Cagrilintide yog ib qho hluavtaws peptide uas ua raws li qhov kev txiav txim ntawm amylin, ib yam tshuaj uas tso tawm los ntawm cov txiav txiav uas tswj cov ntshav qabzib thiab qab los noj mov.Nws yog tsim los ntawm 38 amino acids thiab muaj ib daim ntawv cog lus disulfide.Cagrilintide khi rau ob qho tib si amylin receptors (AMYR) thiab calcitonin receptors (CTR), uas yog G protein-coupled receptors qhia nyob rau hauv ntau yam ntaub so ntswg, xws li lub paj hlwb, pancreas, thiab pob txha.Los ntawm kev ua kom cov receptors no, cagrilintide tuaj yeem txo cov khoom noj, txo cov ntshav qabzib, thiab nce kev siv zog.Cagrilintide tau raug tshawb xyuas raws li kev kho mob rau kev rog rog, ib qho teeb meem metabolic uas muaj roj ntau hauv lub cev thiab muaj kev pheej hmoo ntawm ntshav qab zib, kab mob plawv, thiab mob qog noj ntshav.Cagrilintide tau pom cov txiaj ntsig tau zoo hauv kev tshawb fawb tsiaj thiab kev sim tshuaj, ua kom pom qhov hnyav poob thiab txhim kho glycemic tswj hauv cov neeg mob rog rog uas muaj lossis tsis muaj ntshav qab zib hom 2.
Daim duab 1. Homology qauv ntawm cagrilintide (23) khi rau AMY3R.(A) N-terminal ib feem ntawm 23 (xiav) yog tsim los ntawm ib qho amphipathic a-helix, tob faus rau hauv lub TM domain ntawm AMY3R, thaum lub C-terminal ib feem tau kwv yees kom txais yuav ib qho kev sib txuas ntxiv uas khi rau sab nraud ntawm lub cev. tus neeg txais kev pab.(29,30) Cov fatty acid txuas rau N-terminus ntawm 23, proline residues (uas txo qis fibrillation), thiab C-terminal amide (tseem ceeb rau kev sib khi receptor) yog qhov tseem ceeb hauv cov sawv cev ntawm cov nplaum.AMY3R yog tsim los ntawm CTR (grey) khi rau RAMP3 (receptor-activity modifying protein 3; txiv kab ntxwv).Cov qauv qauv tsim tau siv cov qauv hauv qab no: cov qauv tsim ntawm CGRP (calcitonin receptor-zoo li receptor; pdb code 6E3Y) thiab apo siv lead ua qauv ntawm 23 qaum qaum (pdb code 7BG0).(B) Zoom ntawm 23 qhov tseem ceeb ntawm N-terminal disulfide daim ntawv cog lus, ib qho chaw ntsev sab hauv nruab nrab ntawm qhov seem 14 thiab 17, "leucine zipper motif," thiab ib qho kev sib txuas hauv hydrogen ntawm cov residues 4 thiab 11. (hloov los ntawm 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. Kev loj hlob ntawm Cagrilintide, ntev -Acting Amylin Analogue. J Med Chem. 2021 Aug 12;64(15:11183-11194.)
Qee qhov kev siv tshuaj lom neeg ntawm cagrilintide yog:
Cagrilintide tuaj yeem hloov kho cov haujlwm ntawm cov neurons hauv hypothalamus, thaj tsam ntawm lub hlwb uas tswj kev qab los noj mov thiab lub zog sib npaug (Lutz li al., 2015, Front Endocrinol (Lausanne)).Cagrilintide tuaj yeem cuam tshuam kev tua ntawm orexigenic neurons, uas txhawb kev tshaib kev nqhis, thiab qhib anorexigenic neurons, uas suppress kev tshaib kev nqhis.Piv txwv li, cagrilintide tuaj yeem txo qhov kev qhia ntawm neuropeptide Y (NPY) thiab agouti-txog peptide (AgRP), ob lub zog orexigenic peptides, thiab nce kev qhia ntawm proopiomelanocortin (POMC) thiab cocaine- thiab amphetamine-regulated transcript (CART), ob. anorexigenic peptides, nyob rau hauv lub arcuate nucleus ntawm lub hypothalamus (Roth li al., 2018, Physiol Behav).Cagrilintide tseem tuaj yeem txhim kho cov nyhuv satiating ntawm leptin, ib yam tshuaj hormones uas qhia lub cev lub zog.Leptin yog secreted los ntawm cov ntaub so ntswg adipose thiab khi rau leptin receptors ntawm hypothalamic neurons, inhibiting orexigenic neurons thiab activating anorexigenic neurons.Cagrilintide tuaj yeem ua rau muaj kev nkag siab zoo ntawm leptin receptors thiab potentiate leptin-induced activation ntawm cov teeb liab transducer thiab activator ntawm transcription 3 (STAT3), ib qho kev hloov pauv uas kho leptin cov teebmeem ntawm cov noob qhia (Lutz li al., 2015, Front Endocrinol) (Lausanne) .Cov teebmeem no tuaj yeem txo cov zaub mov noj thiab nce kev siv zog, ua rau poob phaus.
