具有抗呼吸道合胞病毒活性的模块化α-螺旋模拟物。
Modular alpha-helical mimetics with antiviral activity against respiratory syncitial virus.
作者信息
Shepherd Nicholas E, Hoang Huy N, Desai Vishal S, Letouze Eric, Young Paul R, Fairlie David P
机构信息
Centre for Drug Design and Development, Institute for Molecular Bioscience University of Queensland, Brisbane, Qld 407, Australia.
出版信息
J Am Chem Soc. 2006 Oct 11;128(40):13284-9. doi: 10.1021/ja064058a.
A 13-residue peptide sequence from a respiratory syncitial virus fusion protein was constrained in an alpha-helical conformation by fusing two back-to-back cyclic alpha-turn mimetics. The resulting peptide, Ac-(3-->7; 8-->12)-bicyclo-FP[KDEFD][KSIRD]V-NH(2), was highly alpha-helical in water by CD and NMR spectroscopy, correctly positioning crucial binding residues (F488, I491, V493) on one face of the helix and side chain-side chain linkers on a noninteracting face of the helix. This compound displayed potent activity in both a recombinant fusion assay and an RSV antiviral assay (IC(50) = 36 nM) and demonstrates for the first time that back-to-back modular alpha-helix mimetics can produce functional antagonists of important protein-protein interactions.
通过融合两个背对背的环状α-转角模拟物，呼吸道合胞病毒融合蛋白的一个13个残基的肽序列被限制在α-螺旋构象中。所得肽Ac-(3→7; 8→12)-双环-FP[KDEFD][KSIRD]V-NH₂在水中通过圆二色光谱和核磁共振光谱显示出高度的α-螺旋性，将关键结合残基（F488、I491、V493）正确定位在螺旋的一个面上，而侧链-侧链连接体位于螺旋的非相互作用面上。该化合物在重组融合试验和呼吸道合胞病毒抗病毒试验中均显示出强效活性（IC₅₀ = 36 nM），并首次证明背对背的模块化α-螺旋模拟物可以产生重要蛋白质-蛋白质相互作用的功能性拮抗剂。
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