Medicinal Chemistry and Pharmacology of Antivirals Targeting Enterovirus D68 and SARS-CoV-2
My lab is interested in developing chemical probes for drug target validation using both cell culture and animal models. In this presentation I will introduce two ongoing projects, the enterovirus D68 antivirals and the SARS-CoV-2 antivirals. EV-D68 generally causes respiratory illnesses in children, and in severe cases can lead to neurological complications such as acute flaccid myelitis. In the first project, I will present our progress in developing antivirals targeting the viral 2A protease and the 2C protein.
In the second project, I will introduce our efforts in developing inhibitors targeting SARS-CoV-2 Mpro and PLpro. SARS-CoV-2 is the causative pathogen for COVID-19. SARS-CoV-2 encodes two viral proteases, the main protease (Mpro) and the papain-like protease (PLPro). These two proteases cleave the viral polyproteins during the viral replication and are validated antiviral drug targets. In addition, PLpro has been shown to modulate host immune response. Through high-throughput screening and subsequent structure-based drug design, several inhibitors have been discovered with both potent enzymatic inhibition and cellular antiviral activity against SARS-CoV-2. To elucidate their mechanism of action, we solved multiple X-ray co-crystal structures of Mpro and PLpro with inhibitors. The significance of our study is the discovery of dual inhibitors targeting both viral Mpro and host cathepsin L, both of which are critical for the viral replication. In addition, the non-covalent Mpro inhibitors we designed represent the most potent ones reported so far.