Кисспептины и их синтетические аналоги: строение, механизм действия и перспективы клинического применения
ПАТОФИЗИОЛОГИЯ — МЕДИЦИНЕ
Аннотация
В литературном обзоре проведено сравнение нативного кисспептина (КП) и его синтетических аналогов, в том числе с модификациями, улучающими его стабильность в организме человека, и охарактеризованы возможности их терапевтического применения в коррекции нарушений репродуктивной функции. КП представляет собой ключевой нейропептид, регулирующий репродуктивную функцию через активацию рецептора KISS1R и стимуляцию секреции гонадотропин-рилизинг гормона (Гн РГ). Установлено, что кисспептин-10 и кисспептин-54 обладают различной фармакокинетикой, однако КП-10 не менее эффективно активирует рецептор KISS1R. Механизм действия КП связан с активацией Gq/11-белкового каскада, приводящей к повышению внутриклеточного кальция и активации фосфолипазы C. Описаны модификации кисспептинов, улучающие их стабильность, в том числе замена аминокислот, добавление защитных групп, которые замедляют деградацию и смогут значительно увеличить период полужизни пептида в крови. Рассмотрены основные области применения кисспептинов в клинической практике, в том числе в лечении нарушений репродуктивной функции: при гипогонадотропном гипогонадизме, бесплодии, задержке полового созревания,гормонозависимых опухолях и онкологии. Синтетические аналоги кисспептина, особенно те, что модифицированы для улучшения стабильности, представляют значительный интерес для разработки новых терапевтических стратегий в области репродуктивной медицины. Разрабатываются синтетические аналоги КП, устойчивые к деградации матриксными металлопротеиназами (MMP-2/9). Перспективны фосфиновые аналоги, ингибирующие MMP и продлевающие период полувыведения.
Библиографические ссылки
1. Lee J.H., Miele M.E., Hicks D.J., Phillips K.K., Trent J.M., Weissman B.E. et al. Ki SS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88(23):1731–1737. https://doi.org/10.1093/JNCI/88.23.1731.
2. Kutzleb C., Busmann A., Wendland M., Maronde E. Discovery of novel regulatory peptides by reverse pharmacology: spotlight on chemerin and the RF-amide peptides metastin and QRFP. Curr Protein Pept Sci. 2005;6(3):265–278. https://doi.org/10.2174/1389203054065419.
3. Skorupskaite K., George J.T., Anderson R.A. The kisspeptin-Gn RH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20(4):485–500. https://doi.org/10.1093/HUMUPD/DMU009.
4. Ciaramella V., Della Corte C.M., Ciardiello F., Morgillo F. Kisspeptin and cancer: molecular interaction, biological functions, and future perspectives. Front Endocrinol (Lausanne). 2018;9:115. https://doi.org/10.3389/FENDO.2018.00115.
5. Kanda S., Oka Y. Structure, synthesis, and phylogeny of kisspeptin and its receptor. Adv Exp Med Biol. 2013;784:9–26. https://doi.org/10.1007/978-1-4614-6199-9_2.
6. Kotani M., Detheux M., Vandenbogaerde A., Communi D., Vanderwinden J.M., Le Poul E. et al. The metastasis suppressor gene Ki SS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276(37):34631–34636. https://doi.org/10.1074/JBC.M104847200.
7. Sachania S., Nawar N., Ghelut A., Dhillo W., Jonas K.C. Are all kisspeptins equal? The effect of kisspeptin 10 and kisspeptin 54 on kisspeptin-mediated signalling. Endocrine Abstracts. 2019;65:356. https://doi.org/10.1530/ENDOABS.65.P356.
8. Ohtaki T., Shintani Y., Honda S., Matsumoto H., Hori A., Kanehashi K. et al. Metastasis suppressor gene Ki SS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411:613–617. https://doi.org/10.1038/35079135.
