Anti-viral drug discovery
Since January 2020, staff from NDM’s Structural Biology Division (STRUBI), Diamond and the Rosalind Franklin Institute have worked to create, characterise and distribute a wide variety of SARS-Cov-2 viral proteins for the purposes of drug screens. This has evolved into a UK wide COVID-19 Protein Production Consortium (CPPC).
Amongst 29 SAR-Cov2 specific proteins, there are several potentially druggable enzymes and proteins inhibiting anti-viral immunity; and several of these could be targeted in all coronaviruses to provide defence against future pandemics. STRUBI scientists working at Diamond solved the structure of the SARS-CoV-2 main protease and completed a large XChem crystallographic fragment screen against it, which was led by Professor Frank von Delft (XChem) The follow up on this initiative was managed externally through an open crowdsourcing and crowd-funding initiative, the COVID Moonshot. On 11th May, the first biochemical and structural data from Moonshot compounds was released and by the 12th June over 500 compounds had been tested, demonstrating that the design-make-test process was fully in place.
In seeking to target other coronaviral specific enzymes NDM scientists have solved structures for the SARS-Cov-2 viral RNA polymerase (Professor Jonathan Grimes), and papain-like protease, which also inhibits the interferon responses by deubiquitinylating host proteins. In collaboration with partners in ExScientia and the Weizmann Institute, Professor Stuart’s team have screened the 15K Gates’ ReFRAME library of licensed drugs, identifying two potential inhibitors amongst licenced drugs.