent, for example, sugars, polyhydric alcohols such as mannitol, sorbitol, or sodium chloride. The long-term absorption of injectable compositions can be effected by including in the composition an agent that delays absorption, for example, monostearate or gelatin.

[0044] An injectable sterile solution can be prepared by incorporating the required amount of the active compound into a suitable solvent by one or a combination of the raw materials listed above, and subsequently, if necessary, by performing sterile microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the other necessary raw materials listed above. In the case of sterile powders for the preparation of injectable sterile solutions, suitable preparation methods are vacuum drying and freeze-drying (lyophilization), which obtain the powders of the active ingredient and any additional desired ingredients from their pre-sterile filtered solutions.

[0045] The pharmaceutical compositions of the present disclosure can be administered in combination with other therapeutic agents that are part of the current standard treatment for kidney disease, pancreatic disease, or tissue injury, particularly those that can benefit from the modulation of excessive immune inflammation. For example, fenoldopam, which was discovered as a selective dopamine 1 receptor agonist, has been utilized with respect to acute kidney injury and can be used in treatment together with the subject peptide.

[0046] Method of treatment In the present invention, at least one peptide is administered to patients (e.g., human patients) suffering from kidney diseases including AKI and AP. In certain embodiments, a therapeutically effective amount of the peptide is administered together with a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers are known in the art as described below. Common routes of administration are parenteral (e.g., intravenous, subcutaneous, or intramuscular), as would be well understood by those of ordinary skill in the medical arts. Other routes of administration are, of course, possible. Administration can be effected by single or multiple administrations. The amount of peptide administered and the frequency of dosing can be optimized by a physician for a particular patient.

[0047] SARS-CoV-2 virus infection causes pathological conditions and mortality and shows a selective pattern of tissue damage. Acute inflammatory injury occurring in specific tissues can spread and seed throughout the body, leading to multiple organ failure and death. For example, an important feature of severe acute pancreatitis is the development of multiple organ injury in the lungs and kidneys, which are the leading secondary affected tissues. Kidney injury also occurs in the onset of less severe acute pancreatitis, but in this situation, it recovers rapidly. The link between injury in one organ leading to other dysfunctions is relevant to numerous types of acute injury and this proposal. Some important COVID-19 patients, especially those with severe diseases, are expected to show a distinct pattern of tissue damage. SARS-CoV-2 infection can also damage the kidneys, and its most prominent effect is on the proximal tubules, which are the sites of renalarase (RNLS) synthesis. SARS-CoV-2 infection of the kidneys is expected to reduce circulating RNLS levels, which primes the target tissues for damage by the virus and other factors. We expect that the kidneys and pancreas are important pathological targets and that the decrease in plasma RNLS levels increases kidney injury and primes the pancreas for AP. Injury to these organs further reduces plasma RNLS levels, driving a negative feedback loop.

[0048] Clinical studies indicate that both kidney injury and acute pancreatitis frequently occur in SARS-CoV-2 infection. Clinical studies of the natural course of SARS-CoV-2 infection have just begun, but clear patterns of injury are emerging. In a limited study of 55 patients, evidence of acute pancreatitis was observed in 17%, and there was an 8% incidence of renal dysfunction. This cohort of inpatients appeared to have mostly moderate rather than severe disease. Other studies have reported that blood creatinine levels in COVID-19 patients correlate with severity, and the incidence of kidney injury in COVID-19 patients has been reported to be up to one-third of inpatients. Among 52 patients with severe SARS-CoV-2 infection, 17% required dialysis. The presence of underlying kidney disease, a condition associated with reduced plasma RNLS levels, significantly increases the risk of death from SARS-CoV-2. Damage to proximal tubular cells, the site of RNLS production, by SARS-COV-2 has been reported in pathological studies.

