Development Of New Indications Of Drugs

Enteroviruses can cause hand foot mouth disease(HFMD)in mild cases,and nervous system complications or even death in severe cases.The vast majority of severe and fatal cases are caused by EV71.The widespread popularity of EV71 in the world has brought a serious threat to the health of human beings(especially infants).Although the State Food and drug administration has approved the development and application of the vaccine,the vaccine can only prevent EV71 infection.At present,due to the lack of specific drugs in the treatment of patients with EV71,it is urgent to develop safe and effective anti EV71 drugs.FDA approved compound composition,target and safety information are known.Developing new indications of anti EV71 not only saves the development time and financial resources of anti EV71 drugs,but also provides new information for the preparation of anti EV71 drugs,and enriches the anti EV71 function of the compound itself.Therefore,in this study,13 compounds with good anti EV71 activity were obtained from 1430 compounds approved by FDA through primary screening and secondary screening.Combined with the properties and anti EV71 activity of these 13 compounds,we selected three target compounds,No.3,No.5 and No.12,for in-depth study.Then,we evaluated the anti EV71 efficacy of these three target compounds,all of which had high therapeutic index(>17.76,> 18.79 and 21.31 respectively),and all of them could well protect the cytopathy caused by EV71,and also could significantly reduce the virus production of EV71's offspring.The results of efficacy evaluation showed that the three target compounds had good anti EV71 activity.Finally,we studied the mechanism of the three target compounds against EV71.The results showed that the three compounds did not directly kill EV71 in vitro;compound 3 inhibited EV71 in the preventive mode,mixed mode and therapeutic mode,while compounds 5 and 12 only inhibited EV71 in the therapeutic mode;the three compounds reduced the production of EV71 progeny virus and RNA level by inhibiting the early stage of EV71 replication.Compounds 3 and 12 had no effect on the activity of 2A protease,but significantly inhibited the activity of 3C protease in vitro,while compound 5 had no effect on the activity of 2A protease and 3C protease.The results showed that the three compounds had strong anti-EV71 activities;compounds 3 and 12 may inhibit the replication and proliferation of EV71 by acting on3 C protease,which is the first time we found that they can act on 3C protease;we also found that compounds 5 and 12 have antiviral activity for the first time.Therefore,compounds 3,5 and 12 have the potential to further develop their new indications against EV71.