An update review of emerging small-molecule therapeutic options for COVID-19

Tian, Dengke; Liu, Yuzhi; Liang, Chengyuan; Xin, Liang; Xie, Xiaolin; Zhang, Dezhu; Wan, Minge; Li, Han; Fu, Xueqi; Liu, Hong; Cao, Wenqiang

The SARS-CoV-2 outbreak and pandemic that began near the end of 2019 has posed a challenge to global health. At present, many candidate small-molecule therapeutics have been developed that can inhibit both the infection and replication of SARS-CoV-2 and even potentially relieve cytokine storms and other related complications. Meanwhile, host-targeted drugs that inhibit cellular transmembrane serine protease (TMPRSS2) can prevent SARS-CoV-2 from entering cells, and its combination with chloroquine and dihydroorotate dehydrogenase (DHODH) inhibitors can limit the spread of SARS-CoV-2 and reduce the morbidity and mortality of patients with COVID-19. The present article provides an overview of these small-molecule therapeutics based on insights from medicinal chemistry research and focuses on RNA-dependent RNA polymerase (RdRp) inhibitors, such as the nucleoside analogues remdesivir, favipiravir and ribavirin. This review also covers inhibitors of 3C-like protease (3CL(pro)), papain-like protease (PL(pro)) and other potentially innovative active ingredient molecules, describing their potential targets, activities, clinical status and side effects.