Hydrogen Exchange-Mass Spectrometry Measures Stapled Peptide Conformational Dynamics and Predicts Pharmacokinetic Properties
Hydrogen Exchange-Mass Spectrometry Measures Stapled Peptide Conformational Dynamics and Predicts Pharmacokinetic Properties
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DOI：
10.1021/ac403173p
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发表时间：
2013-12-03
影响因子：
7.4
通讯作者：
Annis, D. Allen
中科院分区：
文献类型：
--
作者：
Shi, Xiangguo (Eric);Wales, Thomas E.;Annis, D. Allen
肽类药物由于其构象灵活性和蛋白酶与骨架酰胺键的相互作用，传统上具有较差的药理学性质。使用全烃交联策略将“钉合肽”环化以增强其α-螺旋构象，从而产生改善的蛋白酶抗性和药物样性质。在这里，我们证明，氢交换质谱（HX-MS）有效地探测构象动力学的钉合肽来源于生存素-borealin蛋白质-蛋白质界面，并预测其对蛋白水解降解的敏感性。在钉合肽中，根据钉合位置，与天然肽序列相比，酰胺交换减少了超过五个数量级。此外，氘化动力学与蛋白水解速率直接相关，以揭示改善药物特性的最佳吻合钉放置。
Peptide drugs have traditionally suffered from poor pharmacoldnetic properties due to their conformational flexibility and the interaction of proteases with backbone amide bonds. "Stapled Peptides" are cyclized using an all-hydrocarbon cross-linking strategy to reinforce their alpha-helical conformation, yielding improved protease resistance and drug-like properties. Here we demonstrate that hydrogen exchange-mass spectrometry (HX-MS) effectively probes the conformational dynamics of Stapled Peptides derived from the survivin-borealin protein-protein interface and predicts their susceptibility to proteolytic degradation. In Stapled Peptides, amide exchange was reduced by over five orders-of-magnitude versus the native peptide sequence depending on staple placement. Furthermore, deuteration kinetics correlated directly with rates of proteolysis to reveal the optimal staple placement for improved drug properties.