[0049] Inflammatory response to SARS-CoV-2 infection Based on clinical findings, the pathogenesis of SARS-CoV-2 can be divided into the following stages: (I) initial viral response, (II) pulmonary disease phase, and (III) hyperinflammatory stage. One study that recorded the time course of these responses in patients with mild to severe SARS-CoV-2 pathogenesis found a significant increase in serum IL6 levels throughout the two-week period only in patients with severe disease. Elevated plasma IL6 is relevant in that it serves as a marker of AP severity and can cause damage to the kidneys. IL6 and its precursor IL1 are being investigated in treatment trials for SARS-CoV-2 infection. Other observations include that interferon-gamma (IFN-gamma) levels, which are thought to be important in the control of viral infection, were suppressed in both mild and severe disease.

[0050] Renalase functions as a survival-promoting factor in AKI and AP models. RNLS is a 37-kD secreted protein mainly produced by renal proximal tubular cells, but also produced in other tissues. Its main intracellular target is the widely distributed plasma membrane calcium efflux transporter, plasma membrane calcium ATPase 4b (PMCA4b). Activation of PMCA4b is required for the protective function of RNLS in cell AP models and other tissues. Through the use of selective PMCA4b inhibitors and gene deletion models, we found that PMCA4b is required for RNLS to have protective cellular effects.

[0051] A method of treating kidney diseases, including kidney diseases associated with SARS-CoV-2, AKI and AP, in a patient (e.g., a human patient) in need of such treatment, comprising administering to the patient an effective amount of one or more of the disclosed peptides together with a pharmaceutically acceptable carrier, is provided herein.

[0052] Therapeutically effective dosages and dosing regimens In certain embodiments, the therapeutically effective dosage of the peptide can be administered 1, 2, 3, or 4 times or less within a 3-month period.

[0053] The therapeutically effective dosages and dosing regimens of the foregoing methods can vary as would be readily understood by one of ordinary skill in the art. The dosing regimen can be adjusted to provide the optimal desired response. For example, in certain embodiments, a single dose of the peptide may be administered, while in certain embodiments, doses divided over several times may be administered over time, and the dose may be proportionally reduced or increased in subsequent dosings as indicated by the circumstances. For example, in certain embodiments, the disclosed peptides can be administered once or twice a week by subcutaneous, intravenous, or intramuscular injection. In certain embodiments, the disclosed peptides can be administered once or twice a month by subcutaneous, intravenous, or intramuscular infusion. In certain embodiments, the disclosed peptides can be administered once or twice a year by subcutaneous, intravenous, or intramuscular infusion. In certain embodiments, the disclosed peptides can be administered once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, twice a year, or once a year as indicated by the patient's circumstances or condition.

[0054] The therapeutically effective dose of the peptide administered to the patient (whether administered as a single dose or multiple doses) should be sufficient to treat kidney disease or AP. Such a therapeutically effective amount can be determined by evaluating the change in symptoms in the patient.

[0055] Exemplary dosages can vary depending on the size and health of the individual being treated and the condition being treated. In certain embodiments, an effective amount of the disclosed peptide is about 2200 mg, however, in certain situations, the dosage can be higher or lower. In certain embodiments, a therapeutically effective amount can be 50 - 5000 mg, 60 - 4500 mg, 70 - 4000 mg, 80 - 3500 mg, 90 - 3000 mg, 100 - 2500 mg, 150 - 2000 mg, 200 - 1500 mg, 250 - 1000 mg or any dosage therebetween. For example, in certain embodiments, a therapeutically effective amount can be about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100, about 3200, about 3300, about 3400, about 3500, about 3600, about 3700, about 3800, about 3900, about 4000, about 4100, about 4200, about 4300, about 4400, about 4500, about 4600, about 4700, about 4800, about 4900, about 5000 mg or more.

[0056] Similarly, in certain embodiments, an effective amount of the peptide is about 25 mg / kg, however, in certain embodiments, the concentration can be higher or lower. In certain embodiments, an effective amount can be about 1 - 50 mg / kg, about 5 - 40 mg / kg, about 10 - 30 mg / kg or about 15 - 25 mg / kg or any value therebetween. For example, in certain embodiments, an effective amount can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg / kg or more.

[0057] The disclosed method of treatment can also be combined with other known methods of treatment, as the situation may require. For example, a lenalase agonist may counteract the potential "cytokine storm" that leads to excessive tissue damage and death in SARS-CoV-2 and potentially other respiratory viral diseases. For example, the H1N1 pandemic resulted in extensive kidney damage. The following examples reflect SARS-CoV-2 according to the current literature.

