Studies Of Anti-Middle East Respiratory Syndrome Coronavirus Treatment Based On The Mechanism Of Virus Invasion And Immunomodulation

Middle East respiratory syndrome coronavirus(MERS-CoV)is a novel coronavirus,which could cause Middle East respiratory syndrome and a series of complications.Since 2012,MERS broke out in the Middle East and South Korea,and spread to 27 countries and regions.Its high pathogenicity and mortality(34.7%)pose a serious threat to public health.Currently,there is no available vaccine or treatment for MERS.The treatments for MERS patients are supportive,which could only alleviate the symptoms of patients and reduce complication incidence.Therefore,there is an urgent need for developing effective therapeutics for MERS.In this article,we conduct the research from two main directions of antiviral drug development.On the one hand,MERS-CoV-mediated membrane fusion inhibitors are developed based on the infectious mechanism of MERS-CoV;on the other hand,anti-MERS immunomodulators are developed due to the importance of innate immunity in antiviral treatmentIn the first part,since MERS-CoV-mediated fusion between MERS-CoV envelope and host cell membrane is the key process for MERS-CoV infection,preventing membrane fusion could have antiviral effect.The key structure of membrane fusion is a six-helix bundle(6-HB)formed by the interaction of HR1(heptad repeat 1)and HR2(heptad repeat 2)domains.Therefore,blocking the formation of 6-HB is an effective antiviral means.Based on the structure of HR2 and its interaction with HR1,we designed a series of HR2 derivatives through computer-aided drug design,and selected peptide inhibitor HR1(PIH).PIH can effectively combine with HR1 to prevent the formation of 6-HB between HR1 and HR2.In addition,PIH showed good inhibitory activity for the MERS-COV-mediated membrane fusion.Particularly,we developed PIH-modified gold nanorods(PIH-AuNRs).PIH-AuNRs not only enhanced the inhibitory activity of PIH,but also significantly improved biostability.Moreover,PIH-AuNRs had good biocompatibility.Therefore,PIH-AuNRs are a promising anti-MERS agent,which provide a new reference for anti-MERS research.In the second part,we develop immunomodulators based on the stimulator of interferon gene(STING).STING is an important protein in innate immunity,which can be activated by some small molecular compound.Activated STING can induce signal transduction,leading to the secrection of interferon-β(IFN-β)and other pro-inflammatory cytokines.Therefore,the development of STING-based immunomodulators is a new effective anti-MERS method.Based on the structure of STING,we designed and synthesized Compound-1 and Compound-2,aiming to activate STING and achieve anti-MERS effect by positively regulating immune response.However,Compound-1 and Compound-2 showed potent inhibitory activity of STING activation.In addtion,Animal studies suggested that Compound-2 exhibited good inhibitory activity in vivo.Therefore,Compound-1 and Compound-2 can be used as STING inhibitors for the treatment of STING-related diseases,such as non-alcoholic hepatitis,lupus erythematosus and aicardi-goutieres syndrome.In this study,we developed inhibitors for MERS-CoV and STING,which not only improves the understanding of disease regulation mechanisms,but also provides a unique tool to accelerate the development of drug research.