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Peptoid NPhe4 in AGRP-Based c[Pro1-Arg2-Phe3-Phe4-Xxx5-Ala6-Phe7-DPro8] Scaffolds Maintain Mouse MC4R Antagonist Potency
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-27 , DOI: 10.1021/acsmedchemlett.9b00641
Mark D Ericson 1 , Katie T Freeman 1 , Carrie Haskell-Luevano 1
Affiliation  

The melanocortin receptors are involved in numerous physiological functions and are regulated by agonists derived from the proopiomelanocortin gene transcript and two endogenous antagonists, agouti and agouti-related protein (AGRP). The key binding and functional determinant of AGRP, an MC3R and MC4R antagonist, is an Arg-Phe-Phe tripeptide sequence located on an exposed hexapeptide (Arg-Phe-Phe-Asn-Ala-Phe) loop. It has previously been observed that cyclizing this sequence through a DPro-Pro motif (c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8]) resulted in a macrocyclic scaffold with MC4R antagonist activity, with increased MC4R potency when a diaminopropionic acid (Dap) residue is substituted at position 5. In this report, a series of 11 single-peptoid substitutions were performed in the AGRP-derived macrocycles. While most peptoid substitutions decreased MC4R antagonist potency, it was observed that NPhe4 (compounds 4 and 11) or NDab5 (diaminobutyric acid, compound 7) maintained MC4R antagonist potency. The NPhe4 substitutions also resulted in MC5R antagonist and inverse agonist activity equipotent to the parent scaffolds. These data may be used in the design of future MC4R and MC5R antagonist leads and probes that possess increased metabolic stability due to the presence of peptoid residues.

中文翻译:

基于 AGRP 的 c[Pro1-Arg2-Phe3-Phe4-Xxx5-Ala6-Phe7-DPro8] 支架中的 Peptoid NPhe4 维持小鼠 MC4R 拮抗剂效力

黑皮质素受体参与多种生理功能,并受源自阿黑皮质素原基因转录本的激动剂和两种内源性拮抗剂、刺豚鼠和刺鼠相关蛋白 (AGRP) 的调节。AGRP(一种 MC3R 和 MC4R 拮抗剂)的关键结合和功能决定因素是位于暴露的六肽 (Arg-Phe-Phe-Asn-Ala-Phe) 环上的 Arg-Phe-Phe 三肽序列。之前已经观察到通过 DPro-Pro 基序 (c[Pro 1 -Arg 2 -Phe 3 -Phe 4 -Asn 5 -Ala 6 -Phe 7 -DPro 8]) 产生了具有 MC4R 拮抗剂活性的大环支架,当二氨基丙酸 (Dap) 残基在第 5 位被取代时,MC4R 效力增加。在本报告中,在 AGRP 衍生的大环中进行了一系列 11 个单肽类取代. 虽然大多数拟肽取代降低了 MC4R 拮抗剂的效力,但观察到 NPhe 4(化合物411)或 NDab 5(二氨基丁酸,化合物7)保持了 MC4R 拮抗剂的效力。NPhe 4替代还导致 MC5R 拮抗剂和反向激动剂活性与亲本支架等效。这些数据可用于设计未来的 MC4R 和 MC5R 拮抗剂引线和探针,由于类肽残基的存在,它们具有更高的代谢稳定性。
更新日期:2020-03-27
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