[0058] Potential drug combinations

Table 1-1

Table 1-2

[0059] The therapeutically effective dosages and dosing regimens of the foregoing methods can vary as readily understood by one of ordinary skill in the art. The dosing regimen can be adjusted to provide the optimal desired response. For example, in certain embodiments, a single bolus dose of the peptide may be administered, while in certain embodiments, divided doses over several times may be administered over time, and the dose may be proportionally decreased or increased in subsequent dosings as indicated by the situation. For example, in certain embodiments, the disclosed peptide can be administered once or twice a week by subcutaneous, intravenous, or intramuscular injection. In certain embodiments, the disclosed peptide can be administered once or twice a month by subcutaneous, intravenous, or intramuscular injection. In certain embodiments, the disclosed peptide can be administered once or twice a year by subcutaneous, intravenous, or intramuscular injection. In certain embodiments, the disclosed peptide can be administered once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, twice a year, or once a year by subcutaneous, intravenous, or intramuscular injection as indicated by the patient's situation or condition.

[0060] Example: Peptide Synthesis The peptide was synthesized on a ChemMatrix Rink Amide resin using a standard Fmoc-synthesis protocol in an APEX396 automatic synthesizer. For the removal of the Fmoc protecting group, the resin was swollen with N,N-dimethylformamide (DMF) for 30 minutes, treated with 20% piperidine-DMF at 50 °C for 8 minutes, and washed three times with DMF. For the coupling reaction, the Fmoc-protected amino acid, 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), diisopropyl-carbodiimide (DCI), and N-methyl-2-pyrrolidine (NMP) were added to the resin. The mixture was vortexed at 50 °C for 20 minutes. Then, the resin was washed once with DMF. The cycle of Fmoc deprotection and coupling steps was repeated until the last amino acid residue was coupled. After the removal of the last Fmoc protecting group, the resin was treated with 20% acetic anhydride-NMP for 20 minutes, and then washed with DMF and dichloromethane (DCM) and air-dried. The peptide was cleaved from the resin using a trifluoroacetic acid (TFA) cocktail [95% TFA, 2.5% water, and 2.5% triisopropylsilane (TIS)] for 3 hours. The crude peptide was precipitated by adding ice-cold anhydrous ethyl ether, washed three times with anhydrous ethyl ether, and dried under vacuum. Some specific representative examples of synthesis are given below.

[0061] [Ala 220 -Ac-renalase A(205 - 240)-CONH2 (Peptide 10): It was synthesized by solid-phase synthesis outlined above. It was confirmed to have a purity of over 95% by high-performance liquid chromatography (HPLC), and confirmed by mass spectrometry and amino acid analysis.

[0062] [Ser 220 -Ac-renalase A(205 - 240)-CONH2: It was synthesized by solid-phase synthesis outlined above. It was confirmed to have a purity of over 95% by high-performance liquid chromatography (HPLC), and confirmed by mass spectrometry and amino acid analysis.

[0063] [Ala 220 -Ac-Renalase A(214~240)-CONH2: Synthesized by solid-phase synthesis as outlined above. Confirmed to have a purity of 95% or more by high-performance liquid chromatography (HPLC), and confirmed by mass spectrometry and amino acid analysis.

[0064] Ac-Renalase A(205~240)-CONH2: Synthesized by solid-phase synthesis as outlined above. Confirmed to have a purity of 95% or more by high-performance liquid chromatography (HPLC), and confirmed by mass spectrometry and amino acid analysis.

[0065] [Ala 220 -Ac-Renalase A(205~253)-CONH2: Synthesized by solid-phase synthesis as outlined above. Confirmed to have a purity of 95% or more by high-performance liquid chromatography (HPLC), and confirmed by mass spectrometry and amino acid analysis.

[0066] Ac-Renalase A(205~240)-OH (Peptide 81): Synthesized by solid-phase synthesis as outlined above using 2-chlorotrityl-resin instead of Rink-Amide resin. Confirmed to have a purity of 95% or more by high-performance liquid chromatography (HPLC), and confirmed by mass spectrometry and amino acid analysis.

