ʻO Cagrilintide kahi peptide synthetic e hoʻohālike i ka hana a amylin, he hormone i huna ʻia e ka pancreas e hoʻoponopono i nā pae glucose koko a me ka ʻai.Aia ia me 38 amino acids a loaʻa kahi paʻa disulfide.Hoʻopaʻa ʻo Cagrilintide i nā mea hoʻokipa amylin (AMYR) a me calcitonin receptors (CTR), ʻo ia nā G protein-coupled receptors i hōʻike ʻia i loko o nā ʻiʻo like ʻole, e like me ka lolo, ka pancreas, a me ka iwi.Ma ka hoʻoulu ʻana i kēia mau mea loaʻa, hiki i ka cagrilintide ke hōʻemi i ka ʻai ʻana i ka meaʻai, hoʻohaʻahaʻa i nā pae glucose koko, a hoʻonui i ka hoʻolilo ikehu.Ua noiʻi ʻia ʻo Cagrilintide ma ke ʻano he lapaʻau kūpono no ka momona, kahi maʻi metabolic i hōʻike ʻia e ka momona o ke kino a me ka piʻi ʻana o ka maʻi diabetes, maʻi cardiovascular, a me ka maʻi kanesa.Ua hōʻike ʻo Cagrilintide i nā hopena hoʻohiki i nā noiʻi holoholona a me nā hoʻokolohua lapaʻau, e hōʻike ana i ka nui o ke kaumaha o ke kaumaha a me ka hoʻomaikaʻi ʻana i ka mana glycemic i nā maʻi obese me ka maʻi diabetes type 2 a i ʻole.
Kiʻi 1. Homology model of cagrilintide (23) i hoʻopaʻa ʻia i AMY3R.(A) Hoʻokumu ʻia ka ʻāpana N-terminal o 23 (uliuli) e kahi amphipathic a-helix, kanu hohonu ʻia i loko o ka waihona TM o AMY3R, aʻo ka ʻāpana C-terminal e wānana ʻia e hāpai i kahi conformation lōʻihi e hoʻopaʻa i ka ʻāpana extracellular o ka mea hoʻokipa.(29,30) ʻO ka momona momona i hoʻopili ʻia i ka N-terminus o 23, nā koena proline (e hōʻemi i ka fibrillation), a me ka amide C-terminal (pono no ka hoʻopaʻa ʻana i ka mea hoʻopaʻa) e hōʻike ʻia i nā hōʻike lāʻau.Hoʻokumu ʻia ʻo AMY3R e CTR (hina) i hoʻopaʻa ʻia i RAMP3 (mea hoʻololi hoʻololi i ka protein 3; ʻalani).Ua hana ʻia ke kumu hoʻohālike me ka hoʻohana ʻana i nā ʻano hoʻohālike penei: kahi ʻano paʻakikī o CGRP (calcitonin receptor-like receptor; pdb code 6E3Y) a me kahi apo crystal structure o ka iwi kuamoʻo 23 (pdb code 7BG0).(B) Hoʻonui i ka 23 e hōʻike ana i ka pilina N-terminal disulfide, he alahaka paʻakai i loko ma waena o ke koena 14 a me 17, he "leucine zipper motif," a me kahi paʻa hydrogen i loko ma waena o nā koena 4 a me 11. (i hoʻololi ʻia mai 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. Hoʻomohala ʻana o Cagrilintide, he lōʻihi. -Acting Amylin Analogue. J Med Chem. 2021 Aug 12;64(15):11183-11194.)
ʻO kekahi o nā noi olaola o cagrilintide:
Hiki i ka Cagrilintide ke hoʻololi i ka hana o nā neurons i ka hypothalamus, ka ʻāpana o ka lolo e hoʻomalu i ka ʻai a me ke koena o ka ikehu (Lutz et al., 2015, Front Endocrinol (Lausanne)).Hiki i ka Cagrilintide ke pale i ka puhi ʻana i nā neurons orexigenic, ka mea e hoʻoulu ai i ka pōloli, a hoʻāla i nā neurons anorexigenic, e hoʻopau i ka pōloli.No ka laʻana, hiki i ka cagrilintide ke hōʻemi i ka hōʻike o ka neuropeptide Y (NPY) a me ka peptide pili i agouti (AgRP), ʻelua peptides orexigenic potent, a hoʻonui i ka hōʻike o proopiomelanocortin (POMC) a me ka cocaine- a me ka amphetamine-regulated transcript (CART), ʻelua. anorexigenic peptides, i loko o ka arcuate nucleus o ka hypothalamus (Roth et al., 2018, Physiol Behav).Hiki nō hoʻi i ka Cagrilintide ke hoʻoikaika i ka hopena māʻona o ka leptin, he hormone e hōʻailona ai i ke kūlana ikehu o ke kino.Hoʻopili ʻia ʻo Leptin e ka ʻiʻo adipose a hoʻopaʻa ʻia i nā leptin receptors ma nā neurons hypothalamic, ke kāohi nei i nā neurons orexigenic a me ka hoʻoulu ʻana i nā neurons anorexigenic.Hiki i ka Cagrilintide ke hoʻonui i ka naʻau o ka leptin receptors a me ka potentiate leptin-induced activation of signal transducer and activator of transcription 3 (STAT3), kahi mea transcription e hoʻopili i nā hopena o leptin ma ka hōʻike gene (Lutz et al., 2015, Front Endocrinol (Lausanne)) .Hiki i kēia mau hopena ke hōʻemi i ka ʻai ʻana i ka meaʻai a hoʻonui i ka hoʻolilo ʻana i ka ikehu, e alakaʻi ana i ka pohō kaumaha.
