Dragovich P S, Prins T J, Zhou R, Fuhrman S A, Patick A K, Matthews D A, Ford C E, Meador J W, Ferre R A, Worland S T
Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA.
J Med Chem. 1999 Apr 8;42(7):1203-12. doi: 10.1021/jm980537b.
The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a 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 ketomethylene-containing inhibitors typically display slightly reduced 3CP inhibition activity relative to the corresponding peptide-derived molecules, but they also exhibit significantly improved antiviral properties. Optimization of the ketomethylene-containing compounds is shown to provide several highly active 3C protease inhibitors which function as potent antirhinoviral agents (EC90 = <1 microM) against multiple virus serotypes in cell culture.
描述了各种含酮亚甲基的人鼻病毒（HRV）3C蛋白酶（3CP）抑制剂的基于结构的设计、化学合成及生物学评价。这些化合物由一个拟肽结合决定簇和一个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。相对于相应的肽衍生分子，含酮亚甲基的抑制剂通常表现出略低的3CP抑制活性，但它们也展现出显著改善的抗病毒特性。结果表明，对含酮亚甲基化合物进行优化可得到几种高活性的3C蛋白酶抑制剂，这些抑制剂在细胞培养中对多种病毒血清型具有强效抗鼻病毒作用（EC90 = <1 microM）。
