Development of Sustained-Release Anti-coronavirus Nucleoside Phosphonate compounds

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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.