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US-12617830-B2 - Analogues of PYY

US12617830B2US 12617830 B2US12617830 B2US 12617830B2US-12617830-B2

Abstract

Analogues of PYY differing from native human PYY by substitution of Ser23 with Ala23, Glu23, Lys23, Gln23 or AIB23. Further optional features include substitutions at further positions, loss of the Tyr1 residue of native human PYY and amidation of the C-terminus. Suitable for use as pharmaceuticals for treating and preventing disorders, in particular diabetes and obesity.

Inventors

  • Stephen Robert Bloom

Assignees

  • IP2IPO INNOVATIONS LIMITED

Dates

Publication Date
20260505
Application Date
20231130
Priority Date
20171204

Claims (20)

  1. 1 . A method of causing weight loss or treating weight gain in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a) an analogue of PYY which differs from the sequence of native human PYY (SEQ ID NO: 1) in the following respects: i Ser23 is substituted with Ala23, Glu23, or Aib23, ii Asn18 is substituted with Leu18, Aib18 or Ala18, and iii the analogue of PYY further differs from the sequence of native human PYY in at least one of the following respects: Tyr1 is absent, Glu10 is substituted with Lys10 or Gln10, Asp11 is substituted with Gly11, Arg19 is substituted with His19, Tyr27 is substituted with Phe27, Leu30 is substituted with His30, and Val31 is substituted with Leu31, wherein Lys4 is not substituted, and the C-terminal residue optionally terminates in a primary amide group (—C(O)NH 2 ) in place of a carboxylic acid group (—CO 2 H); or b) a derivative of the analogue, wherein the derivative is selected from the group consisting of amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidization, PEGylation, and fusion to another peptide or a protein to form a fusion protein; or c) a salt or solvate of the analogue or the derivative of the analogue.
  2. 2 . The method of claim 1 , wherein the C-terminal residue terminates in a primary amide group (—C(O)NH 2 ) in place of a carboxylic acid group (—CO 2 H).
  3. 3 . The method of claim 1 , wherein Ser23 is substituted with Ala23.
  4. 4 . The method of claim 1 , wherein the analogue of PYY is selected from the group consisting of Y1372 (SEQ ID NO: 20), Y1419 (SEQ ID NO: 23), Y1421 (SEQ ID NO: 24), Y1518 (SEQ ID NO: 32), Y1528 (SEQ ID NO: 33), Y1558 (SEQ ID NO: 35), Y1568 (SEQ ID NO: 36), and Y1579 (SEQ ID NO: 41).
  5. 5 . The method of claim 4 , wherein the analogue of PYY is compound Y1419 (SEQ ID NO: 23).
  6. 6 . The method of claim 1 , wherein Glu10 is unsubstituted, Asn18 is substituted with Leu18, and Ser23 is substituted with Ala23.
  7. 7 . The method of claim 1 , wherein Asn18 is substituted with Leu18, and Val31 is unsubstituted.
  8. 8 . The method of claim 1 , wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the analogue of PYY or derivative thereof together with a pharmaceutically acceptable carrier, and optionally a further therapeutic agent.
  9. 9 . The method of claim 8 , wherein the further therapeutic agent is selected from an analogue of GLP-1, an analogue of glucagon, and a derivative of either thereof.
  10. 10 . The method of claim 8 , wherein the pharmaceutical composition further comprises Zn2+ ions.
  11. 11 . The method of claim 1 , wherein the subject is overweight, obese, diabetic, or of a healthy weight.
  12. 12 . The method of claim 11 , wherein the subject is diabetic, the subject has Type II diabetes, or the subject has Type I diabetes.
  13. 13 . The method of claim 1 , wherein the administration is parental.
  14. 14 . The method of claim 1 , wherein the administration is subcutaneous.
  15. 15 . The method of claim 4 , wherein the analogue of PYY is compound Y1372 (SEQ ID NO: 20).
  16. 16 . The method of claim 4 , wherein the analogue of PYY is compound Y1421 (SEQ ID NO: 24).
  17. 17 . The method of claim 4 , wherein the analogue of PYY is compound Y1518 (SEQ ID NO: 32).
  18. 18 . The method of claim 4 , wherein the analogue of PYY is compound Y1528 (SEQ ID NO: 33).
  19. 19 . The method of claim 4 , wherein the analogue of PYY is compound Y1558 (SEQ ID NO: 35).
