Samantha Grimes

Samantha’s research project will focus on the biochemical and genetic determinants of small molecule inhibitors of coronavirus replication. The pandemic SARS-CoV-1 (COVID-19) pandemic has with incredible force demonstrated the capacity of CoVs to emerge to cause profound health consequences and societal disruption, perhaps unprecedented in human history. The need for effective countermeasures (antivirals, monoclonal antibodies, vaccines) is both immediate and long-term. The Denison lab has been a world leader over the past 10 years in preparing for this eventuality, preforming pre-clinical development on two drugs already in human testing in COVID- 19 patients: Remdesivir and EIDD-1931. Both are nucleoside analogs that target the viral RNA dependent RNA polymerase to interfere with viral RNA synthesis by chain termination (remdesivir) and lethal mutagenesis (EIDD-1931). An important feature of both compounds is their ability to evade the unique CoV proofreading exonuclease to inhibit the viral polymerase. Samantha’s project will focus on the use of remdesivir and EIDD-1931 in combination to test their impact on efficacy, prevention of resistance, mechanism of action against the proofreading exonuclease, and testing additional nucleoside analog inhibitors as well as potential direct inhibitors of the exonuclease. She will initiate work with the model CoV, murine hepatitis virus, which has been directly applicable in the results to MERS and SARS-CoV. This will allow rapid progress and testing at BSL2. Concurrently she will initiate training for work at BSL3 with SARSCoV- 2 and will be able to apply her results on inhibitor efficacy, combination Rx, exonuclease mutations and other findings directly to SARS-CoV-2. Based on our previous studies, student outcomes and her project, I believe this work will be of high impact from both research productivity and training perspectives.

Relevance to CBID: The project has high relevance to the CBID in that the project will use small molecule inhibitors to directly attack CoV replication and determine the virological response to identify new targets. Additionally, this project will work to directly support global efforts to control the COVID-19 pandemic and address future zoonotic CoVs. Further, the project is integrated across multiple disciplines – genetics, biochemistry, pathogenesis, drug development - and is based on established collaborations with a pharmaceutical company and UNC for animal model development. Samantha is very interested in this interface of fundamental biology, biochemistry, and throughput to translational potential. Samantha’s background and training are in microbiology and immunology with demonstrated success in these areas. Now with training and direct application to viral inhibition the project is likely to lead to important discoveries and prepare her for a career at the interface of Chemistry and Biology.

Mentor: Mark R. Denison, M.D.