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

摘要。COVID-19是一代人一次的流行病，对整个世界产生了可怕的，不稳定的影响。 世界虽然Remdesivir已成为唯一一种经证实有效的药物，但其广泛分布已被证明是有效的。 受供应短缺的困扰。仔细审查临床前数据证据表明，这些问题主要来自 从瑞德西韦上优化不佳的磷酸盐前药部分， Remdesivir更难。对文献的仔细回顾表明，其母体核苷GS-441524很可能是 更理想的新型冠状病毒药物我们假设GS-441524是药效学等效药物， Remdesivir，其产生活性核苷酸三磷酸以抑制SARS-CoV-2 RNA聚合酶的能力。 除了GS-441524明显更容易合成之外，我们认为其直接给药将 与remdesivir相比，使活性三磷酸核苷抑制剂的组织分布均匀; 抑制剂水平最终将在受SARS-CoV-2折磨最严重的肺上皮细胞中达到。 这一建议将在体外水平和治疗方面取得根本性的生物化学进展 in the vivo体内level水平.我们将在一个广泛的小组中比较GS-4441524和Remdesivir的生物活化率 的主要人类细胞类型和描绘的确切分子机制和酶的生物转化 Remdesivir和GS-441524转化为活性三磷酸物质。与此同时，我们将建立 在小鼠和非人灵长类动物中，GS-441524和remdesivir之间的药效学等效性。最后， 我们将证明GS-441524在体内产生活性三磷酸的能力最终优于Remdesivir上级 抑制剂，当每一种以其最大耐受剂量施用时。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.