Abstract：
Human influenza viruses cause acute respiratory symptoms that can lead to death. Due to the emergence of antiviral drug-resistant strains, there is an urgent requirement for novel antiviral agents and innovative therapeutic strategies. Using the peptidomimetic ketobenzothiazole protease inhibitor RQAR-Kbt (IN-1, aka N-0100) as a starting point, we report how substituting P2 and P4 positions with natural and unnatural amino acids can modulate the inhibition potency toward matriptase, a prototypical type II transmembrane serine protease (TTSP) that acts as a priming protease for influenza viruses. We also introduced modifications of the peptidomimetics N-terminal groups, leading to significant improvements (from μM to nM, 60 times more potent than IN-1) in their ability to inhibit the replication of influenza H1N1 virus in the Calu-3 cell line derived from human lungs. The selectivity towards other proteases has been evaluated and explained using molecular modeling with a crystal structure recently obtained by our group. By targeting host cell TTSPs as a therapeutic approach, it may be possible to overcome the high mutational rate of influenza viruses and consequently prevent potential drug resistance.
摘要：
人类流感病毒引起急性呼吸道症状，可导致死亡。由于抗病毒耐药菌株的出现，迫切需要新型抗病毒药物和创新的治疗策略。使用拟肽酮苯并噻唑蛋白酶抑制剂RQAR-Kbt（IN-1，又名N-0100）作为起点，我们报告了如何用天然和非天然氨基酸取代P2和P4位置可以调节对蛋白裂解酶的抑制效力，一种典型的II型跨膜丝氨酸蛋白酶（TTSP），可作为流感病毒的引发蛋白酶。我们还引入了肽模拟物N端组的修饰，导致显着改善（从μM到nM，在抑制源自人肺的Calu-3细胞系中H1N1流感病毒复制的能力方面，其效力是IN-1的60倍）。对其他蛋白酶的选择性已经使用分子模型进行了评估和解释，具有我们小组最近获得的晶体结构。通过靶向宿主细胞TTSP作为治疗方法，有可能克服流感病毒的高突变率，从而防止潜在的耐药性。
