Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic highlighted the critical need to understand the molecular mechanisms governing viral entry into host cells. This study investigates the spectrum of cellular receptors utilized by SARS-CoV-2 and the subsequent biochemical and cellular events that facilitate infection. Focusing on membrane biology, we employed a combination of *in silico* structural modeling, *in vitro* binding assays using recombinant proteins, and live-cell imaging with various human cell lines, including those expressing different levels of known and putative receptors. Key findings confirm the central role of Angiotensin-Converting Enzyme 2 (ACE2) as the primary entry receptor, but also reveal the functional involvement of alternative receptors, such as neuropilin-1 (NRP1) and CD147, in mediating viral attachment and fusion, particularly in non-pulmonary tissues. The research details the membrane-proximal interactions that govern spike protein conformational changes and the role of host proteases in receptor cleavage. These results provide a comprehensive molecular map of SARS-CoV-2 tropism and offer potential targets for broad-spectrum antiviral therapies aimed at disrupting the initial stages of viral cell entry.