Molecular basis of the new COVID-19 target neuropilin-1 in complex with SARS-CoV-2 S1 C-end rule peptide and small-molecule antagonists

Klaewkla, Methus; Charoenwongpaiboon, Thanapon; Mahalapbutr, Panupong

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the current coronavirus 2019 (COVID-19) pandemic, uses its spike (S1) protein for host cell attachment and entry. Apart from angiotensin-converting enzyme 2, neuropilin-1 (NRP1) has been recently found to serve as another host factor for SARS-CoV-2 infection; thus, blocking S1–NRP1 interaction can be a potential treatment for COVID-19. Herein, molecular recognition between SARS-CoV-2 S1 C-end rule (CendR) heptapeptide including small-molecule antagonists (EG00229 and EG01377) and the NRP1 was investigated using molecular dynamics simulations and binding free energy calculations based on MM/PBSA method. The binding affinity and the number of hot-spot residues of EG01377/NRP1 complex were higher than those of CendR and EG00229 systems, in line with the reported experimental data as well as with the lower water accessibility at the ligand-binding site. The (i) T316, P317, and D320 and (ii) S346, T349, and Y353 residues were confirmed to respectively form H-bonds with the positively charged guanidinium group and the negatively charged carboxyl moiety of all studied ligands. Moreover, Rosetta protein design was employed to improve CendR peptide binding affinity to NRP1. The newly designed peptides, especially R683G and A684M, exhibited higher binding efficiency than the native CendR heptapeptide as well as the small-molecule EG00229 by forming more H-bonds and hydrophobic interactions with NPR1, suggesting that these designed peptides could be promising NRP1 inhibitors to combat SARS-CoV-2 infection.