  20. 20 . The method of claim 4 , wherein the analogue of PYY is compound Y1568 (SEQ ID NO: 36).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional application of U.S. application Ser. No. 17/868,559, filed Jul. 19, 2022, which is a divisional of U.S. application Ser. No. 16/769,760, filed Jun. 4, 2020, now U.S. Pat. No. 11,421,012, issued Aug. 23, 2022, which is the National Stage of International Application No. PCT/GB2018/053513, filed Dec. 4, 2018, which claims the benefit of and priority to Great Britain Patent Application No. 1720188.0, filed Dec. 4, 2017, the contents of which are incorporated by reference in their entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in XML format via EFS-Web and is hereby incorporated by reference in its entirety. Said XML copy, Dec. 2, 2023, is named METS_016_03US_SubSeqList_ST26.xml, and is 63,623 bytes in size. FIELD OF THE INVENTION This application relates to analogues of peptide YY (PYY), which are useful in treating disorders such as diabetes and obesity, either alone or in combination with other agents, especially in combination with GLP-1 analogues. BACKGROUND OF THE INVENTION According to the National Health and Nutrition Examination Survey (NHANES, 2011 to 2012), over two thirds of adults in the United States are overweight or obese. In the United States, 78% percent of males and 74% percent of women, of the age of 20 or older, are either overweight or obese. In addition, a large percentage of children in the United States are overweight or obese. The cause of obesity is complex and multi-factorial. Increasing evidence suggests that obesity is not a simple problem of self-control but is a complex disorder involving appetite regulation and energy metabolism. In addition, obesity is associated with a variety of conditions associated with increased morbidity and mortality in a population. Although the etiology of obesity is not definitively established, genetic, metabolic, biochemical, cultural and psychosocial factors are believed to contribute. In general, obesity has been described as a condition in which excess body fat puts an individual at a health risk. There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type-2 diabetes disease risk, increases independently with increased body mass index (BMI). Indeed, this risk has been quantified as a five percent increase in the risk of cardiac disease for females, and a seven percent increase in the risk of cardiac disease for males, for each point of a BMI greater than 24.9 (see Kenchaiah et al., N. Engl. J. Med. 347:305, 2002; Massie, N. Engl. J. Med. 347:358, 2002). In addition, there is substantial evidence that weight loss in obese persons reduces important disease risk factors. Even a small weight loss, such as 10% of the initial body weight in both overweight and obese adults has been associated with a decrease in risk factors such as hypertension, hyperlipidemia, and hyperglycemia. Although diet and exercise provide a simple process to decrease weight gain, overweight and obese individuals often cannot sufficiently control these factors to effectively lose weight. Pharmacotherapy is available; several weight loss drugs have been approved by the Food and Drug Administration that can be used as part of a comprehensive weight loss program. However, many of these drugs have serious adverse side effects. When less invasive methods have failed, and the patient is at high risk for obesity related morbidity or mortality, weight loss surgery is an option in carefully selected patients with clinically severe obesity. However, these treatments are high-risk, and suitable for use in only a limited number of patients. It is not only obese subjects who wish to lose weight. People with weight within the recommended range, for example, in the upper part of the recommended range, may wish to reduce their weight, to bring it closer to the ideal weight. Thus, a need remains for agents that can be used to effect weight loss in overweight and obese subjects. PYY is a 36-amino acid peptide produced by the L cells of the gut, with highest concentrations found in the large bowel and the rectum. Two endogenous forms, PYY and PYY 3-36, are released into the circulation. PYY 3-36 is further produced by cleavage of the Tyr-Pro amino terminal residues of PYY by the enzyme dipeptidyl peptidase IV (DPP-IV). PYY 3-36 binds to the Y2 receptor of the Y family of receptors (De Silva and Bloom, Gut Liver, 2012, 6, p 10-20). Studies have shown that peripheral administration of PYY 3-36 to rodents and humans leads to marked inhibition of food intake, leading to the prospect that analogues of PYY may be useful in treating conditions such as obesity (see, e.g. Batterham et al, Nature, 2002, 418, p 650-654; Batterham et al, New England Journal of Medicine, 2003, 349, p 941-948). PYY has also been implicated in altering the metabolism of subjects and has been proposed as a treat