Structure-Based Design of a Dual-Targeted Covalent Inhibitor Against Papain-like and Main Proteases of SARS-CoV‑2

The
two proteases, PLpro and Mpro, of SARS-CoV-2
are essential for replication of the virus. Using a structure-based
co-pharmacophore screening approach, we developed a novel dual-targeted
inhibitor that is equally potent in inhibiting PLpro and
Mpro of SARS-CoV-2. The inhibitor contains a novel warhead,
which can form a covalent bond with the catalytic cysteine residue
of either enzyme. The maximum rate of the covalent inactivation is
comparable to that of the most potent inhibitors reported for the
viral proteases and covalent inhibitor drugs currently in clinical
use. The covalent inhibition appears to be very specific for the viral
proteases. The inhibitor has a potent antiviral activity against SARS-CoV-2
and is also well tolerated by mice and rats in toxicity studies. These
results suggest that the inhibitor is a promising lead for development
of drugs for treatment of COVID-19.

新型冠状病毒（SARS-CoV-2）的两种蛋白酶（protease）——木瓜样蛋白酶（PLpro）与主蛋白酶（Mpro）——对病毒的复制过程至关重要。本研究采用基于结构的共同药效团筛选方法（structure-based co-pharmacophore screening approach），开发出一种新型双靶点抑制剂，其对SARS-CoV-2的PLpro与Mpro均具有同等强效的抑制活性。该抑制剂含有一种新型弹头基团，可与两种酶的催化半胱氨酸残基形成共价键。其共价失活的最大速率，可与目前已报道的最强效病毒蛋白酶抑制剂以及当前临床使用的共价抑制剂药物相媲美。该共价抑制作用对病毒蛋白酶具有极高的特异性。该抑制剂对SARS-CoV-2展现出强效抗病毒活性，且在小鼠与大鼠的毒性研究中表现出良好的耐受性。上述研究结果表明，该抑制剂是开发治疗新型冠状病毒肺炎（COVID-19）药物的极具前景的先导化合物。