Synthesis And Research Of Human Enterovirus 71 Inhibitors Targeting VP1

Hand-foot-mouth disease is one of the common infectious diseases caused by enteroviruses,such as enterovirus 71(EV71)and Coxsackie virus A16(CVAl6).Infected patients are mostly infants and young children under five years of age.Symptoms are usually not serious caused by CVA16,while a small number of cases caused by EV71 will be associated with severe neurological diseases,and even death.At present,EV71 inactivated vaccine was proved which was developed by Beijing KeXing and the Medical Biology Institute of Chinese Medical Sciences Academy independently.But there is no effective drug used for EV71 infection in the market.EV71 contains a hydrophobic pocket that may be a potential drug binding target.A natural lipid buried in the pocket lying at the base of the canyon in the capsid protein VP1.Because expulsion of the pocket factor is required for infection,a tight replacement binder could be a useful antiviral agent acting on the virus capsid.Our study is based on the virus inhibitor TJAB1099 designed by computer-aided drug design and structural drug design.As TJAB1099 has the disadvantages of poor solubility,low bioavailability,high cytotoxicity,and it’s sensitive to acid and alkali,we have been chemically optimized to make it more potent.On one hand,the inhibitor TJAB1099 was prepared as varities of salts in order to improve the solubility,dissolution rate and bioavailability.The mesylate and acetate of TJAB1099 were screened with improved solubility,and the material support was provided for the next safety evaluation.On the other hand,different structures of TJAB1099 were chemically modified to study the structure-activity relationship of these inhibitors.The analogues M11 and M12 were obtained,which laid the foundation for the research and development of effective drugs for HFMD caused by EV71 infection.