Wuhan virus successfully blocked JE and Zika virus infection with peptide inhibitors

Japanese encephalitis virus (JEV) and Zika virus (zikv) belong to Flaviviridae of Flaviviridae, which are arboviruses transmitted by mosquitoes JEV induced encephalitis B has a high rate of death and disability China is a high incidence area of JE, and the number of patients once accounted for 80% of the world's total The use of JEV vaccine has reduced the incidence rate of encephalitis B to some extent However, for the patients who have already been infected, there is still no specific drug or treatment for JEV Since May 2015, zikv began to break out in Brazil and spread rapidly to tropical and temperate regions In addition to mosquito borne transmission, zikv can also be transmitted from person to person through sexual transmission or mother to child vertical transmission, resulting in neonatal microcephaly In February 2016, the World Health Organization (who) declared the zikv epidemic as an "international health emergency" Although the who announced the lifting of the alert in November of the same year, it stressed that the international community still needs to be prepared for a "long-term war" with zikv Therefore, it is an urgent task to find effective drugs for JEV and zikv infection The envelope protein E of flavivirus plays an important role in the process of virus entry into cells E protein is divided into three domains domain I, II and III there is a stem region composed of two α helices between domain III and transmembrane domain In the process of the fusion of virus envelope and cell membrane, the stem area breaks back and fills the gap of E protein domain II in a way similar to "zipper" It draws the virus envelope close to the cell membrane and drives the fusion of the membrane Based on the important role of the stem region of E protein of flavivirus envelope in membrane fusion, a series of polypeptides derived from JEV and zikv stem regions were designed by the researchers of the virus biochemistry group of Wuhan Institute of viruses, Chinese Academy of Sciences to investigate their antiviral effect The results showed that the anti-virus effect of polypeptide derived from the second helix of stem area was better than that of the first helix; in JEV test, the anti JEV effect of polypeptide containing 7 amino acids at the end of stem area was equivalent to that of polypeptide without these 7 amino acids; while in zikv test, it was found that 7 amino acids at the end of stem area were crucial, and the polypeptide without these 7 amino acids could not inhibit zikv infection Among all the tested peptides, P5 derived from JEV has the best antiviral ability, and its effective inhibitory dose to JEV and zikv reaches the nanomolar level, with IC50 of 3.93 nm and 70 nm, respectively Animal experiments confirmed that P5 can reduce the death rate of JEV, reduce the pathological changes and inflammatory response of brain The model of zikv infection was established in mice with IFN receptor deficiency (AG6) It was confirmed that P5 could significantly reduce the virus titer in the brain and testis of zikv infected mice and alleviate the pathological changes caused by zikv This study confirmed that polypeptide P5 can effectively inhibit JEV and zikv infection in vivo and in vitro, and the effective concentration reached the level of nanomolar Based on its clear target, high efficiency of virus inhibition and good biocompatibility of polypeptide inhibitors, this experiment provides a new and efficient pilot drug for clinical treatment of JEV and zikv infection.