9. Izzi-Engbeaya C., Dhillo W.S. Emerging roles for kisspeptin in metabolism. J Physiol. 2022;600(5):1079–1088. https://doi.org/10.1113/JP281712.
10. Abbara A., Clarke S.A., Dhillo W.S. Clinical potential of kisspeptin in reproductive health. Trends Mol Med. 2021;27(8):807–823. https://doi.org/10.1016/J.MOLMED.2021.05.008.
11. Trevisan C.M., Montagna E., de Oliveira R.,Christofolini D.M., Barbosa C.P., Crandall K.A. et al. Kisspeptin/GPR54 system: what do we know about its role in human reproduction? Cell Physiol Biochem. 2018;49(4):1259–1276. https://doi.org/10.1159/000493406.
12. Rønnekleiv O.K., Qiu J., Kelly M.J. Coordinate reproductive activities with metabolism. Semin Reprod Med. 2019;37(03):131–140. https://doi.org/10.1055/S-0039-3400251.
13. Tsoutsouki J., Patel B., Comninos A.N., Dhillo W.S., Abbara A. Kisspeptin in the prediction of pregnancy complications. Front Endocrinol (Lausanne). 2022;19;13:942664. https://doi.org/10.3389/FENDO.2022.942664.
14. Roa J., Navarro V.M., Tena-Sempere M. Kisspeptins in reproductive biology: consensus knowledge and recent developments. Biol Reprod. 2011;85(4):650-–660. https://doi.org/10.1095/biolreprod.111.091538.
15. Gomes V.C.L., Sones J.L. From inhibition of trophoblast cell invasion to proapoptosis: what are the potential roles of kisspeptins in preeclampsia? Am J Physiol Regul Integr Comp Physiol. 2021;321(1):R41–R48. https://doi.org/10.1152/AJPREGU.00258.2020.
16. Mead E.J., Maguire J.J., Kuc R.E., Davenport A.P. Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. Br J Pharmacol. 2007; 151(8):1143–1153. https://doi.org/10.1038/SJ.BJP.0707295.
17. Pfeil E.M., Brands J., Merten N. Heterotrimeric G protein subunit Gαq is a master switch for Gβγ-mediated calcium mobilization by Gi-coupled GPCRs. Mol Cell. 2020;80(6):940–954.e6. https://doi.org/10.1016/J.MOLCEL.2020.10.027.
18. Woll K.A., Van Petegem F. Calcium-release channels: structure and function of IP3 receptors and ryanodine receptors. Physiol Rev. 2022;102(1):209–268. https://doi.org/10.1152/PHYSREV.00033.2020.
19. Xie Q., Kang Y., Zhang C., Xie Y., Wang C., Liu J. et al. The role of kisspeptin in the control of the hypothalamic-pituitary-gonadal axis and reproduction. Front Endocrinol (Lausanne). 2022;13:925206. https://doi.org/10.3389/FENDO.2022.925206.
20. Liu X., Herbison A.E. Kisspeptin regulation of neuronal activity throughout the central nervous system. Endocrinol Metab (Seoul). 2016;31(2):193–205. https://doi.org/10.3803/ENM.2016.31.2.193.
21. Sato K., Shirai R., Hontani M., Shinooka R., Hasegawa A., Kichise T. et al. Potent vasoconstrictor kisspeptin-10 induces atherosclerotic plaque progression and instability: reversal by its receptor GPR54 antagonist. J Am Heart Assoc. 2017;6(4). https://doi.org/10.1161/JAHA.117.005790.
22. Dinh H., Kovács Z.Z.A., Márványkövi F. et al. The kisspeptin-1 receptor antagonist peptide-234 aggravates uremic cardiomyopathy in a rat model. Sci Rep. 2023:14046. https://doi.org/10.1038/s41598-023-41037-0.
23. Qu C., Park J.Y., Yun M.W., He Q.T., Yang F., Kim K. et al. Scaffolding mechanism of arrestin-2 in the c Raf/M EK1/ERK signaling cascade. Proc Natl Acad Sci U S A. 2021;118(37):e2026491118. https://doi.org/10.1073/pnas.2026491118.
