Drug Discovery And Structural Studies On EV71 Proteinases

Hand,foot and mouth disease is common in infants and young children.It usually causes fever,oral ulcers,and rashes on the hands and feet.Enterovirus 71(EV71)is one of the major causative agents of HFMD.Compared with other pathogens,it can cause neurological complications.Currently there is no effective antiviral drug targeting this virus.2A and 3C proteinases(2Apro and 3Cpro)are two cysteine proteinases encoded in the virus genome.They share the same enzymatic mechanism,but their roles in the virus replication are different.2Apro cleaves at the junction between VP1-2A and 3Cpro is responsible for the processing other sites.As they play essential roles in the processing of viral replication,hijack of host cell translation,and evasion of innate immunity,they are considered as prime targets for developing antivirals.Fragment-based drug design is an effective approach to find novel lead compounds.We screened a fragment library using the EV71 3Cpro crystal system.In the first round of screening,two fragments,compounds 953 and 2139,were found to bind in either the RNA-binding site or S1' site of the substrate binding groove of the 3C proteinase.Binding of these compounds to the enzyme was verified by 1H NMR.It was suggested that the linking compound 2139 and 2-Phenylquinolone could generate a compound binding to the S1 site by on the computer-aided design using the software Dock,which was supported by using Glide routine in the suite Schrodinger.Attempts were made to obtain better crystals of enzymatically active EV71 2Apro to provide a structural framework for the design of covalent inhibitors.We also produced the protein of HRV2 2Apro to expand the scope of the drug program targeting 2Apro.