Research And Development Of Drugs For Treatment Of Hand-Foot-and-mouth Disease

Hand-foot-and-mouth disease(HFMD)is a common infectious disease among infants and young children in China.It can be caused by infection by several enteroviruses,such as enterovirus 71(EV71)and Coxsackie A16(CoxA16).Clinical symptoms of HFMD include red herpes or ulcer on the hands and feet,and around the mouth.The infection is usually accompanied by fever,fatigue among others.Some patients may even have myocarditis and other serious complications,which can lead to death in severe cases.HFMD is a serous threat to children’s health.There is currently no effective drug for HFMD pathogenic viruses.In clinical practise,broad-spectrum antiviral drugs and adjuvant drugs are usually used for symptomatic treatment.Effective,low-toxic and well tolerated targeted drugs for children are urgently needed.Enterovirus 71(EV71)is the most harmful virus among HFMD pathogenic viruses.In this thesis,anti EV71 inhibitors were developed,and different novel compounds were prepared targeting the EV71 3C protease and capsid.The compounds were optimized for anti EV71 potency,as well as mice plasma stability,pharmacokinetic,and other properties of druggability.For the 3C protease inhibitors,a novel P2-P1’linked macrocyclic inhibitor was successfully synthesized for the first time,and its complex structure with 3C protease was characterized by X-ray crystallography.For the capsid inhibitors,a promising compound K3 was identified with excellent in vivo efficacy in an EV71 infected mouse model.The research work of the two targets provides valuable reference for the subsequent development of cures for HFMD.