Cagrilintide ndi peptide yopangidwa yomwe imatsanzira zochita za amylin, timadzi tomwe timapangidwa ndi kapamba chomwe chimayang'anira kuchuluka kwa shuga m'magazi ndi njala.Amapangidwa ndi 38 amino acid ndipo ali ndi chomangira cha disulfide.Cagrilintide imamangiriza ku ma amylin receptors (AMYR) ndi ma calcitonin receptors (CTR), omwe ndi mapuloteni a G omwe amapangidwa m'magulu osiyanasiyana, monga ubongo, kapamba, ndi fupa.Poyambitsa zolandilira izi, cagrilintide imatha kuchepetsa kudya, kuchepetsa kuchuluka kwa shuga m'magazi, ndikuwonjezera kugwiritsa ntchito mphamvu.Cagrilintide yafufuzidwa ngati chithandizo chothandizira kunenepa kwambiri, matenda a metabolic omwe amadziwika ndi mafuta ochulukirapo komanso chiwopsezo cha matenda a shuga, matenda amtima, ndi khansa.Cagrilintide yawonetsa zotsatira zabwino m'maphunziro a nyama ndi mayeso azachipatala, kuwonetsa kuchepa thupi kwakukulu komanso kuwongolera bwino kwa glycemic mwa odwala onenepa omwe ali ndi matenda amtundu wa 2 kapena opanda.
Chithunzi 1. Homology chitsanzo cha cagrilintide (23) chomangidwa ku AMY3R.(A) N-terminal gawo la 23 (buluu) limapangidwa ndi amphipathic a-helix, yokwiriridwa kwambiri mu TM domain ya AMY3R, pamene gawo la C-terminal likunenedweratu kuti lidzalandira conformation yowonjezera yomwe imamanga mbali ya extracellular ya cholandirira.(29,30) Mafuta a asidi omwe amamangiriridwa ku N-terminus ya 23, zotsalira za proline (zomwe zimachepetsa fibrillation), ndi C-terminal amide (yofunikira kuti imangirire receptor) imasonyezedwa muzithunzithunzi za ndodo.AMY3R imapangidwa ndi CTR (imvi) yomangidwa ku RAMP3 (receptor-activity modifying protein 3; lalanje).Mapangidwe apangidwe adapangidwa pogwiritsa ntchito ma template otsatirawa: mawonekedwe ovuta a CGRP (calcitonin receptor-like receptor; pdb code 6E3Y) ndi apo crystal structure ya 23 backbone (pdb code 7BG0).(B) Mawonekedwe a 23 akuwonetsa mgwirizano wa N-terminal disulfide, mlatho wamchere wamkati pakati pa zotsalira 14 ndi 17, "leucine zipper motif," ndi mgwirizano wamkati wa hydrogen pakati pa zotsalira 4 ndi 11. (zosinthidwa kuchokera ku 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. Development of Cagrilintide, Long -Acting Amylin Analogue. J Med Chem. 2021 Aug 12; 64 (15): 11183-11194.)
Zina mwazachilengedwe zogwiritsa ntchito cagrilintide ndi:
Cagrilintide imatha kusintha magwiridwe antchito a neurons mu hypothalamus, dera laubongo lomwe limayang'anira chikhumbo komanso mphamvu zamagetsi (Lutz et al., 2015, Front Endocrinol (Lausanne)).Cagrilintide imatha kuletsa kuwombera kwa orexigenic neurons, komwe kumayambitsa njala, ndikuyambitsa anorexigenic neurons, omwe amapondereza njala.Mwachitsanzo, cagrilintide imatha kuchepetsa mawu a neuropeptide Y (NPY) ndi peptide yokhudzana ndi agouti (AgRP), ma peptide awiri amphamvu orexigenic, ndikuwonjezera mawu a proopiomelanocortin (POMC) ndi cocaine- ndi amphetamine-regulated transcript (CART), awiri. anorexigenic peptides, mu arcuate nucleus ya hypothalamus (Roth et al., 2018, Physiol Behav).Cagrilintide imathanso kukulitsa mphamvu yokhutiritsa ya leptin, timadzi timene timawonetsa mphamvu za thupi.Leptin imatulutsidwa ndi minofu ya adipose ndipo imamangiriza ku leptin receptors pa hypothalamic neurons, kulepheretsa orexigenic neurons ndikuyambitsa anorexigenic neurons.Cagrilintide imatha kukulitsa chidwi cha ma leptin receptors ndikupangitsa kuti leptin-induced activation ya transducer ndi activator ya transcript 3 (STAT3), chinthu cholembera chomwe chimayimira zotsatira za leptin pa gene expression (Lutz et al., 2015, Front Endocrinol (Lausanne)) .Zotsatirazi zimatha kuchepetsa kudya ndikuwonjezera mphamvu zamagetsi, zomwe zimapangitsa kuti thupi likhale lolemera.
