Development of Sustained-Release Anti-coronavirus Nucleoside Phosphonate compounds

自2019年秋季SARS CoV-2在中国出现以来，全球已报告近2亿例COVID-19病例;其中400多万人死亡。在美国，该病毒已造成60多万人死亡。尽管对减轻病毒传播的非药物干预措施有了很好的了解，并开发了几种高效疫苗，但全球疫情仍在迅速蔓延。在资源有限的情况下，疫苗供应一直不足，即使在疫苗已广泛供应数月的地方，也有相当一部分公众拒绝接种疫苗。此外，随着新的更具传播性的病毒变体的出现，这些变体对第一代疫苗刺激的免疫力不太敏感，已经注意到越来越多的突破性感染。虽然这些突破性感染中的大多数不会导致住院治疗，但有些会，并且存在进一步免疫进化将进一步损害疫苗功效的重大担忧。虽然疫苗方面的进一步进展是可以预期的，但非常需要高效和耐受性良好的抗病毒剂。目前，美国食品和药物管理局目前批准的抗病毒治疗只有两种模式，即Remdesivir和针对病毒刺突蛋白的单克隆抗体。这两种治疗方式都需要肠胃外给药，极大地限制了它们的一般用途，特别是在资源有限的情况下。此外，随着病毒刺突蛋白在人群中的进化，一些单克隆抗体已经失去了对新的循环病毒变体的效力。这种进化预计将继续，因为关键的病毒表位是由自然感染期间产生的人类免疫反应形成的。在本补充中，我们建议将我们的合成化学应用于remdesivir碱和其他核苷，以开发耐受性良好的化合物，这些化合物对SARS CoV-2和其他冠状病毒的RNA聚合酶具有高水平的活性，可以口服，并在各种相关组织类型中达到活性三磷酸的均匀治疗浓度。如果成功，我们预计这些化合物可能在COVID-19和其他冠状病毒感染患者中具有广泛的医疗适用性。

Since the emergence of SARS CoV-2 in China in the fall of 2019, nearly 200 million cases of COVID-19 have been reported globally; over 4 million of these individuals have died. In the US, the virus has been responsible for over 600,000 deaths. Despite a good understanding of non-pharmaceutical interventions that mitigate viral transmission and the development of several highly efficacious vaccines, the global epidemic has continued at a brisk pace. Vaccine availability has been scant in resource limited settings and, even where it has been widely available for months, substantial segments of the public have declined vaccination. In addition, as new more transmissible viral variants emerge that are less susceptible to immunity stimulated by first generation vaccines, an increasing number of breakthrough infections have been noted. Although most of these breakthrough infections do not result in hospitalization, some do, and there is a significant concern that further immunological evolution will further compromise vaccine efficacy. Although further progress on the vaccine front is to be expected, highly effective and well tolerated antiviral agents are sorely needed. At present, the only two modes of antiviral therapy currently approved by the US Food and Drug Administration are Remdesivir and monoclonal antibodies directed at the viral spike protein. Both of these therapeutic modalities require parenteral administration, greatly limiting their general utility, especially in resource limited settings. In addition, as the viral spike protein has evolved within the human population, several of the monoclonals have lost their efficacy against new circulating viral variants. This evolution is expected to continue as critical viral epitopes are shaped by human immune responses generated during natural infection. In this supplement, we propose to apply our synthetic chemistry to the remdesivir base and other nucleosides to develop well-tolerated compounds with high levels of activity against the RNA polymerase of SARS CoV-2 and other coronaviruses that can be delivered orally and achieve uniformly therapeutic concentrations of the active triphosphate in a wide variety of relevant tissue types. If successful, we anticipate that these compounds could have broad medical applicability in patients with COVID-19 and other coronavirus infections.