24. Babwah A.V., Pampillo M., Min L., Kaiser U.B., Bhattacharya M. Single-cell analyses reveal that KISS1R-expressing cells undergo sustained kisspeptin-induced signaling that is dependent upon an influx of extracellular Ca2+. Endocrinology. 2012;153(12): 5875–5887. https://doi.org/10.1210/EN.2012-1747.
25. Bianco S.D.C., Vandepas L., Correa-Medina M., Gereben B., Mukherjee A., Kuohung W. et al. KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology. 2011;152(4):1616–1626. https://doi.org/10.1210/EN.2010-0903.
26. Kroll H., Bolsover S., Hsu J., Kim S.H., Bouloux P.M. Kisspeptin-evoked calcium signals in isolated primary rat gonadotropin-releasing hormone neurones. Neuroendocrinology. 2011;93(2):114–120. https://doi.org/10.1159/000321678.
27. Stincic T.L., Kelly M.J. Estrogenic regulation of reproduction and energy homeostasis by a triumvirate of hypothalamic arcuate neurons. J Neuroendocrinol. 2022;34(6):e13145. https://doi.org/10.1111/jne.13145.
28. Felip A., Zanuy S., Pineda R., Pinilla L., Carrillo M., Tena-Sempere M. et al. Evidence for two distinct Ki SS genes in non-placental vertebrates that encode kisspeptins with different gonadotropin-releasing activities in fish and mammals. Mol Cell Endocrinol. 2009;312(1-2):61–71. https://doi.org/10.1016/j.mce.2008.11.017.
29. Tomita K., Oishi S., Ohno H., Peiper S.C., Fujii N. Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase. J Med Chem. 2008;51:7645–7649. https://doi.org/10.1021/jm800930w.
30. Kirby H.R., Maguire J.J., Colledge W.H., Davenport A.P. International union of basic and clinical pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function. Pharmacol Rev. 2010;62(4):565–578. https://doi.org/10.1124/PR.110.002774.
31. Roseweir A.K., Millar R.P. Kisspeptin antagonists. Adv Exp Med Biol. 2013;784:159–186. https://doi.org/10.1007/978-1-4614-6199-9_8.
32. Gutiérrez-Pascual E., Leprince J., Martínez-Fuentes A.J., Ségalas-Milazzo I., Pineda R., Roa J. et al. In vivo and in vitro structure-activity relationships and structural conformation of kisspeptin-10-related peptides. Mol Pharmacol. 2009;76(1):58–67. https://doi.org/10.1124/MOL.108.053751.
33. Niida A., Wang Z., Tomita K., Oishi S., Tamamura H., Otaka A. et al. Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity. Bioorg Med Chem Lett. 2006;16(1):134–137. https://doi.org/10.1016/J.BMCL.2005.09.054.
34. Orsini M.J., Klein M.A., Beavers M.P., Connolly P.J., Middleton S.A., Mayo K.H. Metastin (Ki SS-1) mimetics identified from peptide structure-activity relationship-derived pharmacophores and directed small molecule database screening. J Med Chem. 2007;50(3):462–471. https://doi.org/10.1021/jm0609824.
35. Szeliga A., Podfigurna A., Bala G., Meczekalski B. Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand? J Endocrinol Invest. 2020;43:555–561. https://doi.org/10.1007/S40618-019-01160-0.
36. Matsui H., Asami T. Effects and therapeutic potentials of kisspeptin analogs: regulation of the hypothalamic-pituitarygonadal axis. Neuroendocrinology. 2014;99(1):49–60. https://doi.org/10.1159/000357809.
37. Radwańska P., Gałdyszyńska M., Piera L., Drobnik J. Kisspeptin-10 increases collagen content in the myocardium by focal adhesion kinase activity. Sci Rep. 2023;3:19977. https://doi.org/10.1038/S41598-023-47224-3.
