Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 263, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2023.115908
Keywords
Dual inhibitor; Angiotensin-converting enzyme 2; Neuropilin-1; Virtual screening; SARS-CoV-2
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This study identifies a dual-targeting peptide, AP-1, that effectively inhibits variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. The findings suggest that AP-1 could be a promising broad-spectrum agent for treating emerging VOCs of SARS-CoV-2.
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 (Kd = 6.1 +/- 0.2 nM) and NRP1 (Kd = 13.4 +/- 1.2 nM) and approximately 102- and 8-fold stronger than positive inhibitors S471-503 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-CoV2 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.
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