Identification of a new class of chaperon-based antiviral candidates against SARS-CoV-like viruses

Currently, there are no clinically approved antiviral drugs that are highly effective against coronaviruses. Our understanding of the molecular-cellular processes pertaining to the life cycle of SARS-CoV-2 remains limited. Emerging evidence, however, demonstrates that RNA viruses including coronaviruses distinctively depend on host proteostasis components (e.g. Hsp70 chaperone system) for their replication thus providing a valuable new drug target. We recently discovered a new Achilles heel in the replication process of RNA viruses, which involves a set of Hsp70 cofactors that are largely dispensable for primary host proteostasis functions, but vital for the viral life cycle making them ideal antiviral targets. Our preliminary findings demonstrate that inhibiting these cofactors significantly perturb Respiratory syncytial virus, Zika, and dengue replication, which provides an effective model for the development of antiviral agents against coronavirus infections. As proof of concept, we have successfully generated and testing two prototype peptides to target the cofactor vital for Zika replication. This project involves a range of experts with broad knowledge and experience on host proteostasis, Hsp70 system, RNA virus replication, medicinal chemistry, and peptidomimetics/drug development that allows for a pioneering multidiscipline study that will potentially deliver remarkable translational outcomes with the discovery of a unique proprietary lead candidate (plus a backup) for further pre-clinical evaluations as a novel antiviral agent. Importantly, this new class of antiviral agents will be immune to the high mutation rates of coronaviruses. Therefore our strategy will generate antiviral agents that are long-standing and superior to vaccine-based approaches that may rapidly lose effectiveness as the virus accumulates mutations.