38. Sleeboom J.J.F., van Tienderen G.S., Schenke-Layland K., van der Laan L.J.W., Khalil A.A., Verstegen M.M.A. The extracellular matrix as hallmark of cancer and metastasis: From biomechanics to therapeutic targets. Sci Transl Med. 2024;16(728):eadg3840. https://doi.org/10.1126/scitranslmed.adg3840.
39. Kleimenova T., Polyakova V., Linkova N., Drobintseva A., Medvedev D., Krasichkov A. The expression of kisspeptins and matrix metalloproteinases in extragenital endometriosis. Biomedicines. 2024;12(1):94. https://doi.org/10.3390/biomedicines12010094.
40. Takino T., Koshikawa N., Miyamori H., Tanaka M., Sasaki T., Okada Y. et al. Cleavage of metastasis suppressor gene product Ki SS-1 protein/metastin by matrix metalloproteinases. Oncogene. 2003;22(30):4617–4626. https://doi.org/10.1038/SJ.ONC.1206542.
41. Jayasena C.N., Nijher G.M.K., Comninos A.N., Abbara A., Januszewki A., Vaal M.L. et al. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. J Clin Endocrinol Metab. 2011;96(12):E1963–E1972. https://doi.org/10.1210/JC.2011-1408.
42. Patel B., Koysombat K., Mills E. G, Tsoutsouki J., Comninos A.N., Abbara A., Dhillo W.S. The emerging therapeutic potential of kisspeptin and neurokinin B. Endocrine Reviews. 2024;45(1);30–68. https://doi.org/10.1210/endrev/bnad023.
43. Abbara A., Eng P.C., Phylactou M., Clarke S.A., Mills E., Chia G. et al. Kisspeptin-54 accurately identifies hypothalamic gonadotropin-releasing hormone neuronal dysfunction in men with congenital hypogonadotropic hypogonadism. Neuroendocrinology. 2021;111(12):1176–1186. https://doi.org/10.1159/000513248.
44. Hu K.L., Chen Z., Li X. Advances in clinical applications of kisspeptin-Gn RH pathway in female reproduction. Reprod Biol Endocrinol. 2022;20(1):81. https://doi.org/10.1186/s12958-022-00953-y.
45. Abdulbagi M., Wang L., Siddig O., Di B., Li B. D-amino acids and D-amino acid-containing peptides: potential disease biomarkers and therapeutic targets? Biomolecules. 2021;11(11):1716. https://doi.org/10.3390/BIOM11111716.
46. Asami T., Nishizawa N., Ishibashi Y. Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides. Bioorg Med Chem Lett. 2012;22(20):6391–6396. https://doi.org/10.1016/j.bmcl.2012.08.069.
47. Zhang X., Matziari M., Xie Y., Fernig D., Rong R., Meng J. Functional examination of novel kisspeptin phosphinic peptides. PLo S One. 2018;13(4):e0195089. https://doi.org/10.1371/JOURNAL.PONE.0195089.
48. Yi T., Tan K., Cho S.G., Wang Y., Luo J., Zhang W. et al. Regulation of embryonic kidney branching morphogenesis and glomerular development by KISS1 receptor (Gpr54) through NFAT2- and Sp1-mediated Bmp7 expression. J Biol Chem. 2010;285(23): 17811–17820. https://doi.org/10.1074/JBC.M110.130740.
49. Georgiadis D., Dive V. Phosphinic peptides as potent inhibitors of zinc-metalloproteases. Top Curr Chem. 2015;360:1–38. https://doi.org/10.1007/128_2014_571.
50. Georgiadis D., Skoulikas N., Papakyriakou A., Stratikos E. Phosphinic peptides as tool compounds for the study of pharmacologically relevant Zn-metalloproteases. ACS Pharmacol Transl Sci. 2022;5(12):1228–1253. https://doi.org/10.1021/acsptsci.2c00183.