[0067] Example Test Reduction of damage in experimental AP by renalase agonist: RNLS agonist [Ala 220-Ac-renalase A(205 - 240)-NH2(peptide 10) showed promising and dramatic effects on the AP reaction (Figure 2). Although we did not find an effect on the earliest reactions associated with acinar cells (not shown), the later reactions (6 hours), which are mostly mediated by inflammatory cells, were such that peptide 10 was able to reduce the active trypsin level (A in Figure 2) and dramatically reduce tissue neutrophils (B in Figure 2), and as determined by the OPA-1 and Parkin levels, showed a reduction in mitochondrial damage (C, D in Figure 2). From this, it is suggested that peptide 10 has a very large impact on reducing pancreatitis damage regarding the events after the first 1 - 2 hours of AP. This probably represents the inhibition of a central inflammatory pathway in the etiology of AP, and a possible target is inflammatory activation (Figure 5). Most AP patients have a long-term presence after the onset of the disease, and the subsequent onset reaction is most important for determining the severity of AP. Therefore, the beneficial effect of peptide 10 should be therapeutically valuable even in the later stages of the disease. Against this background, we have shown that the RNLS agonist reduces damage when administered 2 hours after the onset of cerulein AP and 12 hours after the induction of arginine AP.

[0068] Reduction of damage in a renal model by an RNLS peptide agonist: We have found that the RNLS peptide agonist is also protective in a model of renal injury. We have shown that the peptide [Ala 220 -Ac-renalase A(205 - 240)-NH2 of the present invention eliminates cisplatin-induced injury in cultured kidney cells. In Figure 3, we show that this peptide reduces damage in a cultured proximal tubule cell line. We have also shown that this RNLS agonist peptide reduces renal ischemia-reperfusion injury in a preclinical mouse model (Figure 3). Data for such RNLS agonists are shown below.

[0069] Figure 4 shows that the RNLS agonist, renallase A(205 - 240)-OH (peptide 81), reduces kidney injury after cisplatin-induced treatment. An important measure of this toxicity is the decrease in kidney mass, which is limited when renallase A(205 - 240)-OH is administered. The effect of the peptide on the decline in kidney function seen in cisplatin-induced kidney injury is more dramatic. As seen in the right panel of Figure 4, plasma creatinine levels increased four-fold 17 days after cisplatin treatment, and the RNLS agonist decreased this towards the normal range. This preliminary data suggests that the RNLS agonist can reduce damage to kidney cells and is effective also in an in vivo AKI model.

[0070] RNLS agonist, [Ala 220 -Ac-renallase A(205 - 240)-NH2 reduces COVID19-induced innate immune response (Figure 5): We have found that RNLS agonists can have anti-inflammatory effects. The amplification of the inflammatory response mediates severe pancreatitis, kidney injury, and SARS-CoV-2 infection. In the case of SARS-CoV-2, these can be induced by the response to viral antigens. To address this problem, we exposed blood from healthy donors to a mixture of peptides contained in three major SARS-CoV-2 capsid proteins (SARS-CoV-2 proteins S, M, or N) from Miltenyi Biotec at a concentration of 0.19 nM in blood samples. To this, a buffer control or the RNLS peptide was added at 50 μg / ml. After 3 hours of incubation, the samples were assayed for cytokine production by ELISA and compared by two-way analysis of variance / Turkey's comparison (2way ANOVA / Turkey’s comparison). As shown in Figure 5, the SARS-CoV-2 peptides stimulated the cytokine response to varying degrees, with peptides S and M giving strong responses for each reaction (P<0.01), while there was little response with peptide N (not shown). Both SARS-CoV-2 peptides S and M increased the levels of interferon-gamma, and this response was dramatically reduced by the RNLS agonist [Ala 220 -Ac-renalase A(205~240)-NH2. Since interferon-gamma is thought to be important for the suppression of viral growth, the effects of this RNLS agonist need to be avoided, as described below. However, other potentially beneficial effects were observed. Thus, [Ala 220 -Ac-renalase A(205~240)-NH2, peptide 10, inhibited the increase in SARS-CoV-2-peptide-induced TNF-alpha as well as IL1-beta and IL6 (p<0.01). These innate immune responses are involved in causing damage to both the kidney and the pancreas. They are also judged to be central to the hyperinflammatory state that characterizes severe SARS-CoV-2 infection and results in many deaths.

