I-Cagrilintide iyi-peptide yokwenziwa elingisa isenzo se-amylin, ihomoni ekhishwa amanyikwe elawula amazinga kashukela egazini kanye nesifiso sokudla.Yakhiwe ngama-amino acid angama-38 futhi iqukethe isibopho se-disulfide.I-Cagrilintide ibophezela kukho kokubili ama-amylin receptors (AMYR) nama-calcitonin receptors (CTR), okuyi-G protein-coupled receptors evezwa ezicutshini ezihlukahlukene, njengobuchopho, amanyikwe, nethambo.Ngokuvula lawa ma-receptors, i-cagrilintide inganciphisa ukudla, amazinga eglucose egazi aphansi, futhi andise ukusetshenziswa kwamandla.I-Cagrilintide iye yaphenywa njengendlela yokwelapha ukukhuluphala okungase ibe khona, ukuphazamiseka kwe-metabolic ebonakala ngokukhuluphala ngokweqile kanye nengozi eyengeziwe yesifo sikashukela, isifo senhliziyo nemithambo yegazi, kanye nomdlavuza.I-Cagrilintide ibonise imiphumela ethembisayo ezifundweni zezilwane nasezivivinyweni zomtholampilo, ezibonisa ukuncipha okukhulu kwesisindo kanye nokulawulwa okuthuthukisiwe kwe-glycemic ezigulini ezikhuluphele ezinesifo sikashukela sohlobo 2 noma ezingenalo.
Umfanekiso 1. Imodeli ye-Homology ye-cagrilintide (23) eboshelwe ku-AMY3R.(A) Ingxenye ye-N-terminal ye-23 (eluhlaza okwesibhakabhaka) yakhiwe i-amphipathic a-helix, engcwatshwe ngokujulile esizindeni se-TM se-AMY3R, kuyilapho ingxenye ye-C-terminal ibikezelwa ukuthi izokwamukela i-conformation enwetshiwe ebopha ingxenye engaphandle kwe-extracellular umamukeli.(29,30) I-fatty acid enamathiselwe ku-N-terminus engu-23, izinsalela ze-proline (ezinciphisa i-fibrillation), kanye ne-C-terminal amide (ibalulekile ekubopheni i-receptor) agqanyiswa ezenzweni zenduku.I-AMY3R yakhiwe nge-CTR (grey) eboshwe ku-RAMP3 (i-receptor-activity modifying protein 3; orange).Imodeli yesakhiwo idalwe kusetshenziswa izakhiwo zesifanekiso ezilandelayo: isakhiwo esiyinkimbinkimbi se-CGRP (i-calcitonin receptor-like receptor; ikhodi ye-pdb 6E3Y) kanye nesakhiwo se-apo crystal yomgogodla we-23 (pdb code 7BG0).(B) Sondeza phezulu kokungu-23 okugqamisa ibhondi ye-N-terminal disulfide, ibhuloho likasawoti langaphakathi phakathi kwezinsalela ezingu-14 no-17, “i-leucine zipper motif,” kanye nebhondi ye-hydrogen yangaphakathi phakathi kwezinsalela ezingu-4 no-11. (ithathwe ku-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.)
Ezinye zezinto eziphilayo ze-cagrilintide yilezi:
I-Cagrilintide ingashintsha umsebenzi wama-neurons ku-hypothalamus, isifunda sobuchopho esilawula ukudla kanye nebhalansi yamandla (Lutz et al., 2015, Front Endocrinol (Lausanne)).I-Cagrilintide ingavimbela ukudubula kwama-orexigenic neurons, avusa indlala, futhi enze kusebenze ama-anorexigenic neurons, acindezela indlala.Isibonelo, i-cagrilintide inganciphisa ukuvezwa kwe-neuropeptide Y (NPY) kanye ne-peptide ehlobene ne-agouti (AgRP), ama-peptide amabili e-orexigenic anamandla, futhi ikhulise ukuvezwa kwe-proopiomelanocortin (POMC) kanye ne-cocaine- kanye ne-amphetamine-regulated transcript (CART), ezimbili. ama-peptide anorexigenic, ku-nucleus ye-arcuate ye-hypothalamus (Roth et al., 2018, Physiol Behav).I-Cagrilintide ingaphinda ithuthukise umphumela wokusuthisa we-leptin, ihomoni ebonisa isimo samandla omzimba.I-Leptin ikhiqizwa izicubu ze-adipose futhi ibophezela kuma-leptin receptors kuma-hypothalamic neurons, ivimbela ama-orexigenic neurons futhi isebenze ama-anorexigenic neurons.I-Cagrilintide ingakhuphula ukuzwela kwama-leptin receptors futhi yenze kusebenze i-leptin-induced ye-transducer yesiginali kanye ne-activator ye-transcription 3 (STAT3), into ebhaliwe elamula imiphumela ye-leptin ekukhulumeni kofuzo (Lutz et al., 2015, Front Endocrinol (Lausanne)) .Le miphumela inganciphisa ukudla futhi yandise ukusetshenziswa kwamandla, okuholela ekulahlekelweni kwesisindo.
