Cagrilintide ndeye synthetic peptide inotevedzera chiito cheamylin, hormone yakavanzwa nepancreas inogadzirisa mazinga eglucose yeropa uye chido.Inoumbwa ne38 amino acids uye ine disulfide bond.Cagrilintide inosunga kune ese amylin receptors (AMYR) uye calcitonin receptors (CTR), ayo ari G protein-coupled receptors anoratidzwa mumhando dzakasiyana siyana, senge uropi, pancreas, uye pfupa.Nekuita izvi zvinogamuchirwa, cagrilintide inogona kuderedza kudya, kuderedza mazinga eglucose eropa, uye kuwedzera simba rekushandisa.Cagrilintide yakaongororwa senzira yekurapa kufutisa, chirwere chemetabolism chinoratidzwa nemafuta akawandisa emuviri uye njodzi yakawedzera yechirwere cheshuga, chirwere chemoyo, uye kenza.Cagrilintide yakaratidza mhedzisiro inovimbisa muzvidzidzo zvemhuka uye miedzo yekiriniki, zvichiratidza kurasikirwa kukuru kwehuremu uye nekuvandudza glycemic control muvarwere vakafuta vane kana vasina Type 2 chirwere cheshuga.
Mufananidzo 1. Homology muenzaniso we cagrilintide (23) yakasungwa kuAMY3R.(A) N-terminal chikamu che23 (blue) inoumbwa neamphipathic a-helix, yakavigwa zvakadzika muTM domain ye AMY3R, nepo C-terminal chikamu chinofungidzirwa kuti chichatora conformation yakawedzerwa inosunga chikamu che extracellular che. receptor.(29,30) Mafuta ane mafuta akabatanidzwa kuN-terminus ye23, proline residues (iyo inoderedza fibrillation), uye C-terminal amide (inokosha pakugamuchira receptor) inosimbiswa mumifananidzo yetsvimbo.AMY3R inoumbwa neCTR (grey) yakasungwa kuRAMP3 (receptor-activity modifying protein 3; orenji).Chimiro chechimiro chakasikwa uchishandisa zvinotevera template zvivako: chimiro chakaoma cheCGRP (calcitonin receptor-like receptor; pdb code 6E3Y) uye apo crystal structure ye 23 backbone (pdb code 7BG0).(B) Zoom kumusoro kwe23 inoratidzira N-terminal disulfide bond, bhiriji remunyu remukati pakati pezvakasara 14 ne17, "leucine zipper motif," uye yemukati hydrogen bond pakati pezvisara 4 uye 11. (yakashandurwa kubva kuKruse 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.)
Mamwe emabiological application ecagrilintide ndeaya:
Cagrilintide inogona kuenzanisa mashandiro eeuroni mu hypothalamus, nharaunda yehuropi inodzora kudya uye simba chiyero (Lutz et al., 2015, Front Endocrinol (Lausanne)).Cagrilintide inogona kurambidza kupfurwa kweorexigenic neurons, iyo inomutsa nzara, uye inomisa anorexigenic neurons, iyo inodzvinyirira nzara.Semuenzaniso, cagrilintide inogona kuderedza kutaura kweuropeptide Y (NPY) uye peptide yakabatana negouti (AgRP), maviri ane simba orexigenic peptides, uye kuwedzera kutaura kwe proopiomelanocortin (POMC) uye cocaine- uye amphetamine-regulated transcript (CART), maviri. anorexigenic peptides, mune arcuate nucleus ye hypothalamus (Roth et al., 2018, Physiol Behav).Cagrilintide inogona zvakare kuwedzera satiating mhedzisiro yeleptin, hormone inotaridza chimiro chesimba remuviri.Leptin inovanzwa neadipose tissue uye inosunga kune leptin receptors pane hypothalamic neurons, inhibiting orexigenic neurons uye activate anorexigenic neurons.Cagrilintide inogona kuwedzera kunzwisiswa kweleptin receptors uye potentiate leptin-induced activation yechiratidzo transducer uye activator yekunyora 3 (STAT3), chinhu chekunyora chinopindirana nemhedzisiro yeleptin pane gene kutaura (Lutz et al., 2015, Front Endocrinol (Lausanne) .Izvi zvinogona kuderedza kudya kwekudya uye kuwedzera simba rekushandisa, zvichiita kuti uremu huremerwe.
