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

抽象的。新冠肺炎是一种千载难逢的流行病，它在整个世界产生了可怕的、破坏稳定的影响 世界。虽然雷米西韦已成为唯一被证实有效的药物，但其广泛的分布 受到供应短缺的困扰。仔细审查临床前数据的证据表明，这些问题主要源于 从瑞德韦上优化不佳的磷酸盐亲药物部分，最终使制造 想要更难。仔细阅读文献表明，它的母体核苷GS-441524很可能 更理想的新冠肺炎药物。我们假设GS-441524在药效学上等同于 雷米昔韦能够产生活性核苷酸三磷酸来抑制SARS-CoV-2RNA聚合酶。 除了GS-441524更容易合成外，我们认为它的直接给药将 使活性核苷酸三磷酸抑制剂能够在组织中均匀分布，与瑞德韦相比；更高 抑制物的水平最终将在受SARS-CoV-2影响最严重的肺上皮细胞中达到。 这一提议将在体外水平和治疗水平上取得基本的生化进展。 在活体水平上。我们将在一个广泛的小组中比较GS-4441524和redesivir的生物激活率 并描述了生物转化的确切分子机制和酶 Remsivir和GS-441524为活性三磷酸物种。同时，我们将建立 GS-441524和瑞美昔韦在小鼠和非人灵长类动物中的药效学等效性。最后， 我们将在体内证明GS-441524在产生活性三磷酸方面最终优于瑞希韦。 抑制剂，当每种药物都以其最大耐受量给药时。如果我们的假设被证明是正确的， 这些数据将支持GS-441524用于IND和临床试验。

ABSTRACT. Covid-19 is a once in a generation epidemic that has had dire, destabilizing impacts across the world. While remdesivir has emerged as the only drug with proven efficacy, its widespread distribution has been plagued by supply-shortages. Careful review of pre-clinical data evidence that these problems largely derive from the poorly optimized phosphate pro-drug moieties on remdesivir, which ultimately make manufacturing remdesivir more difficult. Careful review of the literature indicates that, its parent nucleoside, GS-441524, is likely the more optimal Covid-19 drug. We hypothesize that GS-441524 is pharmacodynamically equivalent drug to remdesivir, 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; higher levels 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 advancements at the in vivo level. We will compare the rates bioactivation of GS-4441524 and remdesivir across a broad panel of primary human cell types and delineate the exact molecular mechanism and enzymes which bio-transform remdesivir and GS-441524 into the active triphosphate species. At the same time, we will establish pharmacodynamic 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 triphosphate inhibitor, 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.