Journal Article Epublish
PubMed: 40722799 DOI: 10.3390/biomedicines13071730
Neuropilin-1: A Conserved Entry Receptor for SARS-CoV-2 and a Potential Therapeutic Target.
Biomedicines 13(7)
Authors: Vivany Maydel Sierra-Sánchez, Citlali Margarita Blancas-Napoles, Aina Daniela Sánchez-Maldonado, Indira Medina, Rodrigo Romero-Nava, Fengyang Huang, Enrique Hong, Asdrúbal Aguilera-Méndez, Sergio Adrian Ocampo-Ortega, Santiago Villafaña
Affiliations
- Laboratorio de Terapia Génica Experimental, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico.
- Laboratorio de Investigación en Obesidad y Asma, Hospital Infantil de México "Federico Gómez", Ciudad de Mexico 06720, Mexico.
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Ciudad de Mexico 14330, Mexico.
- Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás Hidalgo, Morelia 58040, Mexico.
Abstract
Background/Objectives: Neuropilin-1 (NRP1) is a key co-receptor for SARS-CoV-2, complementing the ACE2 receptor. Several investigations have documented highly conserved sequences in this receptor, supporting the implication of NRP1 as a key mediator in SARS-CoV-2 cellular entry mechanisms. Methods: To investigate this hypothesis, we examined 104,737 SARS-CoV-2 genome fastas from GISAID genomic data, corresponding to isolates collected between 2020 and 2025 in Mexico. Specifically, we focused on the RRAR motif, a known furin-binding site for NRP-1 and the binding site for ACE2 with the spike protein. Our analysis revealed high conservation (>98%) of the RRAR domain compared to a rapidly diminishing ACE2-binding domain. A complementary analysis, using Data from Gene Expression Omnibus (GEO, GSE150316), showed that NRP1 expression in lung tissue remains relatively stable, whereas ACE2 displayed high inter-individual variability and lower abundance compared to NRP1. Based on this evidence, we designed two humans-rats NRP1 siRNAs that were tested in vivo using a melittin-induced lung injury model. Results: The RT-PCR assays confirmed an effective NRP1 knockdown, and the siRNA-treated group showed a significant reduction in the lesions severity. These findings highlight NRP1 as a stable and relevant therapeutic target and suggest the protective potential of siRNA-mediated gene silencing. Conclusions: The evidence presented here supports the rational design of NRP1-directed therapies for multiple circulating SARS-CoV-2 variants in Mexico.
MeSH
Sars-Cov-2, Lung, Neuropilins, Neuropilin-1, Therapeutics, Severe Acute Respiratory Syndrome-Related Coronavirus, Gene Expression