I-Cagrilintide yi-peptide yokwenziwa elinganisa isenzo se-amylin, ihomoni efihliweyo yi-pancreas elawula amanqanaba e-glucose yegazi kunye nokutya.Iqulethwe ngama-amino acid angama-38 kwaye iqulethe ibhondi ye-disulfide.I-Cagrilintide ibophelela kuzo zombini i-amylin receptors (AMYR) kunye ne-calcitonin receptors (CTR), eziyi-G protein-coupled receptors ezibonakaliswe kwii-tissue ezahlukeneyo, ezifana nengqondo, i-pancreas, kunye nethambo.Ngokusebenzisa la ma-receptors, i-cagrilintide inokunciphisa ukutya, ukunciphisa amanqanaba e-glucose yegazi, kunye nokwandisa inkcitho yamandla.I-Cagrilintide iphandwe njengonyango olunokubakho lokutyeba, ukuphazamiseka kwemetabolism ephawulwa ngamafutha amaninzi kunye nomngcipheko owongeziweyo wesifo seswekile, isifo sentliziyo kunye nomhlaza.I-Cagrilintide ibonise iziphumo ezithembisayo kwizifundo zezilwanyana kunye nezilingo zeklinikhi, ezibonisa ukulahleka kwesisindo esibalulekileyo kunye nokuphucula ulawulo lwe-glycemic kwizigulane ezityebileyo kunye okanye ngaphandle kohlobo lwe-2 yeswekile.
Umzobo 1. Imodeli ye-Homology ye-cagrilintide (23) ebophelelwe kwi-AMY3R.(A) Inxalenye ye-N-terminal ye-23 (blue) yenziwe nge-amphipathic a-helix, ingcwatywe ngokunzulu kwi-TM domain ye-AMY3R, ngelixa i-C-terminal inxalenye iqikelelwa ukuba ithathe i-conformation eyandisiweyo ebophelela i-extracellular part of the umamkeli.(29,30) I-asidi e-fatty efakwe kwi-N-terminus ye-23, i-proline residues (enciphisa i-fibrillation), kunye ne-C-terminal amide (ibalulekile ekubopheni i-receptor) igxininiswe kwiimpawu zentonga.I-AMY3R yenziwe nge-CTR (grey) ebophelelwe kwi-RAMP3 (i-receptor-umsebenzi wokuguqula iprotheni 3; i-orange).Imodeli yesakhiwo idalwe ngokusebenzisa izakhiwo zetemplate ezilandelayo: isakhiwo esiyinkimbinkimbi seCGRP (i-calcitonin receptor-like receptor; pdb code 6E3Y) kunye ne-apo crystal structure ye-23 backbone (pdb code 7BG0).(B) Sondeza i-23 ebonisa i-N-terminal disulfide bond, ibhulorho yetyuwa yangaphakathi phakathi kwe-residue 14 kunye ne-17, "i-leucine zipper motif," kunye ne-hydrogen bond yangaphakathi phakathi kweentsalela ze-4 kunye ne-11. (iguqulelwe kwi-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. Uphuhliso lweCagrilintide, ixesha elide -Acting Amylin Analogue. J Med Chem. 2021 Aug 12; 64 (15): 11183-11194.)
Ezinye zebhayoloji usetyenziso lwecagrilintide zezi:
I-Cagrilintide inokulungelelanisa umsebenzi we-neurons kwi-hypothalamus, ummandla wengqondo olawula ukutya kunye nokulinganisela kwamandla (Lutz et al., 2015, Front Endocrinol (Lausanne)).I-Cagrilintide inokuthintela ukudubula kwe-orexigenic neurons, evuselela indlala, kwaye isebenze i-anorexigenic neurons, ecinezela indlala.Umzekelo, i-cagrilintide inokunciphisa ukubonakaliswa kwe-neuropeptide Y (NPY) kunye ne-peptide enxulumene ne-agouti (AgRP), iipeptide ezimbini ezinamandla ze-orexigenic, kunye nokwandisa ukubonakaliswa kwe-proopiomelanocortin (POMC) kunye ne-cocaine- kunye ne-amphetamine-regulated transcript (CART), ezimbini. iipeptides anorexigenic, kwinucleus arcuate ye hypothalamus (Roth et al., 2018, Physiol Behav).ICagrilintide inokuphucula isiphumo sokutya kwe-leptin, ihomoni ebonisa imeko yamandla omzimba.I-Leptin ifihliwe yi-adipose tissue kwaye ibophelela kwi-leptin receptors kwi-hypothalamic neurons, inhibiting neurons ye-orexigenic kunye nokuvula i-anorexigenic neurons.I-Cagrilintide inokunyusa uvakalelo lwe-leptin receptors kunye nokwenza i-leptin-induced activation ye-transducer yesiginali kunye ne-activator ye-transcription 3 (STAT3), into ebhaliweyo edibanisa iziphumo ze-leptin kwi-gene expression (Lutz et al., 2015, Front Endocrinol (Lausanne) .Ezi ziphumo zinokunciphisa ukutya kunye nokwandisa inkcitho yamandla, okukhokelela ekulahlekeni kwesisindo.
