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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Science 2020 ; 368 (6489): 409-412 Nephropedia Template TP
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Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors #MMPMID32198291
Zhang L; Lin D; Sun X; Curth U; Drosten C; Sauerhering L; Becker S; Rox K; Hilgenfeld R
Science 2020[Apr]; 368 (6489): 409-412 PMID32198291show ga
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 alpha-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.