Ashhurst Anneliese S, Tang Arthur H, Fajtová Pavla, Yoon Michael, Aggarwal Anupriya, Stoye Alexander, Larance Mark, Beretta Laura, Drelich Aleksandra, Skinner Danielle, Li Linfeng, Meek Thomas D, McKerrow James H, Hook Vivian, Tseng Chien-Te K, Turville Stuart, Gerwick William H, O'Donoghue Anthony J, Payne Richard J
bioRxiv. 2020 Dec 24:2020.12.23.424111. doi: 10.1101/2020.12.23.424111.
The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L activity with IC values in the picomolar range. Lead molecules possessed selectivity over cathepsin B and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro and PLpro. We demonstrate that gallinamide A and two lead analogues potently inhibit SARS-CoV-2 infection , with EC values in the nanomolar range, thus further highlighting the potential of cathepsin L as a COVID-19 antiviral drug target.
2019年末严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的出现以及随后的新型冠状病毒肺炎（COVID-19）大流行，已导致大量死亡，并造成全球大规模混乱。迫切需要用于治疗或预防的新型抗病毒药物。组织蛋白酶L是冠状病毒用于进入细胞的关键宿主半胱氨酸蛋白酶，被认为是一个有前景的药物靶点。海洋天然产物加林酰胺A和几种合成类似物被鉴定为组织蛋白酶L活性的有效抑制剂，其半数抑制浓度（IC）值在皮摩尔范围内。先导分子对组织蛋白酶B和其他相关的人类组织蛋白酶具有选择性，并且对病毒蛋白酶Mpro和PLpro没有抑制活性。我们证明，加林酰胺A和两种先导类似物能有效抑制SARS-CoV-2感染，其半数有效浓度（EC）值在纳摩尔范围内，从而进一步突出了组织蛋白酶L作为COVID-19抗病毒药物靶点的潜力。
