DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 Mpro inhibitors.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [K i] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (K i = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (K i = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets.
['Chamakuri|Srinivas|S|', 'Lu|Shuo|S|', 'Ucisik|Melek Nihan|MN|', 'Bohren|Kurt M|KM|0000-0002-3183-4118', 'Chen|Ying-Chu|YC|', 'Du|Huang-Chi|HC|', 'Faver|John C|JC|0000-0002-0181-9283', 'Jimmidi|Ravikumar|R|', 'Li|Feng|F|0000-0002-9680-4614', 'Li|Jian-Yuan|JY|', 'Nyshadham|Pranavanand|P|', 'Palmer|Stephen S|SS|', 'Pollet|Jeroen|J|0000-0003-1420-4015', 'Qin|Xuan|X|', 'Ronca|Shannon E|SE|', 'Sankaran|Banumathi|B|', 'Sharma|Kiran L|KL|0000-0002-1988-389X', 'Tan|Zhi|Z|', 'Versteeg|Leroy|L|', 'Yu|Zhifeng|Z|0000-0001-7278-8253', 'Matzuk|Martin M|MM|0000-0002-1445-8632', 'Palzkill|Timothy|T|', 'Young|Damian W|DW|']
D000818:Animals D000086382:COVID-19 D002478:Cells, Cultured D000086782:Coronavirus 3C Proteases D004305:Dose-Response Relationship, Drug D055808:Drug Discovery D004789:Enzyme Activation D005818:Genetic Engineering D006801:Humans D008958:Models, Molecular D008968:Molecular Conformation D015394:Molecular Structure D011480:Protease Inhibitors D000086402:SARS-CoV-2 D013329:Structure-Activity Relationship D014779:Virus Replication
covalent inhibitors antiviral drug discovery