Design And Mechanism Of Active Compounds Of Phenanthridines Against PEDV And SARS-CoV-2

Coronavirus is a type of positive-stranded RNA virus with the largest genome.We explored the anti-PEDV effects of several phenanthridine-type molecules,which could inhibit multiple viruses by down-regulating the expression of host Hsc70.In order to obtain more active molecules,the structure modification of active molecules was carried out.Based on the research basis of coronavirus and phenanthridine molecules,we launched a drug discovery study targeting SARS-CoV-2 nucleocapsid protein and main protease when SARS-CoV-2 is pandemic during the research process.The first chapter described a research on designing and synthesising of PEDV inhibitors targeting host Hsc70.And 69 derivatives were synthesized.A type of phenanthridone molecule with methoxy substitution at the 4th position and a heterocyclic fragment at the 8th and 9th positions was discovered.These molecules have excellent anti-PEDV activity and retain the ability to down-regulate the host Hsc70.The result provides a new class of anti-PEDV drugs.As the compounds with a broad-spectrum antiviral mechanism,it is possible to act on more coronaviruse.The second chapter described a research on designing and synthesising of SARS-CoV-2 inhibitors.Based on the reported coronavirus nucleocapsid inhibitor PJ34,19 derivatives were designed and synthesized.And compound 70 stands out in the screening of SPR assay.The Dissociation constant with SARS-CoV-2 nucleocapsid protein was 7.8 μM,compared with the PJ34,the activity is increased by nearly 90 times.Learn from the " drug repositioning strategy",a virtual screening based on the main protease was carried out.And compounds 41 and 67 with good inhibitory activity against the main protease were obtained.They showed 85.6% and 71.6% inhibition rates,respectively.The result provides some clues for SARS-CoV-2 drug discovery.The third chapter reviewed the inhibitors of PEDV,their structures and tagets were summarized.And we also made an outlook on the drug discovery of anti-PEDV.