LAUSR

Growing evidence of post‐COVID neurological complications, such as encephalopathy, neurodegeneration, and cognitive impairment, suggests severe acute respiratory syndrome‐related corona virus 2 (SARS‐CoV‐2) viral infection into the central nervous system (CNS). Therefore, understanding the mechanisms of viral entry into the CNS, where human angiotensin‐converting enzyme 2 (ACE2) is barely expressed, is critical for addressing the neurological consequences of COVID‐19. Importantly, the low‐density lipoprotein receptor class A domain containing 3 (LRAD3) is overexpressed in brain cells, suggesting a possible ACE2‐independent alternate pathway of viral entry into brain cells. Herein, the interaction of the chemically synthesized LRAD3 domains with SARS‐CoV‐2 spike protein is reported. It is observed that the extracellular domains of LRAD3 depend on calcium for proper folding and maintaining their structural integrity. The results reveal that domain 1 of LRAD3, which is most accessible from the cell surface, engages with the N‐terminal domain of the viral spike protein. These findings open up possibilities to develop new therapeutic strategies targeting ACE2 independent viral entry pathways.