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bioRxiv · 10.1101/2020.09.15.275891

Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases

Westberg, M.·Su, Y.·Zou, X.·Hurst, B.·Tarbet, B.·Lin, M.
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Abstract

The coronavirus main protease, Mpro, is a key protein in the virus life cycle and a major drug target. Based on crystal structures of SARSCoV2 Mpro complexed with peptidomimetic inhibitors, we recognized a binding characteristic shared with proline-containing inhibitors of hepatitis C virus protease. Initial tests showed that this subclass of HCV protease inhibitors indeed exhibited activity against Mpro. Postulating a benefit for a preorganized backbone conformation, we designed new ketoamide-based Mpro inhibitors based on central proline rings. One of the designed compounds, ML1000, inhibits Mpro with low-nanomolar affinity and suppresses SARSCoV2 viral replication in human cells at sub-micromolar concentrations. Our findings identify ML1000 as a promising new pre-organized scaffold for the development of anti-coronavirus drugs.

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Westberg, M., Su, Y., Zou, X., Hurst, B., Tarbet, B., Lin, M.. 2020-09-15. Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases. https://doi.org/10.1101/2020.09.15.275891

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