Design,Synthesis And Activity Evaluation Of Peptide 3CL Proteaseinhibitor

Coronavirus Disease（COVID-19）is a respiratory disease caused by a highly infectious SARS-Co V-2.Over time,the virus is constantly mutating,with thousands of mutant strains emerging.Therefore,it is great of significance to find candidate compounds that can be taken orally and effective against SARS-Co V-2 mutants.3CL protease(3CL^pro)plays an importance role in the replication of SARS-Co V-2,and has high structural similarity and conservation in mutant strains.Therefore,3CL^pro has become one of the important targets for targeted SARS-Co V-2 drug development.In this article,3CL^pro is used as the research target,and the peptide like inhibitor nirmatrelvir is used as a reference.We modified the structure of its P3,P2and P1,designed and synthesized a total of 7 derivatives,and tested their inhibition rates against 3CL^pro at different concentrations.The inhibitory activity of compound 2-1 is relatively better than that of other derivatives at 1.00μM.Using compound 2-1 as the lead compound,we modified the structure of the groups at P4,P3,P2 and P1 positions and tested the activity of the compound.Each time,we selected a compound with a high 3CL^pro inhibition rate at low concentration as the lead compound for structural modification at the next position,and designed and synthesized a total of 17 derivatives.Among these 24compounds,compounds 2-8,2-16,and 2-20 exhibited high inhibition rates against SARS-Co V-2 3CL^pro at different concentrations,with IC₅₀ values of 33.37 n M,19.49n M,and 38.51 n M,respectively.Because the inhibitory activity of compound 2-16on 3CL^pro is slightly better than that of nirmatrelvir(IC₅₀=41.64 n M),further biological activities such as antiviral activity,cy totoxicity,liver microsome stability,and pharmacokinetic properties were evaluated for compound 2-16.The results show that compound 2-16 has oral absorbability（F=22.8%）,which has further research value.