The SARS-CoV-2 replication-transcription complex is a priority target for broad-spectrum pan-coronavirus drugs (preprint)

In the absence of effective treatment, COVID-19 is likely to remain a global disease burden. Compounding this threat is the near certainty that novel coronaviruses with pandemic potential will emerge in years to come. Pan-coronavirus drugs - agents active against both SARS-CoV-2 and other coronaviruses - would address both threats. A strategy to develop such broad-spectrum inhibitors is to pharmacologically target binding sites on SARS-CoV-2 proteins that are highly conserved in other known coronaviruses, the assumption being that any selective pressure to keep a site conserved across past viruses will apply to future ones. Here, we systematically mapped druggable binding pockets on the experimental structure of fifteen SARS-CoV-2 proteins and analyzed their variation across twenty-seven - and {beta}-coronaviruses and across thousands of SARS-CoV-2 samples from COVID-19 patients. We find that the two most conserved druggable sites are a pocket overlapping the RNA binding site of the helicase nsp13, and the catalytic site of the RNA-dependent RNA polymerase nsp12, both components of the viral replication-transcription complex. We present the data on a public web portal (https://www.thesgc.org/SARSCoV2_pocketome/) where users can interactively navigate individual protein structures and view the genetic variability of drug binding pockets in 3D.

Structure, Mechanism and Crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase (preprint)

The global COVID-19 pandemic is caused by the SARS-CoV-2 virus and has infected over 100 million and caused over 2 million fatalities worldwide at the point of writing. There is currently a lack of effective drugs to treat people infected with SARS-CoV-2. The SARS-CoV-2 Non-structural protein 13 (NSP13) is a superfamily1B helicase that has been identified as a possible target for anti-viral drugs due to its high sequence conservation and essential role in viral replication. In this study we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and the non-hydrolysable ATP analogue (AMP-PNP). Comparisons of these structures reveal details of global and local conformational changes that are induced by nucleotide binding and hydrolysis and provide insights into the helicase mechanism and possible modes of inhibition. Structural analysis reveals two pockets on NSP13 that are classified as "druggable" and include one of the most conserved sites in the entire SARS-CoV-2 proteome. To identify possible starting points for anti-viral drug development we have performed a crystallographic fragment screen against SARS-CoV-2 NSP13 helicase. The fragment screen reveals 65 fragment hits across 52 datasets, with hot spots in pockets predicted to be of functional importance, including the druggable nucleotide and nucleic acid binding sites, opening the way to structure guided development of novel antiviral agents.