[0071] The RNLS agonist [Ala 220-Ac-Lenalase A(205 - 240)-NH2 exhibits anti-inflammatory activity as determined by carrageenan-induced paw edema.

[0072] This test serves as a rapid in vivo model for evaluating the anti-inflammatory efficacy of test substances. The CPE model in mice quantitatively assesses the suppression of edema induced by intradermal injection of carrageenan into the plantar surface of the foot. The standard test period is 6 hours, with edema measured at 0, 2, 4, and 6 hours, and the results here consider the observation time as 10 hours. Carrageenan-induced inflammation is accompanied by the migration of polymorphonuclear leukocytes from the circulating blood to the site of inflammation. Subsequently, myeloperoxidase and other cytokines are released within the interstitial tissue, and plasma exudes into the site of inflammation. The increased paw volume is measured by the water displacement method. Anti-inflammatory drugs reduce paw edema. The results shown in Figures 6 and 7 (the same data in two different formats) indicate that Peptide 10, [Ala 220 -Ac-Lenalase A(205 - 240)-NH2 has an anti-inflammatory effect in this model.

[0073] Procedure 1. Receive 125 CD-1 mice (Charles River Laboratories, male, 5 - 6 weeks old) (SOP1910, SOP1920) and quarantine them (SOP560). 2. Tag the animals (SOP810), measure their body weights, and classify them into 9 groups of 10 mice / group and 5 groups of 7 mice / group based on the average body weight. 3. Prepare a 3% carrageenan solution. 1) Prepare it more than 2 weeks before use. 2) Weigh 600 mg of λ-carrageenan into a glass beaker. 3) Add 20 ml of deionized water. 4) Stir with gentle heating until the carrageenan is completely dissolved. 5) Cool the solution to room temperature. 6) Store at 4 - 8 °C. 4. Store the lenalase peptide as a dry powder at -20 °C until the day of use. 5. Day 0 a. Prepare the test substance with sterile saline (vehicle). b. Dissolve the lenalase peptide on the day of dosing. c. On the day before administration, check the carrageenan solution for clarity (absence of visible signs of contamination). 1) Equilibrate the carrageenan to room temperature. d. Record the body weight of the mice in the experimental notebook. e. Measure and record the initial volume of the plantar. 1) Place a beaker filled with water on the balance and zero the tare. 2) Place the right hind limb on the beaker filled with water on the scale so that the upper part of the ankle joint is at the center of the water meniscus. Record the value displayed on the scale. 3) Since the measurement value changes if the foot is wet, dry the foot after each measurement. 4) Zero the tare of the scale during the measurement, taking into account the decrease in the volume of water. f. Administer the vehicle and the test substance at 10 mg / kg by subcutaneous (SC, SOP1610) injection 30 minutes before the administration of carrageenan, as shown in Table 1.

Table 2

[0074] A test was conducted to compare the suppression of inflammation by Peptide 10 as compared to the corresponding peptide fragment without alanine substitution at position 220 (Peptide 81). The results are shown in Figures 8 and 9 and Table 2 below. The numerical values represent the rate of change from the control, and * means <<0.05 statistical significance.

Table 3

[0075] This result is for Peptide 10, [Ala 220-Ac-Renalase A(205 - 240)-NH2 has higher activity and more persistent activity than peptide 81, Ac-Renalase A(205 - 240)-OH, indicating that this is not inconsistent with peptide 10 being more stable than peptide 81. Note that peptide 10 had activity similar to that of standard dexamethasone and indomethacin. This result is from comparable but different experiments conducted by the same group with the same protocol but different drugs. For example, note that both peptide 10 and peptide 81 were active at 2 hours, but only peptide 10 remained active over a longer period of time.