Mufananidzo 2. Chikafu chekudya mumakonzo mushure mekutonga kweCagrilintide 23. (yakashandurwa kubva kuKruse 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. Budiriro yeCagrilintide, Amylin Analogue Yenguva refu. J Med Chem. 2021 Aug 12; 64(15):11183-11194.)
Cagrilintide inogona kudzora kugadzirwa kwe insulin uye glucagon, mahomoni maviri anodzora mazinga eglucose muropa.Cagrilintide inogona kuvharira glucagon secretion kubva mualpha masero ari pancreas, iyo inodzivirira yakawandisa glucose kugadzirwa nechiropa.Glucagon ihomoni inokurudzira kuparara kweglycogen uye synthesis yeglucose muchiropa, ichisimudza mazinga eglucose.Cagrilintide inogona kudzvanyirira glucagon secretion nekusunga kune amylin receptors uye calcitonin receptors paalpha masero, ayo anobatanidzwa kune inhibitory G mapuroteni anoderedza cyclic adenosine monophosphate (cAMP) mazinga uye calcium influx.Cagrilintide inogonawo kugonesa insulin secretion kubva kumasero ebeta ari pancreas, iyo inosimudzira kutorwa kweglucose nemamhasuru uye adipose tishu.Insulin ihomoni inosimudzira kuchengetwa kweglucose se glycogen muchiropa uye tsandanyama, uye kushandurwa kweglucose kuva mafuta acids mune adipose tissue, kuderedza mazinga eglucose yeropa.Cagrilintide inogona kuwedzera insulin secretion nekusunga kune amylin receptors uye calcitonin receptors pabeta masero, ayo akabatanidzwa kune anokurudzira G mapuroteni anowedzera mazinga ecAMP uye calcium influx.Izvi zvinogona kuderedza mazinga eglucose eropa uye kuvandudza insulin senitivity, iyo inogona kudzivirira kana kubata chirwere cheshuga chechipiri (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
Cagrilintide inogonawo kukanganisa basa re osteoblasts uye osteoclasts, marudzi maviri emasero anobatanidzwa mukugadzirwa kwemapfupa uye resorption.Osteoblasts inokonzera kugadzira mapfupa matsva, nepo osteoclasts inokonzera kuputsa matrix emapfupa ekare.Chiyero pakati pe osteoblasts uye osteoclasts chinotarisa huwandu hwemapfupa uye simba.Cagrilintide inogona kukurudzira kusiyanisa kwe osteoblast uye basa, izvo zvinowedzera kuumbwa kwemapfupa.Cagrilintide inogona kusunga kune amylin receptors uye calcitonin receptors pane osteoblasts, iyo inomutsa intracellular signing nzira dzinokurudzira kuwanda kwe osteoblast, kupona, uye matrix synthesis (Cornish et al., 1996, Biochem Biophys Res Commun. ).Cagrilintide inogonawo kuwedzera kutaura kweosteocalcin, chiratidzo cheosteoblast maturation uye basa (Cornish et al., 1996, Biochem Biophys Res Commun.).Cagrilintide inogonawo kutadzisa osteoclast kusiyanisa uye basa, izvo zvinoderedza pfupa resorption.Cagrilintide inogona kusunga kune amylin receptors uye calcitonin receptors pane osteoclast precursors, iyo inhibit fusion yavo mune yakakura osteoclasts (Cornish et al., 2015).Cagrilintide inogonawo kuderedza kutaura kwetartrate-resistant acid phosphatase (TRAP), chiratidzo che osteoclast chiitiko uye bone resorption (Cornish et al., 2015, Bonekey Rep.).Izvi zvinogona kuvandudza mapfupa emamineral density uye kudzivirira kana kurapa osteoporosis, mamiriro anoratidzwa nekuderera kwepfupa uye kuwedzera njodzi yekutyoka (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
