Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro).

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC50 = 0.085 ± 0.006 and 0.966 ± 0.065 µM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC50 = 1.10 ± 0.12 and 5.15 ± 1.64 µM, respectively) with low cytotoxicity (CC50 ＞ 50 µM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.

Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2.

Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types. We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple α- and ß-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from γ- and δ-coronaviruses. 76E1 cross-protects against SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and therapeutic murine animal models. Structural and functional studies revealed that 76E1 targets a unique epitope within the spike protein that comprises the highly conserved S2' site and the fusion peptide. The epitope that 76E1 binds is partially buried in the structure of the SARS-CoV-2 spike trimer in the prefusion state, but is exposed when the spike protein binds to ACE2. This observation suggests that 76E1 binds to the epitope at an intermediate state of the spike trimer during the transition from the prefusion to the postfusion state, thereby blocking membrane fusion and viral entry. We hope that the identification of this crucial epitope, which can be recognized by 76E1, will guide epitope-based design of next-generation pan-coronavirus vaccines and antivirals.

Retrospective study of risk factors of 43 patients with severe coronavirus disease 2019 pneumonia

Objective To explore the risk factors of 43 patients with severe coronavirus disease 2019 pneumonia(COVID-19) in Hangzhou. Methods The clinical and epidemiological data of COVID-19 confirmed patients during 1 st January 2020 and 20 th March 2020 in Hangzhou were collected.The risk factors of the severe cases were analyzed by univariate and multivariate logistic regression. Results Up to 20 th March 2020,a total of 169 patients were reported in Hangzhou, among which, 43(25.44%) were severe cases.The analysis showed that over 60 years old[χ~2=6.16,P=0.01;OR(95%CI)=3.35(1.29-8.69)],hypertension[χ~2=6.91,P<0.001;OR(95%CI)=3.80(1.40-10.28)],headache as initial onset symptom [χ~2=4.80,P=0.03;OR(95%CI)=3.02(1.12-8.09)] and delayed hospitalization(Z=-2.21,P=0.03) were statistically significant. Conclusions Age over 60 years, hypertension, headache as initial onset symptom are risk factors and delayed hospitalization is influencing factor of severe COVID-19 patients.It is necessary to monitor COVID-19 patients′ condition and take effective treatment timely.