Therapeutics

Therapeutic results generated during the Covid19 pandemic

The Taskforce 5 team developed small molecules to inhibit SARS-CoV-2 replication, proteases and viral RNA masking mechanisms (RNA immune evasion) as follows.

Replication:  In a seminal study combining SAXS, SANS, crystallography, and CryoEM, Taskforce 5 interrogated the assembly of SARS-Cov-2 replication machinery, identified a unique assembly inhibition pocket and tested the successful binding of a small molecule. 

Proteases:  The Taskforce 5 team solved 8 atomic resolution structures of dimeric SARS-CoV-2 Mpro, (including several structures with inhibitors) and the first atomic resolution structure of PLpro, plus 27 more with inhibitors at novel binding sites. These results provided concrete starting points for large pharma-based therapeutics. 

RNA Immune Evasion:  For Nsp15, an endoribonuclease responsible for removing host immune stimulating 5’ uridine tails on negative sense RNA, Taskforce 5 determined 8 crystal structures with and without small molecules and identified several small molecules that bound with micromolar affinity as chemical tools for biology and further optimization.