GS-441524 is Pharmacodynamically Equivalent to Remdesivir and Pharmacokinetically Superior Drug for the Treatment of COVID-19

ABSTRACT. Covid-19 is a once in a generation epidemic that has had dire, destabilizing impacts across theworld. While remdesivir has emerged as the only drug with proven efficacy, its widespread distribution has beenplagued by supply-shortages. Careful review of pre-clinical data evidence that these problems largely derivefrom the poorly optimized phosphate pro-drug moieties on remdesivir, which ultimately make manufacturingremdesivir more difficult. Careful review of the literature indicates that, its parent nucleoside, GS-441524, is likelythe more optimal Covid-19 drug. We hypothesize that GS-441524 is pharmacodynamically equivalent drug toremdesivir, in its ability to generate active nucleotide triphosphate to inhibit the SARS-CoV-2 RNA polymerase.In addition to GS-441524 being significantly easier to synthesize, we contend that its direct administration would enable homogenous tissue distribution of active nucleotide triphosphate inhibitor compared to remdesivir; higherlevels of inhibitor would ultimately be achieved in lung epithelial cells most afflicted by SARS-CoV-2.This proposal will make fundamental biochemical advances at the in vitro level and therapeutic advancementsat the in vivo level. We will compare the rates bioactivation of GS-4441524 and remdesivir across a broad panelof primary human cell types and delineate the exact molecular mechanism and enzymes which bio-transformremdesivir and GS-441524 into the active triphosphate species. At the same time, we will establishpharmacodynamic equivalence between GS-441524 and remdesivir in mice and non-human primates. Finally,we will demonstrate that GS-441524 is ultimately superior to remdesivir in vivo for generating active triphosphateinhibitor, when each is administered at their maximum tolerated doses. Should our hypotheses prove correct,these data will support GS-441524 for IND and clinical trials.