Molecular mechanisms of SARS-CoV-2 entry: implications for biomedical strategies

SUMMARYThe mechanisms by which viruses enter host cells are crucial for their ability to infect and cause disease, serving as major targets for both host immune responses and therapeutic strategies. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry process is primarily driven by the binding of the viral spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) receptor, in conjunction with the activity of endosomal cathepsin L and the serine protease transmembrane protease serine 2 (TMPRSS2). Nevertheless, recent scientific advances have expanded our understanding of SARS-CoV-2 entry mechanisms, uncovering alternative receptors and novel cofactors that may enhance viral tropism and adaptability. Given the critical role of the SARS-CoV-2 S protein in mediating host cell entry, it has become a primary target for prevention and therapeutic strategies. However, the continuous spread of SARS-CoV-2 has led to the emergence of S protein variants that may potentially confer a fitness advantage or modify key aspects of SARS-CoV-2 biology, such as transmissibility, infectivity, antigenicity, and/or pathogenicity, posing significant challenges to the efficacy of current interventions. In this review, we provide an updated and comprehensive overview of the latest advances in SARS-CoV-2 entry pathways and molecular mechanisms, exploring their implications for antiviral drug discovery, vaccine design, and the development of other biomedical strategies while addressing the challenges posed by the ongoing evolution of the virus.