Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors.: 4.: Incorporation of P1 lactam moieties as L-glutamine replacements
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors.: 4.: Incorporation of P1 lactam moieties as L-glutamine replacements
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DOI：
10.1021/jm9805384
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发表时间：
1999-04-08
影响因子：
7.3
通讯作者：
Worland, ST
中科院分区：
文献类型：
--
作者：
Dragovich, PS;Prins, TJ;Worland, ST
本文介绍了各种人鼻病毒（HRV）3C蛋白酶（3CP）抑制剂的结构设计、化学合成和生物学评价，这些抑制剂含有P-1内酰胺部分代替L-谷氨酰胺残基。这些化合物由三肽基或拟肽结合决定簇和丙烯酸乙酯迈克尔受体部分组成，该部分与3C酶的活性位点半胱氨酸残基形成不可逆的共价加合物。相对于相应的L-谷氨酰胺衍生分子，含β-1-内酰胺的抑制剂显示出显著增加的3CP抑制活性沿着改善的抗鼻病毒性质。此外，几种含内酰胺的化合物对HRV 3CP表现出优于几种其他丝氨酸和半胱氨酸蛋白酶的优异选择性，并且不会被各种生物制剂明显降解。最有效的抑制剂之一（AG 7088，平均抗鼻病毒EC 90 0.10接近μ M，n = 46血清型）显示，保证额外的临床前开发，以探索其作为抗鼻病毒剂的潜力。
The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P-1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P-1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 0.10 approximate to mu M, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.