Objective The study aimed to synthesize and characterize pyrimidine-linked benzimidazole hybrids,define their antimicrobial and antifungal activities in vitro,and determine their ability to inhibit the main protease a...Objective The study aimed to synthesize and characterize pyrimidine-linked benzimidazole hybrids,define their antimicrobial and antifungal activities in vitro,and determine their ability to inhibit the main protease and spike glycoprotein of SARS-CoV-2.Methods The ability of the synthesized compounds to inhibit the main protease and spike glycoprotein inhibitory of SARS-CoV-2 was investigated by assessing their mode of binding to the allosteric site of the enzyme using molecular docking.The structures of pyrimidine-linked benzimidazole derivatives synthesized with microwave assistance were confirmed by spectral analysis.Antibacterial and antifungal activities were determined by broth dilution.Results Gram-negative bateria(Escherichia coli and Pseudomonas aeruginosa)were more sensitive than gram-positive bateria(Staphylococcus aureus and Streptococcus pyogenes)to the derivatives.Candida albicans was sensitive to the derivatives at a minimal inhibitory concentration(MIC)of 250μg/mL.The novel derivatives had better binding affinity(kcal/mol)than nelfinavir,lopinavir,ivermectin,remdesivir,and favipiravir,which are under investigation as treatment for SARS-CoV-2 infection.Compounds 2c,2e,and 2g formed four hydrogen bonds with the active cavity of the main protease.Many derivatives had good binding affinity for the RBD of the of SARS-CoV-2 spike glycoprotein with the formation of up to four hydrogen bonds.Conclusion We synthesized novel pyrimidine-linked benzi-midazole derivatives that were potent antimicrobial agents with ability to inhibit the SARS-CoV-2 spike glycoprotein.Understanding the pharmacophore features of the main protease and spike glycoprotein offers much scope for the development of more potent agents.We plan to optimize the properties of the derivatives using models in vivo and in vitro so that they will serve as more effective therapeutic options against bacterial and SARS-CoV-2 infections.展开更多
Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we report...Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.展开更多
文摘Objective The study aimed to synthesize and characterize pyrimidine-linked benzimidazole hybrids,define their antimicrobial and antifungal activities in vitro,and determine their ability to inhibit the main protease and spike glycoprotein of SARS-CoV-2.Methods The ability of the synthesized compounds to inhibit the main protease and spike glycoprotein inhibitory of SARS-CoV-2 was investigated by assessing their mode of binding to the allosteric site of the enzyme using molecular docking.The structures of pyrimidine-linked benzimidazole derivatives synthesized with microwave assistance were confirmed by spectral analysis.Antibacterial and antifungal activities were determined by broth dilution.Results Gram-negative bateria(Escherichia coli and Pseudomonas aeruginosa)were more sensitive than gram-positive bateria(Staphylococcus aureus and Streptococcus pyogenes)to the derivatives.Candida albicans was sensitive to the derivatives at a minimal inhibitory concentration(MIC)of 250μg/mL.The novel derivatives had better binding affinity(kcal/mol)than nelfinavir,lopinavir,ivermectin,remdesivir,and favipiravir,which are under investigation as treatment for SARS-CoV-2 infection.Compounds 2c,2e,and 2g formed four hydrogen bonds with the active cavity of the main protease.Many derivatives had good binding affinity for the RBD of the of SARS-CoV-2 spike glycoprotein with the formation of up to four hydrogen bonds.Conclusion We synthesized novel pyrimidine-linked benzi-midazole derivatives that were potent antimicrobial agents with ability to inhibit the SARS-CoV-2 spike glycoprotein.Understanding the pharmacophore features of the main protease and spike glycoprotein offers much scope for the development of more potent agents.We plan to optimize the properties of the derivatives using models in vivo and in vitro so that they will serve as more effective therapeutic options against bacterial and SARS-CoV-2 infections.
基金supported by Beijing Natural Science Foundation(M21016)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-003 and 2021-CAMS-JZ004)+1 种基金Tsinghua-Peking Center for Life Sciences (045-61020100122)Beijing Advanced Innovation Center for Structural Biology
文摘Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.