[0076] Furthermore, as shown in Figure 10, the decrease in renalase activity correlates with an increase in mortality in COVID-19. However, as shown in Figures 11 - 14, treatment with the renalase agonist BP-1002 has beneficial effects on COVID-19, other infections, and inflammation.

[0077] All references cited herein are hereby incorporated by reference as if fully set forth herein.

[0078] In the description and claims of this specification, the word "comprise" and variations such as "comprises" and "comprising" are not intended to exclude other features, additions, components, integers, or steps. Rather, unless otherwise specified, the scope of these words should be construed broadly to have an inclusive rather than an exclusive meaning.

[0079] The compositions and methods of the present invention are described as illustrative examples in this disclosure, but the present invention is not limited thereto. It should be understood that modifications can be made without departing from the teachings of the present invention as defined by the appended claims, as is well known to those skilled in the art.

Claims

1. R-X ２２０ -Ile ２２１ -Arg ２２２ -Phe ２２３ -Val ２３４ -Ser ２２５ -Ile ２２６ -Asp ２２７ -Asn ２２８ -Lys ２２９ -A peptide containing -R' The superscripted characters represent positions within the renin A chain (1-342), R is selected from Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac-, Ac-Z, H-, H-Z, B-Z- and B, Z is selected from one or more of the amino acid residues at positions 205-219 of the renin A chain, and R' is -NH ２ , Z'-NH ２ , selected from -B and Z'-B, Z' is selected from one or more of the amino acid residues at positions 230-253 of the renin A chain, B is PEG or bis-PEG, and X is an amino acid residue, 【Chemical 1】 In the above formula, R １ and R ２ are independently H, C １ to C ８ n-alkyl optionally substituted by a hydroxyl group, C ３ to C ８ branched alkyl optionally substituted by a hydroxyl group, C ４ to C ８ dibranched alkyl optionally substituted at any one or more positions by a hydroxyl group or a methyl group or both, including all structurally realizable stereoisomeric forms, C ３ to C ６ cycloalkyl, CH ２ -C ３ to C ６ cycloalkyl optionally substituted at any one or more positions by a hydroxyl group or a methyl group or both, and R １ and R ２ may be optionally substituted at any position by methyl or hydroxyl or both, (CH ２ ) ｎ may be interconnected with each other, n is 2, 3, 4 or 5, and the residue of an amino acid, 【Chemical Formula 2】 In the above formula, Y is optionally substituted at one or more arbitrary positions by a methyl group, a hydroxyl group, or both, provided that the carbon atom bonded to the amino group can be substituted only by a methyl group, and n is 2, 3, 4, or 5 (CH ２ ) ｎ , optionally substituted at one or more arbitrary positions by a methyl group, a hydroxyl group, or both, provided that the carbon atom bonded to the amino group can be substituted only by a methyl group, and including all diastereomeric forms that can be structurally realized, a cis- or trans-1,2-cyclopropanediyl, cis- or trans-1,2-cyclobutanediyl, cis- or trans-1,3-cyclobutanediyl, cis- or trans-1,2-cyclopentanediyl, cis- or trans-1,3-cyclopentanediyl, cis- or trans-1,2-cyclohexanediyl, cis- or trans-1,3-cyclohexanediyl, or cis- or trans-1,4-cyclohexanediyl, a residue of an amino acid, and A peptide selected from

2. R-Lys ２０５ -Ile ２０６ -Asp ２０７ -Val ２０８ -Pro ２０９ -Trp ２１０ -Ala ２１１ -Gly ２１２ -Gln ２１３ -Tyr ２１４ -Ile ２１５ -Thr ２１６ -Ser ２１７ -Asn ２１８ -Pro ２１９ -X ２２０ -Ile ２２１ -Arg ２２２ -Phe ２２３ -Val ２３４ -Ser ２２５ -Ile ２２６ -Asp ２２７ -Asn ２２８ -Lys ２２９ -Lys ２３０ -Arg ２３１ -Asn ２３２ -Ile ２３３ -Glu ２３４ -Ser ２３５ -Ser ２３６ -Glu ２３７ -Ile ２３８ -Gly ２３９ -Pro ２４０ -Ser ２４１ -Leu ２４２ -Val ２４３ -Ile ２４４ -His ２４５ -Thr ２４６ -Thr ２４７ -Val ２４８ -Pro ２４９ -Phe ２５０ -Gly ２５１ -Val ２５２ -Thr ２５３ -R', where R is selected from Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac-, H-, PEG and bis-PEG, and R' is -Tyr-Leu-Glu-NH ２ 、Tyr-Leu-NH ２ 、-Tyr-NH ２ 、-NH ２ , selected from -OH and PEG, X ２２０ is selected from Gly, Ser, Ala, Leu, Val, Ile, Nle, β-Ala, cyclopropyl-Gyl, (cyclopropylmethyl)-Gly and Aib, the peptide according to claim 1.

