Defining diverse spike-receptor interactions involved in SARS-CoV-2 entry: Mechanisms and therapeutic opportunities

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped RNA virus that caused the Coronavirus Disease 2019 (COVID-19) pandemic. The SARS-CoV-2 Spike glycoprotein binds to angiotensin converting enzyme 2 (ACE2) on host cells to facilitate viral entry. However, the presence of SARS-CoV-2 in nearly all human organs - including those with little or no ACE2 expression - suggests the involvement of alternative receptors. Recent studies have identified several cellular proteins and molecules that influence SARS-CoV-2 entry through ACE2-dependent, ACE2-independent, or inhibitory mechanisms. In this review, we explore how these alternative receptors were identified, their expression patterns and roles in viral entry, and their impact on SARS-CoV-2 infection. Additionally, we discuss therapeutic strategies aimed at disrupting these virus-receptor interactions to mitigate COVID-19 pathogenesis.