School of Chemistry, The University of Sydney, Sydney, NSW2006, Australia.
School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW2006, Australia.
J Med Chem. 2022 Feb 24;65(4):2956-2970. doi: 10.1021/acs.jmedchem.1c01494. Epub 2021 Nov 3.
Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 infection , with EC values in the nanomolar range. Reduced antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2); however, a synergistic improvement in antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy.
组织蛋白酶 L 是冠状病毒用于细胞进入的关键宿主半胱氨酸蛋白酶，是针对新型 SARS-CoV-2 抗病毒药物的有前途的药物靶点。海洋天然产物鹅膏蕈氨酸 A 及其几种合成类似物被鉴定为强效组织蛋白酶 L 抑制剂，其 IC 值在皮摩尔范围内。先导分子对其他组织蛋白酶和参与病毒进入的替代宿主蛋白酶具有选择性。鹅膏蕈氨酸 A 在细胞内直接与组织蛋白酶 L 相互作用，与两种先导类似物一起，强烈抑制 SARS-CoV-2 感染，EC 值在纳摩尔范围内。在过表达跨膜蛋白酶丝氨酸 2（TMPRSS2）的细胞中观察到抗病毒活性降低；然而，当与 TMPRSS2 抑制剂联合使用时，抗病毒活性得到协同改善。这些数据突出了组织蛋白酶 L 作为 COVID-19 药物靶点的潜力，以及可能需要抑制多种病毒进入途径以实现疗效。
