Cagrilintide ke peptide ea maiketsetso e etsisang ketso ea amylin, hormone e hlahisoang ke manyeme e laolang maemo a tsoekere ea mali le takatso ea lijo.E entsoe ka li-amino acid tse 38 mme e na le bond ea disulfide.Cagrilintide e tlama ho li-amylin receptors (AMYR) le li-calcitonin receptors (CTR), tseo e leng li-receptor tse kopantsoeng le protheine ea G tse hlahisoang ke lisele tse fapaneng, joalo ka boko, manyeme le lesapo.Ka ho kenya li-receptor tsena, cagrilintide e ka fokotsa ho ja lijo, ho theola tsoekere ea mali, le ho eketsa tšebeliso ea matla.Cagrilintide e 'nile ea etsoa lipatlisiso e le phekolo e ka' nang ea e-ba teng bakeng sa botenya, lefu la metabolism le khetholloang ke mafura a mangata a 'mele le kotsi e eketsehileng ea lefu la tsoekere, lefu la pelo le mofetše.Cagrilintide e bontšitse liphello tse tšepisang lithutong tsa liphoofolo le litekong tsa meriana, tse bontšang tahlehelo e kholo ea boima ba 'mele le taolo e ntlafetseng ea glycemic ho bakuli ba batenya ba nang le lefu la tsoekere la mofuta oa 2 kapa ba se nang bona.
Setšoantšo sa 1. Mohlala oa Homology oa cagrilintide (23) o tlameletsoe ho AMY3R.(A) Karolo ea N-terminal ea 23 (blue) e entsoe ke amphipathic a-helix, e patoa ka botebo sebakeng sa TM sa AMY3R, ha karolo ea C-terminal e boleloa esale pele hore e tla amohela conformation e atolositsoeng e tlamang karolo ea extracellular ea moamoheli.(29,30) Asiti e mafura e kopantsoeng le N-terminus ea 23, masala a proline (a fokotsang fibrillation), le C-terminal amide (ea bohlokoa bakeng sa ho tlama li-receptor) li totobatsoa litšoantšong tsa lithupa.AMY3R e thehoa ke CTR (e bohlooho) e tlameletsoeng ho RAMP3 (mosebetsi oa ho amohela-mosebetsi o fetola protheine 3; lamunu).Sebopeho sa sebopeho se entsoe ka ho sebelisa mekhoa e latelang ea template: mohaho o rarahaneng oa CGRP (calcitonin receptor-like receptor; pdb code 6E3Y) le apo crystal sebopeho sa mokokotlo oa 23 (pdb code 7BG0).(B) Atometsa 23 e totobatsang tlamo ea N-terminal disulfide, borokho ba letsoai bo ka hare pakeng tsa masala a 14 le 17, "leucine zipper motif," le tlamahano ea ka hare ea hydrogen pakeng tsa masala a 4 le 11. (e nkiloe ho 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.)
Tse ling tsa ts'ebeliso ea biological ea cagrilintide ke:
Cagrilintide e ka fetola ts'ebetso ea li-neurone ho hypothalamus, sebaka sa boko se laolang takatso ea lijo le botsitso ba matla (Lutz et al., 2015, Front Endocrinol (Lausanne)).Cagrilintide e ka thibela ho thunya ha li-neurons tsa orexigenic, tse tsosang tlala, le ho kenya tšebetsong li-anorexigenic neurons, tse hatellang tlala.Mohlala, cagrilintide e ka fokotsa polelo ea neuropeptide Y (NPY) le peptide e amanang le agouti (AgRP), li-peptide tse peli tse matla tsa orexigenic, mme ea eketsa polelo ea proopiomelanocortin (POMC) le cocaine- le amphetamine-regulated transcript (CART), tse peli. li-peptide tsa anorexigenic, khubung ea arcuate ea hypothalamus (Roth et al., 2018, Physiol Behav).Cagrilintide e ka boela ea ntlafatsa phello ea satiating ea leptin, hormone e bontšang boemo ba matla a 'mele.Leptin e hlahisoa ke lisele tsa adipose mme e tlama ho li-receptor tsa leptin ho li-neuron tsa hypothalamic, e thibelang li-neurons tsa orexigenic le ho kenya tšebetsong li-anorexigenic neurons.Cagrilintide e ka eketsa kutloelo-bohloko ea li-receptor tsa leptin le ho etsa ts'ebetso ea leptin e susumelitsoeng ke leptin le activator ea transcription 3 (STAT3), e leng ntho e ngotsoeng e hokahanyang litlamorao tsa leptin ho polelo ea lefutso (Lutz et al., 2015, Front Endocrinol (Lausanne) .Liphello tsena li ka fokotsa ho ja lijo le ho eketsa litšenyehelo tsa matla, tse lebisang ho theola boima ba 'mele.
