Targeting SARS-CoV-2 entry processes: The promising potential and future of host-targeted small-molecule inhibitors

The COVID-19 pandemic, caused by SARS-CoV-2, has had a huge impact on global health. To respond to rapidly mutating viruses and to prepare for the next pandemic, there is an urgent need to develop small molecule therapies that target critical stages of the SARS-CoV-2 life cycle. Inhibiting the entry process of the virus can effectively control viral infection and play a role in prevention and treatment. Host factors involved in this process, such as ACE2, TMPRSS2, ADAM17, furin, PIKfyve, TPC2, CTSL, AAK1, V-ATPase, HSPG, and NRP1, have been found to be potentially good targets with stability. Through further exploration of the cell entry process of SARS-CoV-2, small-molecule drugs targeting these host factors have been developed. This review focuses on the structural functions of potential host cell targets during the entry of SARS-CoV-2 into host cells. The research progress, chemical structure, structure-activity relationship, and clinical value of small-molecule inhibitors against COVID-19 are reviewed to provide a reference for the development of small-molecule drugs against COVID-19.