Cagrilintide waa peptide synthetic ah oo u ekeysiiya ficilka amylin, hormoon uu soo daayo xameetida kaas oo nidaamiya heerarka gulukooska dhiigga iyo rabitaanka cuntada.Waxay ka kooban tahay 38 amino acids waxayna ka kooban tahay curaarta disulfide.Cagrilintide waxay ku xidhan tahay labada amylin reseptors (AMYR) iyo calcitonin reseptors (CTR), kuwaas oo ah G- protein reseptors-ku-xidhan yahay oo lagu muujiyey unugyo kala duwan, sida maskaxda, xameetida, iyo lafaha.Marka la dhaqaajiyo soo-dhoweeyayaashan, cagrilintide waxay yarayn kartaa qaadashada cuntada, waxay hoos u dhigtaa heerarka gulukooska dhiigga, waxayna kordhin kartaa kharashka tamarta.Cagrilintide ayaa loo baadhay inay tahay daawaynta suurtagalka ah ee buurnaanta, cillad dheef-shiid kiimikaad oo lagu garto dufanka jidhka ee dheeraadka ah iyo khatarta sii kordheysa ee sonkorowga, cudurrada wadnaha iyo xididada, iyo kansarka.Cagrilintide waxay muujisay natiijooyin rajo leh oo ku saabsan daraasadaha xayawaanka iyo tijaabooyinka kiliinikada, taas oo muujinaysa miisaan lumis weyn iyo hagaajinta kontoroolka glycemic ee bukaannada cayilan ee qaba ama aan lahayn nooca 2 ee sonkorowga.
Jaantuska 1. Qaabka Homology ee cagrilintide (23) ee ku xidhan AMY3R.(A) Qaybta N-terminal ee 23 (buluug) waxaa sameeyay amphipathic a-helix, oo si qoto dheer loogu aasay TM-ka AMY3R, halka qaybta C-terminal la saadaaliyay inay qaadato isfaham fidsan oo ku xidhan qaybta ka baxsan unugyada receptor.(29,30) Aashitada dufanka leh ee ku xiran N-terminus ee 23, hadhaaga proline (kaas oo yareeya fibrillation), iyo C-terminal amide (muhiim u ah xiritaanka soo-dhoweynta) ayaa lagu muujiyay matalaad usha.AMY3R waxaa sameeyay CTR (cawlan) oo ku xidhan RAMP3 (protein wax ka beddelka reseptor-ka 3; orange).Qaabka qaabdhismeedka ayaa la sameeyay iyadoo la adeegsanayo qaab-dhismeedka template ee soo socda: qaab-dhismeedka adag ee CGRP (calcitonin reseptor-sida reseptor; pdb code 6E3Y) iyo qaab dhismeedka kristal apo ee laf dhabarta 23 (pdb code 7BG0).(B) Kor u kaca 23 oo muujinaya N-terminal disulfide bond, buundada cusbada gudaha ee u dhaxaysa haraaga 14 iyo 17, "leucine zipper motif," iyo bond gudaha hydrogen inta u dhaxaysa hadhaaga 4 iyo 11. (laga soo qaatay 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. -Ku-simaha Amylin Analogue. J Med Chem. 2021 Agoosto 12;64(15):11183-11194.)
Qaar ka mid ah codsiyada bayoolojiga ee cagrilintide waa:
Cagrilintide waxay wax ka beddeli kartaa dhaqdhaqaaqa neerfaha ee hypothalamus, gobolka maskaxda ee xakameynaya rabitaanka cuntada iyo dheelitirka tamarta (Lutz et al., 2015, Front Endocrinol (Lausanne)).Cagrilintide waxay joojin kartaa toogashada neurons-ka orexigenic, taas oo kicisa gaajada, oo kicisa neerfayaasha anorexigenic, kuwaas oo xakameynaya gaajada.Tusaale ahaan, cagrilintide waxay yareyn kartaa muujinta neuropeptide Y (NPY) iyo peptide-la-xiriira agouti (AgRP), laba peptides orexigenic awood leh, iyo kordhinta muujinta proopiomelanocortin (POMC) iyo kokain-iyo amphetamine-regulated transcript (CART), laba peptides anorexigenic, oo ku jira nukleus arcuate ee hypothalamus (Roth et al., 2018, Physiol Behav).Cagrilintide waxay sidoo kale wanaajin kartaa saameynta dheregista ee leptin, hormoonka tilmaamaya heerka tamarta jirka.Leptin waxaa lagu siidaayaa unug adipose ah wuxuuna ku xiraa soo-qabayaasha leptin-ka ee neurons-ka hypothalamic, xannibaya neerfaha orexigenic iyo firfircoonida neerfayaasha anorexigenic.Cagrilintide waxay kordhin kartaa dareenka leptin reseptors iyo firfircoonida firfircoonida leh ee leptin-ku-abuuray ee transducer signal and activator of transcription 3 (STAT3), oo ah arrin qoraal ah oo dhexdhexaadinaysa saameynta leptin ee muujinta hiddaha (Lutz et al., 2015, Front Endocrinol (Lausanne)) .Saamayntani waxay yarayn kartaa qaadashada cuntada waxayna kordhin kartaa kharashka tamarta, taasoo keenta miisaan lumis.
