Cagrilintide bụ peptide sịntetik nke na-eṅomi omume amylin, homonụ nke pancreas zoro ezo nke na-achịkwa ọkwa glucose ọbara na agụụ.Ọ nwere amino acid 38 ma nwee njikọ disulfide.Cagrilintide na-ejikọ ma ndị na-anabata amylin (AMYR) na ndị na-anabata calcitonin (CTR), bụ ndị nnabata protein jikọtara ọnụ nke G gosipụtara na anụ ahụ dị iche iche, dị ka ụbụrụ, pancreas, na ọkpụkpụ.Site na ịgbalite ndị na-anabata ndị a, cagrilintide nwere ike belata oriri nri, belata ọkwa glucose ọbara, yana ịbawanye mmefu ike.Achọpụtala Cagrilintide dị ka ọgwụgwọ nwere ike ịgwọ oke ibu, ọrịa metabolic nke oke abụba anụ ahụ na-abawanye yana ihe ize ndụ nke ọrịa shuga, ọrịa obi, na ọrịa kansa.Cagrilintide egosila nsonaazụ na-ekwe nkwa na ọmụmụ anụmanụ na nnwale ụlọ ọgwụ, na-egosipụta oke ibu dị arọ yana njikwa glycemic ka mma na ndị ọrịa buru ibu nwere ma ọ bụ na-enweghị ụdị ọrịa shuga 2.
Ọgụgụ 1. Ụdị Homology nke cagrilintide (23) jikọtara na AMY3R.(A) N-terminal akụkụ nke 23 (acha anụnụ anụnụ) hibere site na amphipathic a-helix, nke e liri ya na ngalaba TM nke AMY3R, ebe akụkụ C-terminal na-ebu amụma ịnakwere ngbanwe ogologo nke na-ejikọta akụkụ extracellular nke ahụ. onye nnata.(29,30) A na-eme ka acid fatty na-ejikọta na N-terminus nke 23, proline residues (nke na-ebelata fibrillation), na C-terminal amide (dị mkpa maka njikọ nnabata) na-apụta ìhè na ihe nnọchianya osisi.AMY3R bụ nke CTR (isi awọ) kpụrụ ya na RAMP3 (protein na-emezi-protein 3; oroma).Emepụtara ihe nhazi ahụ site na iji usoro ndebiri ndị a: usoro mgbagwoju anya nke CGRP (calcitonin receptor-like receptor; pdb code 6E3Y) na usoro kristal apo nke ọkpụkpụ azụ 23 (pdb code 7BG0).(B) Mbugharị nke 23 na-eme ka njikọ N-terminal disulfide pụta ìhè, mmiri nnu dị n'ime n'etiti 14 na 17 fọdụrụnụ, "leucine zipper motif," na njikọ hydrogen dị n'ime n'etiti 4 na 11. (nke sitere na 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. Mmepe nke Cagrilintide, ogologo oge -Amylin Analogue na-eme ihe. J Med Chem. 2021 Ọgọst 12;64(15):11183-11194.)
Ụfọdụ ngwa nke cagrilintide bụ:
Cagrilintide nwere ike gbanwee ọrụ neurons na hypothalamus, mpaghara ụbụrụ nke na-achịkwa agụụ na nguzozi ike (Lutz et al., 2015, Front Endocrinol (Lausanne)).Cagrilintide nwere ike igbochi igba egbe nke orexigenic neurons, nke na-akpali agụụ, ma mee ka neurons anorexigenic rụọ ọrụ, nke na-egbochi agụụ.Dịka ọmụmaatụ, cagrilintide nwere ike ibelata okwu neuropeptide Y (NPY) na peptide metụtara agouti (AgRP), peptides abụọ nwere ike orexigenic, na ịbawanye okwu nke proopiomelanocortin (POMC) na cocaine- na amphetamine-regulated transcript (CART), abụọ. peptides anorexigenic, na arcuate nucleus nke hypothalamus (Roth et al., 2018, Physiol Behav).Cagrilintide nwekwara ike ịkwalite mmetụta satiating nke leptin, hormone nke na-egosi ọkwa ike nke ahụ.A na-ezobe Leptin site na anụ ahụ adipose ma na-ejikọ ndị na-anabata leptin na neurons hypothalamic, na-egbochi neurons orexigenic ma na-arụ ọrụ neurons anorexigenic.Cagrilintide nwere ike ime ka uche nke ndị na-anabata leptin dị elu na ntinye aka nke leptin na-eme ka onye na-eme mgbanwe mgbaàmà na onye na-arụ ọrụ nke transcription 3 (STAT3), ihe ntụgharị nke na-eme ka mmetụta leptin na okwu mkpụrụ ndụ (Lutz et al., 2015, Front Endocrinol (Lausanne))) .Mmetụta ndị a nwere ike ibelata oriri nri ma mee ka mmefu ike dịkwuo elu, na-eduga n'ịbelata ibu.
