Taekjip Ha

The coronavirus viral replication cycle goes through a process of generating negative-strand RNA from the positive strand of genomic RNA. This negative-strand RNA serves as a template for the generation of duplicate copies of genomic positive-strand RNA. This proliferation mechanism of positive RNA genomes poses a challenge to the virus when considering that the only helicase encoded by the viral genome (NSP13) possesses 5’ to 3’ unwinding polarity, while the synthesis of the negative-strand RNA necessitates a helicase with 3’ to 5’ polarity to melt the secondary structures that arise in the viral genomic RNA template. The most direct solution to this problem would be for the virus to hijack one of the many host RNA helicases. In the case of SARS-CoV2, it is unclear which of the cellular helicases is hijacked or repurposed by the virus to serve the purpose of the 3’ to 5’ helicase activity. We aim to identify the host RNA helicase among the several candidates, characterize its biochemical activities and solve its structure in complex with viral replication proteins. The interaction interface is a potential target of therapeutic intervention. . We envision that the design of inhibitors that either target the binding of the host helicase to viral replication proteins or inhibit the function of the helicase itself can open new avenue for design of drugs against this virus replication. In addition, the targeted inhibition method we develop will have broad impact by facilitating mechanistic studies of how the host-virus interactions play critical role for viral replication and its restriction by the human cell machineries.