Publication date: Jun 29, 2025
Growing evidence of post-COVID neurological complications, such as encephalopathy, neurodegeneration, and cognitive impairment, suggests 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 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, we report the interaction of the chemically synthesized LRAD3 domains with SARS-CoV-2 spike protein. We observed that the extracellular domains of LRAD3 depend on calcium for proper folding and maintaining their structural integrity. Our results revealed 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.
| Concepts | Keywords |
|---|---|
| Calcium | LRAD3 Ectodomain |
| Covid | neurological disorders |
| Neurodegeneration | Peptide Synthesis |
| Protein | SARS-CoV-2 Entry |
| Viral |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | complications |
| disease | MESH | encephalopathy |
| disease | MESH | cognitive impairment |
| disease | MESH | viral infection |
| disease | MESH | COVID-19 |
| drug | DRUGBANK | Calcium |
| disease | IDO | protein |
| disease | MESH | neurological disorders |