Setšoantšo sa 2. Ho kenngoa ha lijo ka likhoto ka mor'a tsamaiso ea subcutaneous ea Cagrilintide 23. (e nkiloe ho tloha 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, Amylin Analogue ea nako e telele. J Med Chem. 2021 Aug 12; 64(15):11183-11194.)
Cagrilintide e ka laola tlhahiso ea insulin le glucagon, lihomone tse peli tse laolang maemo a tsoekere ea mali.Cagrilintide e ka thibela secretion ea glucagon liseleng tsa alpha manyeme, e thibelang tlhahiso e feteletseng ea tsoekere ke sebete.Glucagon ke hormone e susumetsang ho senyeha ha glycogen le synthesis ea tsoekere sebeteng, e leng se phahamisang boemo ba tsoekere maling.Cagrilintide e ka hatella secretion ea glucagon ka ho tlama ho li-amylin receptors le calcitonin receptors liseleng tsa alpha, tse kopantsoeng le liprotheine tsa G tse thibelang ho fokotsa maemo a cyclic adenosine monophosphate (cAMP) le ho phalla ha calcium.Cagrilintide e ka boela ea matlafatsa secretion ea insulin ho tsoa liseleng tsa beta ka har'a manyeme, e ntlafatsang ho amoheloa ha tsoekere ke mesifa le lisele tsa adipose.Insulin ke hormone e khothalletsang ho bolokoa ha tsoekere e le glycogen sebeteng le mesifa, le phetoho ea tsoekere hore e be mafura a acid ka har'a lisele tsa adipose, e leng ho theolang boemo ba tsoekere maling.Cagrilintide e ka ntlafatsa tlhahiso ea insulin ka ho tlama li-amylin receptors le calcitonin receptors liseleng tsa beta, tse kopantsoeng le liprotheine tsa G tse eketsang maemo a cAMP le khalsiamo e kenang.Liphello tsena li ka fokotsa maemo a tsoekere ea mali le ho ntlafatsa kutloisiso ea insulin, e ka thibelang kapa ea phekola lefu la tsoekere la mofuta oa 2 (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
Cagrilintide e ka boela ea ama mosebetsi oa li-osteoblasts le li-osteoclasts, mefuta e 'meli ea lisele tse amehang ho thehoa ha masapo le ho tsosolosa.Li-osteoblasts li na le boikarabelo ba ho hlahisa matrix a macha a masapo, ha li-osteoclasts li ikarabella bakeng sa ho senya matrix a khale a masapo.Ho leka-lekana pakeng tsa osteoblasts le osteoclasts ho khetholla boima ba masapo le matla.Cagrilintide e ka susumetsa karohano le ts'ebetso ea osteoblast, e eketsang sebopeho sa masapo.Cagrilintide e ka tlama ho li-receptor tsa amylin le li-calcitonin receptors ho li-osteoblasts, tse etsang hore ho be le litsela tsa ho bonahatsa li-intracellular tse khothalletsang ho ata ha osteoblast, ho phela le ho kopanya matrix (Cornish et al., 1996, Biochem Biophys Res Commun. ).Cagrilintide e ka boela ea eketsa polelo ea osteocalcin, letšoao la ho hōla ha osteoblast le mosebetsi (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide e ka boela ea thibela phapang ea osteoclast le mosebetsi, e leng ho fokotsa ho tsosolosoa ha masapo.Cagrilintide e ka tlama ho li-receptor tsa amylin le li-receptor tsa calcitonin ho li-precursors tsa osteoclast, tse thibelang ho kopana ha tsona ho li-osteoclast tse hōlileng tsebong (Cornish et al., 2015).Cagrilintide e ka boela ea fokotsa polelo ea tartrate-resistant acid phosphatase (TRAP), letšoao la ts'ebetso ea osteoclast le resorption ea masapo (Cornish et al., 2015, Bonekey Rep.).Litlamorao tsena li ka ntlafatsa letsoalo la masapo le ho thibela kapa ho phekola lefu la ho fokola ha masapo, boemo bo khetholloang ke ho fokola ha masapo le kotsi e eketsehileng ea ho robeha (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
