Discovering small-molecule therapeutics against SARS-CoV-2

•SARS-CoV-2's high homology with SARS-CoV did not prove beneficial immediately.•Targeting viral attachment and fusion proteins has yielded good early inhibitors.•Small molecules, peptides and peptidomimetics have been designed against SARSCoV-2.•Several avenues of anti-viral drug discovery remain unexplored.•Understanding fundamentals of these processes will yield novel anti-virals. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. The lack of effective treatments, coupled with its etiology, has resulted in more than 400,000 deaths at the time of writing. The SARS-CoV-2 genome is highly homologous to that of SARS-CoV, the causative agent behind the 2003 SARS outbreak. Based on prior reports, clinicians have pursued the off-label use of several antiviral drugs, while the scientific community has responded by seeking agents against traditional targets, especially viral proteases. However, several avenues remain unexplored, including disrupting E and M protein oligomerization, outcompeting host glycan–virus interactions, interfering with the heparan sulfate proteoglycans–virus interaction, and others. In this review, we highlight some of these opportunities while summarizing the drugs currently in use against coronavirus 2019 (COVID-19). Despite the approval of remdisivir, much remains to be accomplished to address the urgent need for a drug to treat COVID-19. This short review explores several novel avenues for discovering small-molecule antagonists against SARS-CoV-2