3. The peptide according to claim 2, wherein R is Ac-.

4. R' is -NH ２ The peptide according to claim 3, wherein

5. X ２２０ The peptide according to claim 4, wherein X is Ala.

6. [Ala ２２０ -Ac-renin A(205-253)-NH ２ The peptide according to claim 1, which is

7. R-Lys ２０５ -Ile ２０６ -Asp ２０７ -Val ２０８ -Pro ２０９ -Trp ２１０ -Ala ２１１ -Gly ２１２ -Gln ２１３ -Tyr ２１４ -Ile ２１５ -Thr ２１６ -Ser ２１７ -Asn ２１８ -Pro ２１９ -X ２２０ -Ile ２２１ -Arg ２２２ -Phe ２２３ -Val ２３４ -Ser ２２５ -Ile ２２６ -Asp ２２７ -Asn ２２８ -Lys ２２９ -Lys ２３０ -Arg ２３１ -Asn ２３２ -Ile ２３３ -Glu ２３４ -Ser ２３５ -Ser ２３６ -Glu ２３７ -Ile ２３８ -Gly ２３９ -Pro ２４０ The peptide according to claim 1, which is R'.

8. The peptide according to claim 7, wherein R represents Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac- or H-.

9. The peptide according to claim 7, wherein R represents a straight chain of poly(ethylene) glycol [PEG] or bis-poly(ethylene) glycol [bis-PEG] having an average molecular weight of 500 to 20,000 amu.

10. R' is -Ser-Leu-Val-NH ２ , -Ser-Leu-NH ２ , -Ser-NH ２ , -NH ２ or -OH, and the peptide according to claim 7

11. The peptide according to claim 7, wherein R' represents a straight chain of poly(ethylene) glycol [PEG] having an average molecular weight of 500 to 20,000 amu.

12. [Bis-PEG ５０００ -Lys ２０５ -Ile ２０６ -Asp ２０７ -Val ２０８ -Pro ２０９ -Trp ２１０ -Ala ２１１ -Gly ２１２ -Gln ２１３ -Tyr ２１４ -Ile ２１５ -Thr ２１６ -Ser ２１７ -Asn ２１８ -Pro ２１９ -Ala ２２０ -Ile ２２１ -Arg ２２２ -Phe ２２３ -Val ２３４ -Ser ２２５ -Ile ２２６ -Asp ２２７ -Asn ２２８ -Lys ２２９ -Lys ２３０ -Arg ２３１ -Asn ２３２ -Ile ２３３ -Glu ２３４ -Ser ２３５ -Ser ２３６ -Glu ２３７ -Ile ２３８ -Gly ２３９ -Pro ２４０ -NH ２ which is the peptide according to claim 7.

13. X ２２０ is the peptide according to claim 7, which represents Gly, Ser, Ala, Leu, Val, Ile, Nle, β-Ala, cyclopropyl-Gyl, (cyclopropylmethyl)-Gly or Aib.