Umzobo 2. Ukutya kokutya kwiigundane emva kokulawulwa kwe-subcutaneous yeCagrilintide 23. (ilungiswe kwi-Kruse T, Hansen JL, Dahl K, Schäffer L, Sensfuss U, Poulsen C, Schlein M, Hansen AMK, Jeppesen CB, Dornonville de la Cour C, UClausen TR, uJohansson E, Fulle S, Skyggebjerg RB, uRaun K. Uphuhliso lweCagrilintide, i-Analogue ye-Amylin yexesha elide. J Med Chem. 2021 Aug 12; 64(15): 11183-11194.)
ICagrilintide inokulawula ukukhuselwa kwe-insulin kunye neglucagon, iihomoni ezimbini ezilawula amanqanaba eglucose egazini.I-Cagrilintide inokuthintela ukukhutshwa kweglucagon kwiiseli ze-alpha kwi-pancreas, ezithintela ukuveliswa kwe-glucose ngokugqithiseleyo ngesibindi.IGlucagon yihomoni ekhuthaza ukuqhekeka kwe-glycogen kunye ne-synthesis yeglucose esibindini, inyusa amanqanaba eglucose egazini.I-Cagrilintide inokucinezela ukukhutshwa kweglucagon ngokuzibophelela kwi-amylin receptors kunye ne-calcitonin receptors kwiiseli ze-alpha, ezidityaniswe ne-inhibitory ye-G proteins ezinciphisa amanqanaba e-cyclic adenosine monophosphate (cAMP) kunye nokungena kwe-calcium.I-Cagrilintide iyakwazi ukwenza i-insulin secretion evela kwiiseli ze-beta kwi-pancreas, ephucula ukufunyanwa kwe-glucose yimisipha kunye nezicubu ze-adipose.I-insulin yi-hormone ekhuthaza ukugcinwa kwe-glucose njenge-glycogen kwisibindi kunye nezihlunu, kunye nokuguqulwa kwe-glucose kwi-fatty acids kwi-adipose tissue, ukunciphisa amanqanaba e-glucose yegazi.I-Cagrilintide inokuphucula ukukhutshwa kwe-insulin ngokuzibophelela kwi-amylin receptors kunye ne-calcitonin receptors kwiiseli ze-beta, ezidityaniswe neeprotheni ze-G ezikhuthazayo ezinyusa amanqanaba e-cAMP kunye ne-calcium.Ezi ziphumo zinokunciphisa amanqanaba e-glucose yegazi kunye nokuphucula ukuvakalelwa kwe-insulin, enokuthintela okanye ukunyanga uhlobo lwe-2 yeswekile (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
I-Cagrilintide inokuchaphazela kwakhona umsebenzi we-osteoblasts kunye ne-osteoclasts, iintlobo ezimbini zeeseli ezibandakanyekayo ekubunjweni kwamathambo kunye ne-resorption.Ii-Osteoblasts zinoxanduva lokuvelisa i-matrix yamathambo amatsha, ngelixa i-osteoclasts inoxanduva lokuphula i-matrix yamathambo amadala.Ibhalansi phakathi kwe-osteoblasts kunye ne-osteoclasts inquma ubunzima bamathambo kunye namandla.I-Cagrilintide inokuvuselela ukuhlukana kwe-osteoblast kunye nomsebenzi, okwandisa ukubunjwa kwamathambo.I-Cagrilintide inokubophelela kwi-amylin receptors kunye ne-calcitonin receptors kwi-osteoblasts, eyenza i-intracellular signaling pathways ezikhuthaza ukwanda kwe-osteoblast, ukusinda, kunye ne-matrix synthesis (Cornish et al., 1996, i-Biochem Biophys Res Commun. ).I-Cagrilintide inokunyusa ukubonakaliswa kwe-osteocalcin, uphawu lokuvuthwa kwe-osteoblast kunye nomsebenzi (Cornish et al., 1996, Biochem Biophys Res Commun.).I-Cagrilintide inokuthintela ukuhlukana kwe-osteoclast kunye nomsebenzi, okunciphisa ukuchithwa kwamathambo.I-Cagrilintide inokubophelela kwi-amylin receptors kunye ne-calcitonin receptors kwi-osteoclast precursors, evimbela ukudibanisa kwabo kwii-osteoclasts ezivuthiweyo (Cornish et al., 2015).I-Cagrilintide inokunciphisa ukubonakaliswa kwe-tartrate-resistant acid phosphatase (TRAP), umakishi we-osteoclast umsebenzi kunye ne-bone resorption (Cornish et al., 2015, i-Bonekey Rep.).Ezi ziphumo zinokuphucula ukuxinana kwamathambo kunye nokuthintela okanye ukunyanga i-osteoporosis, imeko ebonakaliswe bubunzima bamathambo obuphantsi kunye nomngcipheko wokuphuka (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
