Study of and development of antiviral drugs against SARS-CoV2 protease

Division Of Basic Sciences - Nci

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Linked publications & trials

Abstract

The SARS2 Mpro is functional as a dimer; however, its ability to form a dimer is affected by various conditions, such as its state of oxidation and its concentration, Moreover, SARS-CoV-2 Mpro contains 12 cysteines, a large number for a protein of this size. We have observed that the protease has a propensity to undergo oxidation at one or more of these cysteines during purification. This may also occur physiologically, as it would be expected to be under oxidative stress in cells infected with the virus. We have found that Mpro is susceptible to glutathionylation under conditions of oxidative stress. We further showed that the predominantly occurred through glutathionylation of cysteine 300, on the dimer interface, and that thios blocks dimerization of MPro and its activity. This may contribute to viral survival by avoiding killing cells under oxidative stress (such as in bats during migration), and may also reduce the toxicity of Mpro during the latter stages of SARS_CoV-2 replication. We are also working to develop inhibitors of SARS-CoV-2 MPro. In particular, we are exploring nhibitors of dimizeration, especially those that may bind to cysteine 300. This is being dione in collaboratioin with Dr. Brian Peyser and other colleagues in the NCI. In addition, in collaboration with Dr. Mitsuya (HAMB/CCR/NCI), we have developed two inhibitors that bind to the active site of MPro and have potent activity.