Discovery of dual S-RBD/NRP1-targeting peptides: structure-based virtual screening, synthesis, biological evaluation, and molecular dynamics simulation studies

Abstract

Both receptor-binding domain in spike protein (S-RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human neuropilin-1 (NRP1) are important in the virus entry, and their concomitant inhibition may become a potential strategy against the SARS-CoV-2 infection. Herein, five novel dual S-RBD/NRP1-targeting peptides with nanomolar binding affinities were identified by structure-based virtual screening. Particularly, RN-4 was found to be the most promising peptide targeting S-RBD (K_d = 7.4 ± 0.5 nM) and NRP1-BD (the b1 domain of NRP1) (K_d = 16.1 ± 1.1 nM) proteins. Further evidence in the pseudovirus infection assay showed that RN-4 can significantly inhibit the SARS-CoV-2 pseudovirus entry into 293 T cells (EC₅₀ = 0.39 ± 0.09 μM) without detectable side effects. These results suggest that RN-4, a novel dual S-RBD/NRP1-targeting agent, holds potential as an effective therapeutic to combat the SARS-CoV-2 infection.

Keywords:

• SARS-CoV-2
• receptor-binding domain
• neuropilin-1
• dual inhibitors
• virtual screening

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The study was supported by Taizhou Fengcheng Talent Plan young science and technology talent project [NO.2022010], and Research Foundation of Taizhou People’s Hospital [ZL202025].