Daim duab 2. Kev noj zaub mov hauv cov nas tom qab kev tswj hwm subcutaneous ntawm Cagrilintide 23. (hloov los ntawm 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 tuaj yeem tswj hwm qhov tso tawm ntawm insulin thiab glucagon, ob yam tshuaj uas tswj cov ntshav qabzib.Cagrilintide tuaj yeem cuam tshuam glucagon secretion los ntawm alpha hlwb hauv pancreas, uas tiv thaiv cov piam thaj ntau dhau los ntawm lub siab.Glucagon yog ib yam tshuaj uas txhawb kev zom cov glycogen thiab synthesis ntawm cov piam thaj hauv lub siab, nce ntshav qabzib.Cagrilintide tuaj yeem cuam tshuam glucagon secretion los ntawm kev khi rau amylin receptors thiab calcitonin receptors ntawm alpha hlwb, uas yog ua ke rau inhibitory G proteins uas txo qis cyclic adenosine monophosphate (cAMP) qib thiab calcium influx.Cagrilintide tuaj yeem ua kom muaj zog insulin tso tawm los ntawm beta hlwb hauv pancreas, uas txhim kho cov piam thaj los ntawm cov leeg thiab cov ntaub so ntswg adipose.Insulin yog ib yam tshuaj uas txhawb kev khaws cov piam thaj li glycogen hauv daim siab thiab cov leeg, thiab hloov cov piam thaj mus rau fatty acids hauv cov ntaub so ntswg adipose, txo cov ntshav qabzib.Cagrilintide tuaj yeem txhim kho insulin secretion los ntawm kev khi rau amylin receptors thiab calcitonin receptors ntawm beta hlwb, uas yog txuas rau stimulatory G proteins uas nce qib cAMP thiab calcium influx.Cov teebmeem no tuaj yeem txo cov ntshav qabzib thiab txhim kho insulin rhiab heev, uas tuaj yeem tiv thaiv lossis kho mob ntshav qab zib hom 2 (Kruse li al., 2021, J Med Chem; Dehestani li al., 2021, J Obes Metab Syndr.).
Cagrilintide tuaj yeem cuam tshuam rau kev ua haujlwm ntawm osteoblasts thiab osteoclasts, ob hom hlwb uas koom nrog hauv kev tsim cov pob txha thiab resorption.Osteoblasts yog lub luag haujlwm rau tsim cov pob txha tshiab, thaum osteoclasts yog lub luag haujlwm rau kev rhuav tshem cov pob txha qub.Qhov sib npaug ntawm osteoblasts thiab osteoclasts txiav txim siab cov pob txha loj thiab lub zog.Cagrilintide tuaj yeem txhawb kev sib txawv ntawm osteoblast thiab kev ua haujlwm, uas ua rau cov pob txha tsim.Cagrilintide tuaj yeem khi rau amylin receptors thiab calcitonin receptors ntawm osteoblasts, uas ua rau cov kab mob hauv lub cev uas txhawb nqa osteoblast proliferation, ciaj sia taus, thiab matrix synthesis (Cornish li al., 1996, Biochem Biophys Res Commun.).Cagrilintide kuj tseem tuaj yeem ua rau kev nthuav tawm ntawm osteocalcin, ib qho cim ntawm osteoblast maturation thiab muaj nuj nqi (Cornish li al., 1996, Biochem Biophys Res Commun.).Cagrilintide tuaj yeem cuam tshuam kev sib txawv ntawm osteoclast thiab kev ua haujlwm, uas txo cov pob txha resorption.Cagrilintide tuaj yeem khi rau amylin receptors thiab calcitonin receptors ntawm osteoclast precursors, uas inhibit lawv fusion mus rau hauv cov laus osteoclasts (Cornish li al., 2015).Cagrilintide kuj tseem tuaj yeem txo qhov kev qhia ntawm tartrate-resistant acid phosphatase (TRAP), ib qho cim ntawm osteoclast kev ua thiab pob txha resorption (Cornish li al., 2015, Bonekey Rep.).Cov teebmeem no tuaj yeem txhim kho pob txha pob txha pob txha pob txha thiab tiv thaiv lossis kho pob txha pob txha, ib qho mob uas muaj pob txha loj thiab muaj kev pheej hmoo ntawm pob txha (Kruse li al., 2021; Dehestani li al., 2021, J Obes Metab Syndr.)