Chithunzi 2. Kudya zakudya mu makoswe pambuyo pa subcutaneous administration ya Cagrilintide 23. (yosinthidwa kuchokera ku 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. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem. 2021 Aug 12; 64(15):11183-11194.)
Cagrilintide imatha kuwongolera katulutsidwe ka insulin ndi glucagon, mahomoni awiri omwe amawongolera kuchuluka kwa shuga m'magazi.Cagrilintide imatha kuletsa kutulutsa kwa glucagon kuchokera ku ma cell a alpha mu kapamba, zomwe zimalepheretsa kupanga shuga wambiri ndi chiwindi.Glucagon ndi mahomoni omwe amathandizira kuwonongeka kwa glycogen ndi kaphatikizidwe ka shuga m'chiwindi, ndikukweza kuchuluka kwa shuga m'magazi.Cagrilintide imatha kupondereza katulutsidwe ka glucagon pomanga ma amylin receptors ndi ma calcitonin receptors pama cell a alpha, omwe amaphatikizidwa ndi mapuloteni oletsa G omwe amachepetsa milingo ya cyclic adenosine monophosphate (cAMP) ndi kuchuluka kwa calcium.Cagrilintide imathanso kulimbikitsa katulutsidwe ka insulini kuchokera ku maselo a beta mu kapamba, zomwe zimapangitsa kuti glucose atengeke ndi minofu ndi minofu ya adipose.Insulin ndi mahomoni omwe amathandizira kusungidwa kwa glucose monga glycogen m'chiwindi ndi minofu, komanso kusintha kwa glucose kukhala mafuta acids mu minofu ya adipose, kutsitsa kuchuluka kwa shuga m'magazi.Cagrilintide imatha kukulitsa katulutsidwe ka insulini pomanga ma amylin receptors ndi ma calcitonin receptors pama cell a beta, omwe amaphatikizidwa ndi mapuloteni a G omwe amachulukitsa kuchuluka kwa cAMP komanso kuchuluka kwa calcium.Zotsatirazi zimatha kuchepetsa kuchuluka kwa shuga m'magazi ndikuwongolera chidwi cha insulin, chomwe chingalepheretse kapena kuchiza matenda amtundu wa 2 (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
Cagrilintide ingakhudzenso ntchito ya osteoblasts ndi osteoclasts, mitundu iwiri ya maselo yomwe imakhudzidwa ndi kupanga mafupa ndi kubwezeretsanso.Osteoblasts ali ndi udindo wopanga mafupa atsopano, pamene osteoclasts ndi omwe amachititsa kuphwanya mafupa akale.Kugwirizana pakati pa osteoblasts ndi osteoclasts kumatsimikizira fupa ndi mphamvu.Cagrilintide ikhoza kulimbikitsa kusiyana kwa osteoblast ndi ntchito, zomwe zimawonjezera mapangidwe a mafupa.Cagrilintide imatha kumangirira ku ma amylin receptors ndi ma calcitonin receptors pa osteoblasts, omwe amayambitsa njira zolumikizirana zamkati zomwe zimalimbikitsa kuchulukana kwa osteoblast, kupulumuka, ndi kaphatikizidwe ka matrix (Cornish et al., 1996, Biochem Biophys Res Commun. ).Cagrilintide imathanso kukulitsa mawu a osteocalcin, chizindikiro cha kusasitsa kwa osteoblast ndi ntchito (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide imathanso kulepheretsa kusiyanitsa kwa osteoclast ndi ntchito, zomwe zimachepetsa kukhazikika kwa mafupa.Cagrilintide imatha kumangirira ku amylin receptors ndi calcitonin receptors pa osteoclast precursors, zomwe zimalepheretsa kuphatikizika kwawo kukhala osteoclasts okhwima (Cornish et al., 2015).Cagrilintide imathanso kuchepetsa kufotokoza kwa tartrate-resistant acid phosphatase (TRAP), cholembera cha osteoclast ntchito ndi resorption ya mafupa (Cornish et al., 2015, Bonekey Rep.).Zotsatirazi zimatha kupititsa patsogolo kachulukidwe ka mafupa am'mafupa ndikuletsa kapena kuchiza matenda a osteoporosis, mkhalidwe womwe umadziwika ndi kuchepa kwa mafupa komanso chiwopsezo chophwanyika (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
