Progress on COVID-19 chemotherapeutics

ABSTRACT

COVID-19 has caused the outbreak to spread on a global scale due to its high transmission rate and ineffective prevention and treatment. The disease is caused by a new type of single-stranded RNA coronavirus, which was named SARS-CoV-2 by the International Committee on Taxonomy of Viruses. As of November 2021, more than 210 countries and regions around the world have been affected by the coronavirus, and a total of more than 240 million confirmed cases have been reported worldwide, and the death toll has exceeded 4 million. Although the vaccine immunizations have alleviated the COVID-19 pandemic to some extent, however from the perspective of clinical treatment, the development of effective antiviral therapeutics for COVID-19 remains urgent and long-term need. Remdesivir (Veklury, Gilead), which was approved by the US FDA in October 2020, is currently the only officially approved coronavirus polymerase inhibitor. However, the clinical efficacy of remdesivir for COVID-19 remains contentious, as the statistical differences in both mortality rate and clinical improvement between drug-treated and control groups were not clearly verified in several trials. Very recently following remdesivir, Merck announced the first effective antiviral pill against COVID-19 called molnupiravir, which has finished phase III clinical trials with proven efficacy to reduce the risk of hospitalizations and deaths by 50% in patients with mild-to-moderate COVID-19. Based on this result, Merck received the first authorization from the UK (as of November 9, 2021). It is also known that one more antiviral pill developed by Pfizer with the compound code PF-07321332, is already in the final stages of trial data analysis, so it is expected that this will be the second orally available drug for authorization application in the coming few months. Despite the encouraging results achieved by Merck and Pfizer's scientists, the practical challenges and high attrition rates on new drug development remain a difficult reality for the medicinal chemists and pharmaceutical scientists. In this article, we provide an overview of the research hotspots of the development for COVID-19 treatment agents, especially on the representative antiviral compounds that have potential inhibitory effects against SARS-CoV-2. By focusing on specific biotargets of SARS-CoV-2 and their drug molecules, mechanism strategies, and their clinical testing results, we summarize the opportunities and challenges faced by drug developers in stopping the COVID-19 pandemic. This review further provides the current status on development of COVID-19 chemotherapeutics and outlines some future perspectives on potential innovation strategies to mitigate the risk in the new drug discovery. © 2022, Science Press. All right reserved.