Cagrilintide shine peptide na roba wanda yayi kama da aikin amylin, hormone da pancreas ke ɓoye wanda ke daidaita matakan glucose na jini da ci.Ya ƙunshi amino acid 38 kuma ya ƙunshi haɗin disulfide.Cagrilintide yana ɗaure ga duka masu karɓar amylin (AMYR) da masu karɓa na calcitonin (CTR), waɗanda sune masu karɓar furotin G da aka bayyana a cikin kyallen takarda daban-daban, kamar su kwakwalwa, pancreas, da kashi.Ta hanyar kunna waɗannan masu karɓa, cagrilintide na iya rage cin abinci, rage matakan glucose na jini, da ƙara yawan kashe kuzari.An bincika Cagrilintide azaman yuwuwar jiyya don kiba, cuta ta rayuwa wacce ke da yawan kitsen jiki da haɓaka haɗarin ciwon sukari, cututtukan zuciya, da kansa.Cagrilintide ya nuna sakamako mai ban sha'awa a cikin nazarin dabbobi da gwaje-gwaje na asibiti, yana nuna babban asarar nauyi da ingantaccen sarrafa glycemic a cikin marasa lafiya masu kiba tare da ko ba tare da ciwon sukari na 2 ba.
Hoto 1. Tsarin Homology na cagrilintide (23) wanda aka ɗaure zuwa AMY3R.(A) N-terminal part na 23 (blue) an kafa shi ta hanyar amphipathic a-helix, wanda aka binne shi sosai a cikin yankin TM na AMY3R, yayin da sashin C-terminal ya annabta don ɗaukar wani tsayin daka wanda ke ɗaure ɓangaren extracellular na mai karɓa.(29,30) Fatty acid da aka haɗe zuwa N-terminus na 23, ragowar proline (wanda ke rage fibrillation), da kuma C-terminal amide (mahimmanci don ɗaurin mai karɓa) ana nunawa a cikin wakilcin sanda.AMY3R an kafa shi ta hanyar CTR (launin toka) mai ɗaure zuwa RAMP3 (protein mai haɓaka-ayyukan gyare-gyare 3; orange).An ƙirƙiri ƙirar tsarin ta amfani da sifofin samfuri masu zuwa: hadadden tsarin CGRP (mai karɓar mai karɓa na calcitonin; pdb code 6E3Y) da tsarin apo crystal na kashin baya na 23 (pdb code 7BG0).(B) Zuƙowa sama da 23 yana nuna alamar N-terminal disulfide bond, gadar gishiri ta ciki tsakanin ragowar 14 da 17, "leucine zipper motif," da haɗin haɗin hydrogen na ciki tsakanin ragowar 4 da 11. (wanda aka karɓa daga Kruse T, Hansen). JL, Dahl K, Schäffer L, Sensfuss U, Poulsen C, Schlein M. -Aikin Amylin Analogue. J Med Chem. 2021 Aug 12;64(15):11183-11194.)
Wasu daga cikin aikace-aikacen nazarin halittu na cagrilintide sune:
Cagrilintide na iya canza ayyukan neurons a cikin hypothalamus, yankin kwakwalwa wanda ke sarrafa ci da ma'aunin makamashi (Lutz et al., 2015, Front Endocrinol (Lausanne)).Cagrilintide na iya hana harbe-harbe na jijiyoyi na orexigenic, wanda ke motsa yunwa, da kunna neurons na anorexigenic, wanda ke hana yunwa.Alal misali, cagrilintide na iya rage maganganun neuropeptide Y (NPY) da peptide da ke da alaka da agouti (AgRP), peptides biyu masu karfi na orexigenic, da kuma ƙara yawan maganganun proopiomelanocortin (POMC) da cocaine- da amphetamine-regulated transcript (CART), biyu. peptides anorexigenic, a cikin arcuate tsakiya na hypothalamus (Roth et al., 2018, Physiol Behav).Cagrilintide kuma na iya haɓaka tasirin satiating na leptin, hormone wanda ke nuna matsayin kuzarin jiki.Leptin yana ɓoye ta hanyar adipose nama kuma yana ɗaure ga masu karɓar leptin akan jijiyoyi na hypothalamic, yana hana jijiyoyi na orexigenic da kunna ƙwayoyin anorexigenic.Cagrilintide na iya haɓaka haɓakar masu karɓar leptin da haɓakar leptin mai ƙarfi na kunna siginar siginar da mai kunnawa na 3 (STAT3), wani abu na rubutu wanda ke daidaita tasirin leptin akan maganganun kwayoyin halitta (Lutz et al., 2015, Front Endocrinol (Lausanne))) .Wadannan illolin na iya rage cin abinci da kuma kara yawan kashe kuzari, haifar da asarar nauyi.
