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Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases
Preprint
in English
| bioRxiv
| ID: ppbiorxiv-275891
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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Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Language:
English
Year:
2020
Document type:
Preprint