Accurate de novo design of hyperstable constrained peptides.
Accurate de novo design of hyperstable constrained peptides.
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DOI：
10.1038/nature19791
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发表时间：
2016-10-20
期刊：
影响因子：
64.8
通讯作者：
Baker, David
中科院分区：
文献类型：
--
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
天然产生的、具有药理活性的、受共价交联约束的多肽通常具有进化的形状，以精确地适合于其靶标上的结合口袋。这种多肽将小分子药物的稳定性和组织渗透性与大得多的蛋白质疗法的特异性结合在一起，可以具有出色的药学特性。设计具有精确指定三级结构的限制性多肽的能力将使设计任意靶标的形状互补抑制剂成为可能。在这里，我们描述了构象限制性多肽从头设计的计算方法的发展，并用这些方法设计了15-50个残基的二硫键交联和异手性N-C主链环化肽。这些多肽对热和化学变性非常稳定，12个实验确定的X射线和核磁共振结构与计算模型几乎相同。本文提出的计算设计方法和稳定的支架为新一代多肽类药物的开发奠定了基础。
Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets. Here we describe the development of computational methods for de novo design of conformationally-restricted peptides, and the use of these methods to design 15–50 residue disulfide-crosslinked and heterochiral N-C backbone-cyclized peptides. These peptides are exceptionally stable to thermal and chemical denaturation, and twelve experimentally-determined X-ray and NMR structures are nearly identical to the computational models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs.
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影响因子：
2.9
作者：
Kimura RH;Levin AM;Cochran FV;Cochran JR
通讯作者：
Cochran JR
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
3.6
作者：
Cheneval, Olivier;Schroeder, Christina I.;Craik, David J.
通讯作者：
Craik, David J.
影响因子：
3
作者：
Coutsias, EA;Seok, C;Dill, KA
通讯作者：
Dill, KA