Highly potent dual-targeting angiotensin-converting enzyme 2 (ACE2) and Neuropilin-1 (NRP1) peptides: A promising broad-spectrum therapeutic strategy against SARS-CoV-2 infection.

The efficacy of approved vaccines has been diminishing due to the increasing advent of SARS-CoV-2 variants with diverse mutations that favor sneak entry. Nonetheless, these variants recognize the conservative host receptors angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) for entry, rendering the dual blockade of ACE2 and NRP1 an advantageous pan-inhibition strategy. Here, we identified a highly potent dual-targeting peptide AP-1 using structure-based virtual screening protocol. AP-1 had nanoscale binding affinities for ACE2 (K = 6.1 ± 0.2 nM) and NRP1 (K = 13.4 ± 1.2 nM) and approximately 102- and 8-fold stronger than positive inhibitors S and NMTP-5, respectively. Further evidence in pseudovirus cell infection and cytotoxicity assays demonstrated that AP-1 exhibited remarkable entry inhibition of variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. Together, our findings suggest that AP-1 with dual-targeting ACE2/NRP1 efficacy could be a promising broad-spectrum agent for treating SARS-CoV-2 emerging VOCs.