Zhang L,
Lin D,
Sun X,
Curth U,
Drosten C,
Sauerhering L,
Becker S,
Rox K,
Hilgenfeld R.
* University of Lübeck, Germany
Crystal Structure of SARS-CoV-2 Main Protease Provides a Basis for Design of Improved α-Ketoamide Inhibitors.
Science 2020;
368: 409-412
Key words
SARS-CoV-2 - COVID-19 - α-ketoamides - main protease (M
pro)
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 (Mpro) 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 Mpro 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 Mpro with IC50 = 0.67±0.18 μM and displays promising lung tropism and inhalation tolerance in mice.