Jaantus 2. Qaadashada cuntada ee jiirka ka dib maamulka subcutaneous ee Cagrilintide 23. (laga soo xigtay 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.
Cagrilintide waxay nidaamin kartaa dheecaanka insulin iyo glucagon, oo ah laba hormoon oo xakameynaya heerarka gulukooska dhiigga.Cagrilintide waxay joojin kartaa dheecaanka glucagon ee unugyada alfa ee xameetida, taas oo ka hortagaysa soosaarka gulukooska ee beerka.Glucagon waa hoormoon kicinaya burburka glycogen iyo isku dhafka gulukooska ee beerka, kor u qaadista heerka gulukooska dhiigga.Cagrilintide waxay xakameyn kartaa dheecaanka glucagon iyadoo ku xireysa amylin reseptors iyo calcitonin reseptors ee unugyada alfa, kuwaas oo lagu daray borotiinada G ee xannibaya kuwaas oo yareynaya heerarka adenosine monophosphate (cAMP) ee wareegga wareegga iyo qulqulka calcium.Cagrilintide waxay sidoo kale xoojin kartaa dheecaanka insulinta ee unugyada beta ee beeryarada, taas oo kor u qaadeysa qaadashada gulukooska ee muruqyada iyo unugyada adipose.Insulinku waa hoormoon kor u qaada kaydinta gulukooska sida glycogen ee beerka iyo murqaha, iyo beddelka gulukooska oo loo beddelo asiidh dufan ah oo ku jira unugyada adipose, taas oo hoos u dhigta heerka gulukooska dhiigga.Cagrilintide waxay wanaajin kartaa dheecaanka insulinta iyadoo lagu xirayo amylin reseptors iyo calcitonin reseptors ee unugyada beta, kuwaas oo lagu daray borotiinnada G ee kicinaya ee kordhiya heerarka cAMP iyo qulqulka calcium.Saamayntani waxay hoos u dhigi kartaa heerarka gulukooska dhiigga waxayna wanaajin kartaa dareenka insulin, kaas oo ka hortagi kara ama daweyn kara nooca 2 ee sonkorowga (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
Cagrilintide waxay sidoo kale saameyn kartaa shaqada osteoblasts iyo osteoclasts, laba nooc oo unugyo ah oo ku lug leh sameynta lafaha iyo dib u soo noqoshada.Osteoblasts ayaa mas'uul ka ah soo saarista shax lafo cusub, halka osteoclasts ay mas'uul ka yihiin inay jebiyaan matrixka lafaha hore.Isku dheelitirka u dhexeeya lafo-beelka iyo osteoclasts ayaa go'aamiya cufka iyo xoogga lafaha.Cagrilintide waxay kicin kartaa kala duwanaanshaha osteoblast iyo dhaqdhaqaaqa, taas oo kordhisa samaynta lafaha.Cagrilintide waxay ku xidhi kartaa amylin reseptors iyo calcitonin reseptors on osteoblasts, kuwaas oo dhaqaajiya waddooyinka calaamadaynta intracellular kuwaas oo kor u qaadida faafinta osteoblast, badbaadada, iyo matrix synthesis (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide waxay sidoo kale kordhin kartaa muujinta osteocalcin, calaamad u ah korriinka iyo shaqada osteoblast (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide waxay sidoo kale joojin kartaa kala duwanaanshaha osteoclast iyo dhaqdhaqaaqa, taas oo hoos u dhigta lafaha.Cagrilintide waxay ku xidhi kartaa amylin reseptors iyo calcitonin reseptors ee horudhaca osteoclast, kuwaas oo ka hortagaya isku dhafka osteoclasts baaluq (Cornish et al., 2015).Cagrilintide waxay sidoo kale yareyn kartaa muujinta phosphatase acid tartrate (TRAP), calaamad u ah dhaqdhaqaaqa osteoclast iyo dib u soo celinta lafaha (Cornish et al., 2015, Bonekey Rep.).Saamayntani waxay wanaajin kartaa cufnaanta macdanta lafaha waxayna ka hortagi kartaa ama daweyn kartaa lafo-jileecu, xaalad lagu garto cufnaanta lafaha hoose iyo khatarta jabka oo kordhay (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
