Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalab...Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).展开更多
Background:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus affected more people than SARS-CoV-1 and related coronaviruses.Human genetic factors,besides respiratory droplets and direct exposure to the ...Background:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus affected more people than SARS-CoV-1 and related coronaviruses.Human genetic factors,besides respiratory droplets and direct exposure to the virus,are found highly responsible for transmitting SARS-CoV-2 infection.Aim:The objective of this study was to determine the plasma levels of the TMPRSS2 gene and its role in SARS-CoV-2 susceptibility.Methodology:A total of 100 patients,i.e.50 SARS-CoV-2 positive patients as the case group and 50 SARS-CoV-2 negative samples as the control group,were selected randomly and included in this case-control study to determine the association between TMPRSS2 gene and susceptibility to SARS-CoV-2 infection and severity of coronavirus disease 2019(COVID-19).The TMPRSS2 levels of case and control samples were measured through an enzyme-linked immunosorbent assay(ELISA).Following the genomic DNA extraction,a set of reverse and forward primers of human TMPRSS2 gene primers were used for the amplification of the TMPRSS2 gene.Results:In the control group,the ratio of men to women was more or less the same while in the case group 62%of the population were women.The TMPRSS2 level was found to be 4.70±7.7 ng/ml in case samples while it was 4.73±5.7 ng/ml in control samples.Conclusion:The levels of TMPRSS2 in plasma samples of both controls and cases were found to be the same indicating that the entry of SARS-CoV-2 is not dependent on the plasma levels of this protein.展开更多
基金supported by the National Natural Science Foundation of China(No.81974494)CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-070).
文摘Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).
基金supported by grants from the Shaheed Zulfikar Ali Bhutto Institute of Science and Technology(SZABIST)University,Karachi,Pakistan.
文摘Background:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus affected more people than SARS-CoV-1 and related coronaviruses.Human genetic factors,besides respiratory droplets and direct exposure to the virus,are found highly responsible for transmitting SARS-CoV-2 infection.Aim:The objective of this study was to determine the plasma levels of the TMPRSS2 gene and its role in SARS-CoV-2 susceptibility.Methodology:A total of 100 patients,i.e.50 SARS-CoV-2 positive patients as the case group and 50 SARS-CoV-2 negative samples as the control group,were selected randomly and included in this case-control study to determine the association between TMPRSS2 gene and susceptibility to SARS-CoV-2 infection and severity of coronavirus disease 2019(COVID-19).The TMPRSS2 levels of case and control samples were measured through an enzyme-linked immunosorbent assay(ELISA).Following the genomic DNA extraction,a set of reverse and forward primers of human TMPRSS2 gene primers were used for the amplification of the TMPRSS2 gene.Results:In the control group,the ratio of men to women was more or less the same while in the case group 62%of the population were women.The TMPRSS2 level was found to be 4.70±7.7 ng/ml in case samples while it was 4.73±5.7 ng/ml in control samples.Conclusion:The levels of TMPRSS2 in plasma samples of both controls and cases were found to be the same indicating that the entry of SARS-CoV-2 is not dependent on the plasma levels of this protein.