51. Abbara A., Eng P.C., Phylactou M., Clarke S.A., Mills E., Chia G. Kisspeptin-54 accurately identifies hypothalamic gonadotropin-releasing hormone neuronal dysfunction in men with congenital hypogonadotropic hypogonadism. Neuroendocrinology. 2021;111(12):1176–1186. https://doi.org/10.1159/000513248.
52. Carrasco R.A., Leonardi C.E., Hutt K., Singh J., Adams G.P. Kisspeptin induces LH release and ovulation in an induced ovulator. Biol Reprod. 2020;103(1):49–59. https://doi.org/10.1093/biolre/ioaa051.
53. Tsoutsouki J., Abbara A., Dhillo W. Novel therapeutic avenues for kisspeptin. Curr Opin Pharmacol. 2022;67:102319. https://doi.org/10.1016/J.COPH.2022.102319.
54. Tavakoli A., Azar A.T., Taghizabet N., Rezaei-Tazangi F., Ardebili S.N., Mofarahe Z.S. et al. The effect of kisspeptin on the maturation of human ovarian follicles in culture following vitrification-thawing processes. JBRA Assist Reprod. 2023;27(4):668–676. https://doi.org/10.5935/1518-0557.20230045.
55. Meczekalski B., Niwczyk O., Bala G., Szeliga A. Stress, kisspeptin, and functional hypothalamic amenorrhea. Curr Opin Pharmacol. 2022;67:102288. https://doi.org/10.1016/J.COPH.2022.102288.
56. Jyasena C.N., Comninos A.N., Narayanaswamy S. Acute and chronic effects of kisspeptin-54 administration on GH, prolactin and TSH secretion in healthy women. Clin Endocrinol (Oxf). 2014;81(6):891–898. https://doi.org/10.1111/cen.12512.
57. Podfigurna A., Maciejewska-Jeske M., Meczekalski B., Genazzani A.D. Kisspeptin and LH pulsatility in patients with functional hypothalamic amenorrhea. Endocrine. 2020;70:635–643. https://doi.org/10.1007/S12020-020-02481-4.
58. Chan Y.M., Lippincott M.F., Kusa T.O., Seminara S.B. Divergent responses to kisspeptin in children with delayed puberty. JCI Insight. 2018;3(8):e99109. https://doi.org/10.1172/JCI.INSIGHT.99109.
59. Cintra R.G., Wajnsztejn R., Trevisan C.M., Zaia V., Laganà A.S., Bianco B. et al. Kisspeptin levels in girls with precocious puberty: a systematic review and meta-analysis. Horm Res Paediatr. 2020;93(11-12):589–598. https://doi.org/10.1159/000515660.
60. Harihar S., Welch D.R. KISS1 metastasis suppressor in tumor dormancy: a potential therapeutic target for metastatic cancers? Cancer Metastasis Rev. 2023;42:183–196. https://doi.org/10.1007/S10555-023-10090-6.
61. Curtis A.E., Cooke J.H., Baxter J.E., Parkinson J.R.C., Bataveljic A., Ghatei M.A. et al. A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10. Am J Physiol Endocrinol Metab. 2010;298(2). https://doi.org/10.1152/AJPENDO.00426.2009.
62. Scott G., Ahmad I., Howard K., Maclean D., Oliva C., Warrington S. et al. Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men. Br J Clin Pharmacol. 2013;75(2):381–391. https://doi.org/10.1111/J.1365-2125.2012.04385.X.
63. Matsui H., Tanaka A., Yokoyama K., Takatsu Y., Ishikawa K., Asami T. et al. Chronic administration of the metastin/kisspeptin analog KISS1-305 or the investigational agent TAK-448 suppresses hypothalamic pituitary gonadal function and depletes plasma testosterone in adult male rats. Endocrinology. 2012;153(1):5297–5308. https://doi.org/10.1210/en.2012-1388.
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