Small molecules as anti COVID-19 therapeutics: Discovery process, mechanism of action and clinical trials

COVID-19 has become a pandemic and is still breaking out in many countries all over the world due to the emergence of new variants. Several safe and effective vaccines have been approved and succeeded in reducing the rate of patients with severe symptoms and that of mortality. Currently, most countries have chosen to change their policy from “zero Covid” to “live with” the pandemic and opened their boundaries to recover their economy. However, the emergence of new dangerous variants such as Delta or Omicron significantly reduces the effectiveness of vaccines and therefore, is complicating the pandemic control. In addition to the use of vaccines, the development of antiviral drugs is extremely important to tackle this worldwide threat. Currently, the approved anti-COVID-19 agents consist of two main categories, including spike protein (S) targeted monoclonal antibodies and orally available small molecule antiviral agents. However, the biopharmaceutical approach still incurs significant drawbacks such as bad bioavailability, expensive and growing resistance of the virus due to the accumulation of mutations in the receptor binding domain (RBD) of the spike protein in new variants. On the other hand, small molecule antiviral agents are a more appealing approach as their main therapeutic targets are intrinsic enzymes which are less likely to mutate, hence remaining inhibitory activity against different variants. Additionally, the oral availability of these drugs also allows these medications to be taken by individuals without the aid of healthcare professionals, which could alleviate the burden on healthcare systems. Therefore, the research and finding of new orally available antiviral agents is still a necessity. This review is carried out to give an overview of the discovery and development, mechanism of action, clinical trials, and approval status of current small-molecule anti-SARS-CoV-2 drugs.