Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, J1H 5N4, Québec, Canada.
Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, J1H 5N4 Québec, Canada.
ChemMedChem. 2024 Jan 15;19(2):e202300458. doi: 10.1002/cmdc.202300458. Epub 2023 Oct 31.
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.
人类流感病毒会引起急性呼吸道症状，甚至可能导致死亡。由于抗病毒耐药株的出现，目前迫切需要新型抗病毒药物和创新的治疗策略。本研究以肽拟似物苯并噻唑酮蛋白酶抑制剂 RQAR-Kbt（IN-1，又名 N-0100）为起始点，报告了通过取代 P2 和 P4 位置的天然和非天然氨基酸，如何调节其对组织蛋白酶 Matriptase 的抑制效力。Matriptase 是一种典型的 II 型跨膜丝氨酸蛋白酶（TTSP），是流感病毒的启动蛋白酶。我们还对肽拟似物的 N 端基团进行了修饰，这导致其抑制源自人肺的 Calu-3 细胞系中甲型 H1N1 流感病毒复制的能力显著提高（从μM 提高到 nM，比 IN-1 高 60 倍）。通过使用我们最近获得的晶体结构进行分子建模，评估并解释了其对其他蛋白酶的选择性。作为一种治疗方法，靶向宿主细胞 TTSP 可能有助于克服流感病毒的高突变率，从而防止潜在的耐药性。
