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Foundation for SARS-CoV-2 inhibitors discovery

A new international study has provided a template for how to develop directly-acting antivirals with novel modes of action, that would combat COVID-19 by suppressing the SARS-CoV-2 viral infection.

The study focused on the macrodomain part of the Nsp3 gene product that SARS-CoV-2 uses to suppress the host cell’s natural antiviral response. This part of the viral machinery, also known as Mac1, is essential for its reproduction; previous studies have shown that viruses that lack it cannot replicate in human cells, suggesting that blocking it with a drug would have the same effect. 

The study involved a crystallographic fragment screen of the Nsp3 Mac1 protein by an open science collaboration between researchers from the University of Oxford, the XChem platform at Diamond Light Source, the UK’s national synchrotron, and researchers from the QCRG Structural Biology Consortium at the University of California San Francisco.  

The international effort discovered 234 fragment compounds that directly bind to sites of interest on the surface of the protein, and map out chemical motifs and protein-compound interactions that researchers and pharmaceutical companies can draw on to design compounds that could be developed into antiviral drugs.  This work is thus foundational for preparing for future pandemics.  

The research is published in a free article in Sciences Advances (Schuller M, Correy GJ, Gahbauer S et al. Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking. Sci Adv 2021; 7 [16]: eabf8711. doi: 10.1126/sciadv.abf8711.

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