Hoto 2. Abincin abinci a cikin berayen bayan gudanarwar subcutaneous na Cagrilintide 23. (wanda aka karɓa daga Kruse T, Hansen JL, Dahl K, Schäffer L, Sensfuss U, Poulsen C, Schlein M, Hansen AMK, Jeppesen CB, Dornonville de la Cour C, Clausen TR, Johansson E, Fulle S, Skyggebjerg RB, Raun K. Ci gaban Cagrilintide, Dogon Amylin Analogue.
Cagrilintide na iya daidaita fitowar insulin da glucagon, hormones biyu waɗanda ke sarrafa matakan glucose na jini.Cagrilintide na iya hana fitowar glucagon daga ƙwayoyin alpha a cikin pancreas, wanda ke hana haɓakar glucose mai yawa ta hanta.Glucagon hormone ne wanda ke motsa rushewar glycogen da haɗin glucose a cikin hanta, yana haɓaka matakan glucose na jini.Cagrilintide na iya murkushe ɓoyewar glucagon ta hanyar ɗaure masu karɓar amylin da masu karɓa na calcitonin akan ƙwayoyin alpha, waɗanda aka haɗa su da sunadaran G masu hanawa waɗanda ke rage matakan adenosine monophosphate (cAMP) cyclic da kwararar calcium.Cagrilintide kuma yana iya haɓaka fitowar insulin daga ƙwayoyin beta a cikin pancreas, wanda ke haɓaka ɗaukar glucose ta tsokoki da nama mai adipose.Insulin wani hormone ne wanda ke inganta ajiyar glucose a matsayin glycogen a cikin hanta da tsokoki, da kuma canza glucose zuwa acid fatty a cikin adipose tissue, yana rage matakan glucose na jini.Cagrilintide na iya haɓaka ɓoyewar insulin ta hanyar ɗaure masu karɓar amylin da masu karɓa na calcitonin akan ƙwayoyin beta, waɗanda aka haɗa su da sunadaran G masu ƙarfafawa waɗanda ke haɓaka matakan cAMP da kwararar calcium.Wadannan tasirin na iya rage matakan glucose na jini da inganta haɓakar insulin, wanda zai iya hana ko magance nau'in ciwon sukari na 2 (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
Cagrilintide kuma zai iya rinjayar aikin osteoblasts da osteoclasts, nau'in kwayoyin halitta guda biyu waɗanda ke da hannu a cikin samuwar kashi da resorption.Osteoblasts ne ke da alhakin samar da sabon matrix na kashi, yayin da osteoclasts ke da alhakin rushe tsohuwar matrix na kashi.Ma'auni tsakanin osteoblasts da osteoclasts yana ƙayyade yawan kashi da ƙarfi.Cagrilintide na iya tayar da bambance-bambancen osteoblast da aiki, wanda ke ƙara haɓakar kashi.Cagrilintide na iya ɗaure masu karɓar amylin da masu karɓa na calcitonin akan osteoblasts, waɗanda ke kunna hanyoyin siginar intracellular waɗanda ke haɓaka haɓakar osteoblast, rayuwa, da haɗin matrix (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide kuma na iya ƙara bayyanar osteocalcin, alamar osteoblast maturation da aiki (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide kuma na iya hana bambance-bambancen osteoclast da aiki, wanda ke rage haɓakar kashi.Cagrilintide na iya ɗaure ga masu karɓar amylin da masu karɓa na calcitonin akan abubuwan da suka faru na osteoclast, waɗanda ke hana haɗuwarsu cikin manyan osteoclasts (Cornish et al., 2015).Cagrilintide kuma na iya rage maganganun tartrate-resistant acid phosphatase (TRAP), alamar aikin osteoclast da haɓakar kashi (Cornish et al., 2015, Bonekey Rep.).Wadannan tasirin na iya inganta yawan ma'adinai na kashi kuma su hana ko magance osteoporosis, yanayin da ke da ƙananan ƙwayar kashi da ƙara haɗarin karaya (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
