Science· 2020Q1
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
- 3,442citations
- Q1SCImago
- 2020year
Short summary
The crystal structure of the SARS-CoV-2 main protease (Mpro) has been determined, revealing its complex with an improved α-ketoamide inhibitor. This structural insight enables the design of potent Mpro inhibitors with enhanced plasma half-life and lung tropism.
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Key points
- Crystal structures of SARS-CoV-2 Mpro (unliganded and with inhibitor) were solved.
- An α-ketoamide inhibitor was modified with a pyridone ring to improve plasma half-life.
- The optimized inhibitor shows potent Mpro inhibition.
- The inhibitor exhibits pronounced lung tropism and is suitable for inhalative delivery.
AI-generated from the title and abstract; the full text is not read.
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M pro , also called 3CL pro ) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 M pro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M pro . The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
The authors' abstract, as published at the source. Science, 2020 · DOI ↗
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Field: Computational Theory and Mathematics
Computational Theory and MathematicsComputer Science