Dissecting Inhibitor Impacts On Viral RNA Polymerase And Fidelity Control Of RNA Synthesis In SARS-CoV-2

Project Description

Finding antiviral drugs for curing COVID-19 is one
of the most critical endeavors to fight against the pandemic. Among very
few promising choices, Remdesivir (RDV, or GS-5734) is a representative
one that targets directly on the viral RNA synthesis. RDV works as a
prodrug to be metabolized into a nucleotide analogue to interfere with
the function of RNA-dependent RNA polymerase (RdRp), a key component of
replication-transcription machinery encoded in the genomes of all RNA
viruses to conduct the RNA synthesis. The viral RdRps are highly
conserved, sharing a common core structure of a right-hand shape. A
cryo-EM structure of RdRp from SARS-CoV was established last year,
illuminating the assembly of the coronavirus core RNA-synthesis
machinery. Recently this year, a similar high-resolution structure of
RdRp is presented for SARS-CoV-2, which provides a basis for detailed
structural dynamics investigations of the core RNA-synthesis machine, as
an antiviral drug target for the current pandemic, and possibly future
ones. The research goal of this project is to probe how such a
coronavirus RdPp (or Cov-RdRp) conducts fidelity control for the viral
RNA synthesis, and how potential drugs such as RDV and other inhibitors
impact on the RdRp functions. Mutant RdRps capable of gaining drug
resistance are also considered. The research team of this project has
computationally studied transcription elongation dynamics of a viral RNA
polymerase (RNAP) from bacteriophage T7, which shares a similar
right-hand structure with the core Cov-RdRp. The transcription fidelity
control of T7 RNAP has been examined particularly, revealing structural
dynamics and energetic details of how various nucleotides bind to the
active site in the presence of stepwise selections during each
nucleotide addition cycle. Along this line, the research team plans to
conduct high-performance computing by performing all-atom molecular
dynamics (MD) simulations on the Cov-RdRp system, and to study how a
nucleotide analogue such as the one from RDV binds and inserts into the
active site of Cov-RdRp, in comparison with regular or natural
nucleotide substrates. Subsequently, other analogues and inhibitors can
be examined. Variant RdRps with mutations are to be probed for drug
resistance, and a similarly shaped human mitochondrial RNAP can be
further tested for side effects or toxicity.

This project is part of the COVID-19 HPC Consortium.