Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist.
Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist.
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DOI：
10.1021/acs.jmedchem.1c01417
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发表时间：
2021-10-14
影响因子：
7.3
通讯作者：
Haskell-Luevano C
中科院分区：
文献类型：
--
作者：
Ericson MD;Doering SR;Larson CM;Freeman KT;LaVoi TM;Donow HM;Santos RG;Cho RH;Koerperich ZM;Giulianotti MA;Pinilla C;Houghten RA;Haskell-Luevano C
黑皮质素-4 受体 (MC4R) 在食欲中发挥着重要作用。刺激 MC4R 的激动剂配体会降低食欲，而拮抗剂化合物会增加食物消耗。在此，基于功能混合物的位置扫描鉴定出新的 MC4R 拮抗剂序列。在存在和不存在 NDP-MSH 激动剂的情况下筛选包含 12,960,000 个四肽文库的混合物。这些结果导致合成了四十八种单独的四肽，其中筛选了其中四十种对黑皮质素受体的功能活性。发现 13 种化合物对 MC4R 具有纳摩尔拮抗剂效力，其通用四肽序列为 Ac-Aromatic-Basic-Aromatic-Basic-NH2。最显着的结果包括鉴定出四肽 48 [COR1–25, Ac-DPhe(pI)-Arg-Nal(2’)-Arg-NH2]，它是刺豚鼠相关蛋白 [AGRP(86–132)] 的等效 MC4R 拮抗剂，比 miniAGRP(87–120) 更有效，并且对 MC4R 的选择性是 MC3R 的 15 倍。这些四肽可以作为新型食欲诱导疗法的先导，以治疗能量负平衡状态，例如恶病质和厌食症。
The melanocortin-4 receptor (MC4R) plays an important role in appetite. Agonist ligands that stimulate the MC4R decrease appetite, while antagonist compounds increase food consumption. Herein, a functional mixture-based positional scan identified novel MC4R antagonist sequences. Mixtures comprising a library of 12,960,000 tetrapeptides were screened in the presence and absence of NDP-MSH agonist. These results led to the synthesis of forty-eight individual tetrapeptides, of which forty were screened for functional activity at the melanocortin receptors. Thirteen compounds were found to possess nanomolar antagonist potency at the MC4R, with the general tetrapeptide sequence Ac-Aromatic-Basic-Aromatic-Basic-NH2. The most notable results include the identification of tetrapeptide 48 [COR1–25, Ac-DPhe(pI)-Arg-Nal(2’)-Arg-NH2], an equipotent MC4R antagonist to agouti-related protein [AGRP(86–132)], more potent than miniAGRP(87–120), and possesses 15-fold selectivity for the MC4R versus the MC3R. These tetrapeptides may serve as leads for novel appetite-inducing therapies to treat states of negative energy balance, such as cachexia and anorexia.
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影响因子：
7.3
作者：
Doering SR;Freeman K;Debevec G;Geer P;Santos RG;Lavoi TM;Giulianotti MA;Pinilla C;Appel JR;Houghten RA;Ericson MD;Haskell-Luevano C
通讯作者：
Haskell-Luevano C
影响因子：
2.9
作者：
CHEN, WB;SHIELDS, TS;CONE, RD
通讯作者：
CONE, RD
影响因子：
44.5
作者：
Clement, Karine;van den Akker, Erica;Kuehnen, Peter
通讯作者：
Kuehnen, Peter
DOI：
10.1006/bbrc.1993.2125
发表时间：
1993-09-15
影响因子：
3.1
作者：
CHHAJLANI, V;MUCENIECE, R;WIKBERG, JES
通讯作者：
WIKBERG, JES
影响因子：
5
作者：
Chaki, S;Ogawa, S;Okuyama, S
通讯作者：
Okuyama, S