14. The peptide according to claim 13, wherein R is Ac-.

15. R' is -NH ２ The peptide according to claim 14, wherein

16. X ２２０ The peptide according to claim 15, wherein X is Ala.

17. [Ala ２２０ -Ac-Renalase A(205-240)-NH ２ The peptide according to claim 16, which is

18. R-Tyr ２１４ -Ile ２１５ -Thr ２１６ -Ser ２１７ -Asn ２１８ -Pro ２１９ -X ２２０ -Ile ２２１ -Arg ２２２ -Phe ２２３ -Val ２３４ -Ser ２２５ -Ile ２２６ -Asp ２２７ -Asn ２２８ -Lys ２２９ -Lys ２３０ -Arg ２３１ -Asn ２３２ -Ile ２３３ -Glu ２３４ -Ser ２３５ -Ser ２３６ -Glu ２３７ -Ile ２３８ -Gly ２３９ -Pro ２４０ The peptide according to claim 1, which is R'.

19. The peptide according to claim 18, wherein R represents Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac- or H-.

20. The peptide according to claim 18, wherein R represents a straight chain of poly(ethylene) glycol [PEG] having an average molecular weight of 500 to 20,000 amu.

21. R' is -Ser-Leu-Val-NH ２ , -Ser-Leu-NH ２ , -Ser-NH ２ , -NH ２ or -OH, and the peptide according to claim 18

22. The peptide according to claim 18, wherein R' represents a straight chain of poly(ethylene) glycol [PEG] having an average molecular weight of 500 to 20,000 amu.

23. X ２２０ is the peptide according to claim 18, which represents Gly, Ser, Ala, Leu, Val, Ile, Nle, β-Ala, cyclopropyl-Gyl, (cyclopropylmethyl)-Gly or Aib.

24. The peptide according to claim 23, wherein R is Ac-.

25. R' is -NH ２ The peptide according to claim 24, wherein it is such.

26. X ２２０ The peptide according to claim 25, wherein X is Ala.

27. [Ala ２２０ -Ac-renin A(214-240)-NH ２ The peptide according to claim 26, which is

28. R-Tyr ２１４ -Ile ２１５ -Thr ２１６ -Ser ２１７ -Asn ２１８ -Pro ２１９ -X ２２０ -Ile ２２１ -Arg ２２２ -Phe ２２３ -Val ２３４ -Ser ２２５ -Ile ２２６ -Asp ２２７ -Asn ２２８ -Lys ２２９ -Lys ２３０ -Arg ２３１ -Asn ２３２ -Ile ２３３ -Glu ２３４ -Ser ２３５ -Ser ２３６ -Glu ２３７ -Ile ２３８ -Gly ２３９ -Pro ２４０ -Ser ２４１ -Leu ２４２ -Val ２４３ -Ile ２４４ -His ２４５ -Thr ２４６ -Thr ２４７ -Val ２４８ -Pro ２４９ -Phe ２５０ -Gly ２５１ -Val ２５２ -Thr ２５３ The peptide according to claim 1, which is R'.

29. The peptide according to claim 28, wherein R represents Ac-Ala-Gly-Thr-, Ac-Gly-Thr-, Ac-Thr-, Ac- or H-.

30. The peptide according to claim 28, wherein R represents a straight chain of poly(ethylene) glycol [PEG] having an average molecular weight of 500 to 20,000 amu.

31. R' is -Ser-Leu-Val-NH ２ , -Ser-Leu-NH ２ , -Ser-NH ２ , -NH ２ or -OH, and the peptide according to claim 28

32. The peptide according to claim 28, wherein R' represents a straight chain of poly(ethylene) glycol [PEG] having an average molecular weight of 500 to 20,000 amu.

33. X ２２０ is the peptide according to claim 28, which represents Gly, Ser, Ala, Leu, Val, Ile, Nle, β-Ala, cyclopropyl-Gyl, (cyclopropylmethyl)-Gly or Aib.

34. The peptide according to claim 33, wherein R is Ac-.

35. R' is -NH ２ The peptide according to claim 34, wherein the peptide is such that

36. X ２２０ The peptide according to claim 35, wherein X is Ala.

37. [Ala ２２０ -Ac-renin A(214-253)-NH ２ The peptide according to claim 36, which is

38. A method for treating acute kidney injury or acute pancreatitis in a patient in need of such treatment, comprising the step of administering to the patient a therapeutically effective amount of the peptide according to claim 1.

39. A pharmaceutical composition comprising the peptide according to claim 1, admixed with a pharmaceutically acceptable carrier.

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