Abstract
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 [Ki] = 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 (Ki = 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 (Ki = 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.
Highlights
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
On March 11, 2020, the World Health Organization recognized the COVID-19 outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a pandemic
Vaccines are being approved for emergency use to fight COVID-19, there is an urgent need for effective new drug treatments to reduce the morbidity and mortality for patients who have already contracted COVID-19, not yet received the vaccine, are infected with SARS-CoV-2 variants that are more resistant to the vaccines, and for future coronavirus pandemics
Summary
DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 Mpro inhibitors. DEC-Tec involves the creation of libraries of drug-like molecules covalently attached to a unique DNA barcode that enables identification of binders for a target in a pool of millions to billions of compounds. DEC-Tec addresses these pitfalls related to HTS by screening of billions of DNA-tagged small molecules as a single mixture using an affinity selection assay [4, 8,9,10,11,12,13]. The DEC-Tec process involving affinity selection of 4 billion DNA-encoded compounds against Mpro, analysis of SER, and synthesis of the exemplary compounds (including with different electrophiles) off DNA (SI Appendix, Fig. S5 and Table S1) yielded potent and selective inhibitors of Mpro.
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