Abstract
Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (Mpro) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 Mpro, and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 Mpro at 2.5 µM, which is more potent than against SAR-CoV-1 Mpro. We determined the crystal structure of ML188 in complex with SARS-CoV-2 Mpro to 2.39 Å resolution. Sharing 96% sequence identity, structural comparison of the two complexes only shows subtle differences. Non-covalent protease inhibitors complement the design of covalent inhibitors against SARS-CoV-2 main protease and are critical initial steps in the design of DAAs to treat CoVID 19.
Highlights
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]
The current study focuses on SARS2-Main protease (Mpro), a chymotrypsin-like cysteine protease that resides in the viral non-structural protein 5 [13]
To elucidate structural differences in ML188 binding, the cocrystal structure of ML188 in complex with SARS2-Mpro was determined to 2.39 Å resolution (Table S1; Figure 2)
Summary
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. Zoonotic transmissions of coronaviruses to humans have caused at least three major outbreaks during the past two decades; SARS in 2002 [2,3], MERS in 2012 [4], and SARS-2 in 2019–2020 [5,6]. The previous outbreaks were contained with rigorous public health interventions, and basic research and vaccine/drug developments had largely been suspended. As is evident from the current global pandemic [7], coronaviruses pose a major threat to human health, and treatment options need to be developed for the current pandemic and for future coronavirus outbreaks. In addition to the major efforts for developing vaccines around the world, direct acting antivirals (DAAs) are critical to treat vulnerable patients to decrease morbidity and mortality.
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