The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C–H of the CHF₂ moiety and the backbone carbonyl of Leu135 of the enzyme. Structure–activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH₃ and CF₃ analogues, respectively, providing insight into the deployment of this unique amino acid.

中文翻译：

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丙型肝炎病毒NS3蛋白酶的有效抑制剂：使用二氟甲基作为氢键供体

描述了在P1处含有二氟甲基环丙基氨基酸的HCV NS3蛋白酶的有效三肽酰基磺酰胺抑制剂的设计和合成。18与NS3 / 4A蛋白酶复合物的共晶体结构表明，在CHF ₂部分的极化C–H与酶的Leu135的主链羰基之间存在H键。结构与活性之间的关系研究表明，与CH ₃和CF ₃类似物相比，这种H键分别将酶抑制能力提高了13倍和17倍，从而为这种独特氨基酸的应用提供了见识。