Discovery Of HIV-1 Protease Inhibitors In Streptomyces CPCC 202950

Objective:AIDS(AIDS)is a kind of degenerative disease on immune and central nervous system,caused by the human immunodeficiency virus(HIV),which spread quickly in the world from 1981 and has become a significant public health event.In recent years,people have a clear understanding of the mechanism of HIV and found that HIV reverse transcriptase,protease and integrase is the HIV gene in the replication process of the three key enzymes,protease inhibitors can prevent the virus maternal protein split into new HIV-infected cells and viral replication of functional proteins,the discovery of AIDS treatment has made a breakthrough,so far anti-HIV/AIDS drug research and development is mainly for the three key enzyme design.Until now,the design of anti-HIV/AIDS drugs is mainly focused on these three key enzymes.Inhibitor of protease can prevent maternal protein splitting into functional proteins new HIV infecting cells and viral replicating,which makes AIDS treatment have a breakthrough.Now many inhibitors including peptides and non-peptides have been discovered.Glycyrrhizine,indinavir,ritonavir and other HIV protease inhibitors have been widely used in clinical practice,but long-term use of these protease inhibitors will produce significant side effects and drug resistance.So to discover novel HIV protease inhibitors is more important.In our screening course for novel HIV-1 protease inhibitors from microorganisms,Streptomyce CPCC202950 was picked up.A series of positive streptomycin CPCC202950 was obtained by high-throughput screening in the early stage of this study group.In the previous period,a kind of oligopeptide with good activity was obtained by liquid fermentation,but the content was less.Therefore,Metabolites of the rice medium is needed for further study.Methods:Inhibiting activity in the rice medium was determined by high-throughput fluorometric assay HIV-1 protease substrate model.The fermented material was fractionated by means of chromatography with Sephadex LH-20,preparative HPLC,macroporous resin HP-20 and ODS-A,activity tracked by high-throughput fluorometric assay HIV-1 protease substrate model,obtained 22 compounds.Results:We have obtained 22 compounds,which contains 10 oligopeptide compounds,9 amide compounds,2 amino acids and 1 Carboxylic acid compounds.The isolated compounds were detected by high-throughput fluorescent substrate HIV-1 protease model.Compound 3 showed the value of IC50 was 1.79 nM.MTT assay was used to determine the toxicity of Hela and HepG2 cells to more than 100?M.It is promising to get better inhibitors of HIV-1 protease in Streptomyces p.CPCC202950.Conclusion:One of the important ways to discover new drug-lead compounds is to extract and isolate the active substances from the secondary metabolites of microbial fermentation.In this study,the compounds isolated from the secondary metabolites of Streptomyces sp.CPCC202950 had better activity and less cytotoxicity,and were expected to be a new leader in the novel HIV-1 protease inhibitor,which was the structural modification and activity of these compounds In-depth evaluation laid a solid foundation.