约束 C 端氨基酸残基的侧链能极大地增加 Apelin-13 的亲和力、调节信号转导、并改善药代动力学特征。
Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile.
机构信息
Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
出版信息
J Med Chem. 2021 May 13;64(9):5345-5364. doi: 10.1021/acs.jmedchem.0c01941. Epub 2021 Feb 1.
Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ ( 0.08-0.18 nM vs Ape13 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds (Pro12-Phe13 replaced by Aia-Phe, 0.08 nM) and (Pro12-Phe13 replaced by 1Nal-Dbg, 0.08 nM) are the most potent Ape13 analogues activating the Gα pathways (, EC Gα 2.8 nM vs Ape13, EC 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics ( 5.8-7.3 h in rat plasma) and .
侧链受限氨基酸是调节肽类生物特性的有用工具。在这项研究中，我们通过取代 Apelin-13（Ape13）的 Pro12 和 Phe13 位置来应用侧链限制，从而影响 Apelin 受体（APJ）的结合亲和力和信号谱。发现 1Nal、Trp 和 Aia 是 Pro12 的有利取代基，所得类似物对 APJ 具有高亲和力（0.08-0.18 nM 与 Ape13 的 0.7 nM 相比）。此外，受限（d-Tic）或α，α-二取代基（Dbg；d-α-Me-Tyr（OBn））有利于 Phe13 位置。化合物 （Pro12-Phe13 被 Aia-Phe 取代，0.08 nM）和 （Pro12-Phe13 被 1Nal-Dbg 取代，0.08 nM）是迄今为止已知激活 Gα 途径的最有效 Ape13 类似物（, EC Gα 2.8 nM 与 Ape13 的 EC 43 nM 相比），具有高亲和力、对 ACE2 切割的抗性以及改善的药代动力学（在大鼠血浆中 5.8-7.3 h）和 。
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