Structure-based Design Of 2A Protease Inhibitors From Enterovirus 71

Hand,foot and mouth disease(HFMD)is an acute infectious disease caused by enteroviruses mostly for children under 5 years old.The most common viruses for HFMD are Coxsackie A16(CVA16)and Enterovirus 71(EV71).It is generally believed that severe and fatal cases with neurological complications are caused by EV71.2A protease is an essential enzymes for the mature and infection of EV71.It can process the polyprotein produced in the virus life cycle,suppress the host innate immune responses,promote the replication of the viral genome and protein translation,induce cell apoptosis and so on.2A protease is an important target for the development of drugs for treating HFMD.Up to date however there is no specific inhibitors for 2A protease.In this thesis,we use the methods of molecular and structural biology to solve the high-resolution structure of EV71 2A(C110A)protease.Small molecule that can bind at the active pockets was obtained by virtual screening and fragment-based technology.The techniques of saturation transfer differential spectrum(STD)of Nuclear Magnetic Resonance(NMR),bio-layer interference(BLI)and other methods were employed to verify the compound interaction with the protease.The active 2A protease was also obtained,providing a basis for the crystallographic studies of covalent inhibitors.These study sets a foundation for the drug development targeting EV71 related diseases.