Significance
SARS-CoV-2 is the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Potent, broad-spectrum α-ketoamide inhibitors of the main protease (M pro ) of betacoronaviruses and alphacoronaviruses were recently reported by Hilgenfeld and co-workers ( J. Med. Chem. 2020 , DOI: 10.1021/acs.jmedchem.9b01828). X-ray crystallography and structure-based design led to the discovery of submicromolar α-ketoamide inhibitor 13b , which has now been developed specifically against SARS-CoV-2 M pro to shut down the processing of polyproteins translated from viral RNA.
Comment
Starting from commercially available ( R )-2-amino-3-cyclopropylpropanoic acid, Boc-protected pyridone D is synthesized in four steps. γ-Lactam B , a proxy for glutamine, is made using an asymmetric dianionic cyanomethylation of N -Boc- l -(+)-glutamic acid dimethyl ester (Q. Tian et al. Tetrahedron Lett. 2001 , 42 , 6807) and is coupled to the hydrolysis product of D . Five additional transformations yield 13b , which inhibits SARS-CoV-2 M pro with IC 50 = 0.67±0.18 μM and displays promising lung tropism and inhalation tolerance in mice.
References
- Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R.*University of Lübeck, GermanyCrystal Structure of SARS-CoV-2 Main Protease Provides a Basis for Design of Improved α-Ketoamide Inhibitors Science 2020368409–412. [DOI] [PMC free article] [PubMed] [Google Scholar]