Kiʻi 2. ʻO ka ʻai ʻana i nā ʻiole ma hope o ka hoʻokele subcutaneous o Cagrilintide 23. (hoʻololi ʻia mai 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. Hoʻomohala ʻana o Cagrilintide, he Amylin Analogue lōʻihi. J Med Chem. 2021 Aug 12;64(15):11183-11194.)
Hiki i ka Cagrilintide ke hoʻoponopono i ka huna ʻana o ka insulin a me ka glucagon, ʻelua mau hormones e hoʻomalu i ka pae glucose koko.Hiki i ka Cagrilintide ke pale i ka huna ʻana o ka glucagon mai nā cell alpha i loko o ka pancreas, ka mea e pale ai i ka hana ʻana o ka glucose i ke ake.ʻO Glucagon kahi hormone e hoʻoulu ai i ka haki ʻana o ka glycogen a me ka synthesis o ka glucose i loko o ke ake, e hoʻonui ana i nā pae glucose koko.Hiki i ka Cagrilintide ke hoʻopaʻa i ka huna ʻana o ka glucagon ma o ka hoʻopaʻa ʻana i ka amylin receptors a me ka calcitonin receptors ma nā cell alpha, i hui pū ʻia me nā protein inhibitory G e hoʻemi ana i nā pae cyclic adenosine monophosphate (cAMP) a me ka komo ʻana o ka calcium.Hiki i ka Cagrilintide ke hoʻoikaika i ka huna ʻana o ka insulin mai nā cell beta i ka pancreas, kahi e hoʻonui ai i ka lawe ʻana o ka glucose e nā ʻiʻo a me nā kiko adipose.ʻO ka insulin kahi hormone e hāpai i ka mālama ʻana i ka glucose e like me ka glycogen i loko o ke ake a me nā ʻiʻo, a me ka hoʻololi ʻana o ka glucose i nā momona momona i loko o ke kiko adipose, e hoʻohaʻahaʻa ana i nā pae glucose koko.Hiki i ka Cagrilintide ke hoʻoikaika i ka huna ʻana o ka insulin ma o ka hoʻopaʻa ʻana i nā mea loaʻa amylin a me nā mea loaʻa calcitonin ma nā cell beta, i hui pū ʻia me nā protein stimulatory G e hoʻonui ai i nā pae cAMP a me ka komo ʻana o ka calcium.Hiki i kēia mau hopena ke hoʻohaʻahaʻa i ka pae glucose koko a hoʻomaikaʻi i ka ʻike insulin, hiki ke pale a mālama i ka maʻi diabetes type 2 (Kruse et al., 2021, J Med Chem; Dehestani et al., 2021, J Obes Metab Syndr.).
Hiki i ka Cagrilintide ke hoʻopili i ka hana o nā osteoblasts a me nā osteoclast, ʻelua ʻano o nā cell e pili ana i ka hana iwi a me ka resorption.Na Osteoblasts ke kuleana no ka hana ʻana i nā iwi iwi hou, aʻo nā osteoclast ke kuleana no ka wāwahi ʻana i nā iwi iwi kahiko.ʻO ke kaulike ma waena o nā osteoblasts a me nā osteoclast e hoʻoholo i ka nui o ka iwi a me ka ikaika.Hiki i ka Cagrilintide ke hoʻoulu i ka ʻokoʻa osteoblast a me ka hana, kahi e hoʻonui ai i ka hana iwi.Hiki i ka Cagrilintide ke hoʻopaʻa i ka amylin receptors a me ka calcitonin receptors ma nā osteoblasts, ka mea e hoʻoulu ai i nā ala hōʻailona intracellular e hāpai i ka hoʻonui ʻana o ka osteoblast, ke ola, a me ka synthesis matrix (Cornish et al., 1996, Biochem Biophys Res Commun. ).Hiki i ka Cagrilintide ke hoʻonui i ka hōʻike o ka osteocalcin, kahi hōʻailona o ka osteoblast maturation a me ka hana (Cornish et al., 1996, Biochem Biophys Res Commun.).Hiki i ka Cagrilintide ke pale i ka hoʻokaʻawale ʻana o ka osteoclast a me ka hana, e hoʻemi ana i ka hoʻihoʻi ʻana o ka iwi.Hiki i ka Cagrilintide ke hoʻopaʻa i ka amylin receptors a me ka calcitonin receptors ma nā osteoclast precursors, kahi e kāohi ai i kā lākou hui ʻana i nā osteoclasts makua (Cornish et al., 2015).Hiki i ka Cagrilintide ke hōʻemi i ka hōʻike ʻana o ka tartrate-resistant acid phosphatase (TRAP), kahi hōʻailona o ka hana osteoclast a me ka resorption iwi (Cornish et al., 2015, Bonekey Rep.).Hiki i kēia mau hopena ke hoʻomaikaʻi i ka nui o ka mineral iwi a pale a mālama paha i ka osteoporosis, kahi kūlana i hōʻike ʻia e ka iwi haʻahaʻa a me ka piʻi ʻana o ka haʻihaʻi (Kruse et al., 2021; Dehestani et al., 2021, J Obes Metab Syndr.)