Ọgụgụ 2. Nri oriri na oke mgbe nchịkwa subcutaneous nke Cagrilintide 23. (nke sitere na 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 nwere ike ịhazi mmepụta insulin na glucagon, homonụ abụọ na-achịkwa ọkwa glucose ọbara.Cagrilintide nwere ike igbochi secretion glucagon site na mkpụrụ ndụ alfa na pancreas, nke na-egbochi imeju mmepụta glucose dị ukwuu.Glucagon bụ homonụ nke na-akpali ndakpọ glycogen na njikọ nke glucose na imeju, na-ebuli ọkwa glucose ọbara.Cagrilintide nwere ike igbochi secretion glucagon site na ijikọ ndị na-anabata amylin na ndị na-anabata calcitonin na mkpụrụ ndụ alfa, nke jikọtara ya na protein inhibitory G nke na-ebelata ọkwa adenosine monophosphate cyclic (cAMP) na ntinye calcium.Cagrilintide nwekwara ike ime ka insulin na-emepụta site na mkpụrụ ndụ beta dị na pancreas, nke na-eme ka uru ahụ na anụ ahụ adipose dịkwuo elu.Insulin bụ homonụ nke na-akwalite nchekwa glucose dị ka glycogen na imeju na akwara, yana ngbanwe nke glucose na acid fatty na anụ ahụ adipose, na-ebelata ọkwa glucose ọbara.Cagrilintide nwere ike ịkwalite secretion insulin site na ijikọ ndị na-anabata amylin na ndị na-anabata calcitonin na mkpụrụ ndụ beta, nke jikọtara ya na protein G na-akpali akpali nke na-abawanye ọkwa cAMP na ntinye calcium.Mmetụta ndị a nwere ike ibelata ọkwa glucose ọbara ma melite ikike insulin, nke nwere ike igbochi ma ọ bụ gwọọ ụdị ọrịa shuga 2 (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
Cagrilintide nwekwara ike imetụta ọrụ nke osteoblasts na osteoclasts, ụdị mkpụrụ ndụ abụọ na-etinye aka na ọkpụkpụ ọkpụkpụ na resorption.Osteoblasts na-ahụ maka imepụta matrix ọkpụkpụ ọhụrụ, ebe osteoclasts na-ahụ maka ịkụda matriks ọkpụkpụ ochie.Ntuzi n'etiti osteoblasts na osteoclasts na-ekpebi oke ọkpụkpụ na ike.Cagrilintide nwere ike ịkpalite ọdịiche na ọrụ osteoblast, nke na-abawanye nguzobe ọkpụkpụ.Cagrilintide nwere ike jikọta na amylin receptors na calcitonin receptors na osteoblasts, nke na-eme ka ụzọ mgbaàmà intracellular na-akwalite mgbasawanye osteoblast, nlanarị, na matrix synthesis (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide nwekwara ike ịbawanye okwu nke osteocalcin, akara nke osteoblas maturation na ọrụ (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide nwekwara ike igbochi ọdịiche na ọrụ osteoclast, nke na-ebelata resorption ọkpụkpụ.Cagrilintide nwere ike jikọta ndị na-anabata amylin na ndị na-anabata calcitonin na osteoclast precursors, nke na-egbochi njikọ ha n'ime osteoclasts tozuru okè (Cornish et al., 2015).Cagrilintide nwekwara ike belata okwu nke tartrate-eguzogide acid phosphatase (TRAP), ihe nrịbama nke ọrụ osteoclast na ọkpụkpụ resorption (Cornish et al., 2015, Bonekey Rep.).Mmetụta ndị a nwere ike melite njupụta ịnweta ọkpụkpụ ma gbochie ma ọ bụ na-emeso osteoporosis, ọnọdụ nke ọkpụkpụ ọkpụkpụ dị ala na ụbara ihe ize ndụ nke mgbaji (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