Umfanekiso 2. Ukudla kwamagundane ngemva kokuphathwa kwe-subcutaneous kwe-Cagrilintide 23. (ishintshwe ku-Kruse T, Hansen JL, Dahl K, Schäffer L, Sensfuss U, Poulsen C, Schlein M, Hansen AMK, Jeppesen CB, Dornonville de la Cour C, U-Clausen TR, u-Johansson E, u-Fulle S, u-Skyggebjerg RB, u-Raun K. Ukuthuthukiswa kwe-Cagrilintide, i-Amylin Analogue Ebambe Isikhathi Eside. J Med Chem. 2021 Aug 12;64(15):11183-11194.)
I-Cagrilintide ingalawula ukukhiqizwa kwe-insulin neglucagon, amahomoni amabili alawula amazinga kashukela egazini.I-Cagrilintide ingavimbela ukukhiqizwa kwe-glucagon kumaseli e-alpha ku-pancreas, okuvimbela ukukhiqizwa kwe-glucose ngokweqile esibindini.I-Glucagon iyi-hormone ekhuthaza ukuwohloka kwe-glycogen kanye nokuhlanganiswa kwe-glucose esibindini, inyusa amazinga kashukela egazini.I-Cagrilintide ingacindezela ukukhiqizwa kweglucagon ngokubophezela kuma-amylin receptors nama-calcitonin receptors kumaseli e-alpha, ahlanganiswe namaphrotheni e-G avimbelayo anciphisa amazinga e-cyclic adenosine monophosphate (cAMP) kanye nokungena kwe-calcium.I-Cagrilintide ingakwazi futhi ukukhiqiza i-insulin ephuma kumaseli e-beta ku-pancreas, okuthuthukisa ukumuncwa kwe-glucose ngezicubu nezicubu ze-adipose.I-insulin iyi-hormone ekhuthaza ukugcinwa kwe-glucose njenge-glycogen esibindini nasemisipha, kanye nokuguqulwa kwe-glucose ibe ama-acids anamafutha ezicubu ze-adipose, ehlisa amazinga kashukela egazini.I-Cagrilintide ingathuthukisa ukukhiqizwa kwe-insulin ngokubophezela kuma-amylin receptors nama-calcitonin receptors kumaseli e-beta, ahlanganiswe namaphrotheni e-G avuselelayo akhuphula amazinga e-cAMP kanye nokungena kwe-calcium.Le miphumela ingehlisa amazinga kashukela egazini futhi ithuthukise ukuzwela kwe-insulin, engavimbela noma yelaphe uhlobo lwesifo sikashukela sohlobo 2 (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
I-Cagrilintide ingaphinde ithinte umsebenzi we-osteoblasts nama-osteoclasts, izinhlobo ezimbili zamaseli ezihilelekile ekwakhiweni kwamathambo kanye nokuvuselelwa kabusha.Ama-osteoblasts anesibopho sokukhiqiza i-matrix entsha yamathambo, kuyilapho ama-osteoclast anesibopho sokudiliza i-matrix yamathambo amadala.Ibhalansi phakathi kwama-osteoblasts nama-osteoclasts inquma ubukhulu bamathambo namandla.I-Cagrilintide ingashukumisa ukuhlukaniswa kwe-osteoblast nomsebenzi, okwandisa ukwakheka kwamathambo.I-Cagrilintide ingabophezela kuma-amylin receptors kanye nama-calcitonin receptors kuma-osteoblasts, okwenza kusebenze izindlela zokusayina ze-intracellular ezikhuthaza ukwanda kwe-osteoblast, ukusinda, kanye ne-matrix synthesis (Cornish et al., 1996, Biochem Biophys Res Commun. ).I-Cagrilintide ingaphinda ikhulise ukuvezwa kwe-osteocalcin, umaka wokuvuthwa kwe-osteoblast nomsebenzi (Cornish et al., 1996, Biochem Biophys Res Commun.).I-Cagrilintide ingaphinda ivimbele ukuhlukaniswa kwe-osteoclast nomsebenzi, okunciphisa ukubuyiswa kwamathambo.I-Cagrilintide ingabophezela kuma-amylin receptors kanye nama-calcitonin receptors kuma-osteoclast precursors, avimbela ukuhlanganiswa kwawo kuma-osteoclast avuthiwe (Cornish et al., 2015).I-Cagrilintide ingaphinda yehlise ukuvezwa kwe-tartrate-resistant acid phosphatase (TRAP), umaka womsebenzi we-osteoclast kanye ne-bone resorption (Cornish et al., 2015, Bonekey Rep.).Le miphumela ingathuthukisa ukuminyana kwamaminerali amathambo futhi ivimbele noma yelaphe i-osteoporosis, isimo esibonakala ngesisindo esiphansi samathambo kanye nokwanda kwengozi yokuphuka (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
