Develop Potent Methyltransferase Inhibitors to Target Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

The recently emerged coronavirus disease-2019 (COVID-19) that commenced in Wuhan China has spread globally at an unprecedented speed. The etiological pathogen for this pandemic disease is a new, enveloped, positive-sense, single-stranded RNA coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). The genome of SARS-CoV-2 is evolutionarily related to the betacoronavirus that caused the SARS outbreak in 2003. Currently there are no targeted effective therapeutics and no vaccines for the viral prevention. In order to rapidly innovate effective medications for clinical curing of this viral infection, we are launching a drug discovery campaign with combined team efforts to develop new therapeutic agents against COVID-19. We aim to target the nonstructural protein 16 (nsp16) of SARS-CoV-2, the ribose 2′-O-methyltransferase enzyme (2′-O- MTase) that is responsible for the formation of viral RNA cap-1 structure, the last step of the 5'-capping of the coronavirus. The methylation mechanism is important for both viral replication and viral evasion by host immune recognition. Thus, drugs targeting the 5'-capping pathway are ideal for eliminating the virulence of this pathogen. The X-ray crystal structures of nsp16/nsp10 protein complex of SARS-CoV-2 have recently been resolved, which showed a great structural similarity to the SARS-CoV nsp16/nsp10 complex structures. The availability of these high-resolution structures provide the important structural basis for screening and design of nsp16 inhibitors. In this project, we will combine computer-aided in silico screening, sensitive biochemical assays, and antiviral cell assays to identify potent nsp16 inhibitors to combat this coronavirus. We will carry out structure-based high- throughput virtual screening to rapidly discover effective inhibitors of the nsp16 2'-O-MTase. The top screening hits will be subjected to biochemical screening against recombinant nsp16 enzyme of SARS-COV-2. Validated nsp16 2'-O-MTase inhibitors will be tested for antiviral activity against SARS-CoV2 strains. The accomplishment of this drug discovery campaign is to generate a novel avenue of experimental therapy against the existential COVID-19 pandemic via inhibiting the 5'-capping pathway of the coronavirus.