Identification of polyphenols as novel neuropilin-1 cendR pocket inhibitors to block SARS-CoV-2 entry and enhance variant resistance
et al., PLOS One, doi:10.1371/journal.pone.0345051, Mar 2026
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In silico study showing that polyphenols, particularly 6"-O-acetyldaidzin and phloretin, bind to the neuropilin-1 (NRP-1) b1 domain CendR pocket with higher affinity than the synthetic inhibitor EG01377, potentially blocking SARS-CoV-2 spike protein engagement. Curcumin showed a binding affinity of -7.93 kcal/mol, forming hydrogen bonds with ASP-56, GLN-17, and ARG-129, suggesting it may interfere with NRP-1-mediated SARS-CoV-2 entry.
63 preclinical studies support the efficacy of curcumin for COVID-19:
In silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,2,6,7,12,17,19,25,28 (and specifically the receptor binding domainB,3,5,15,18,21 ), MproC,5-7,12,14,16-18,20,21,23,26,28,29,31,49 , RNA-dependent RNA polymeraseD,5-7,18,27 , PLproE,7, ACE2F,3,19,20,22 , nucleocapsidG,13,30 , nsp10H,30, and helicaseI,37 proteins, and inhibition of spike-ACE2 interactionJ,4.
In vitro studies demonstrate inhibition of the spikeA,42 (and specifically the receptor binding domainB,52), MproC,24,42,49,51 , ACE2F,52, and TMPRSS2K,52 proteins, and inhibition of spike-ACE2 interactionJ,4,35 .
In vitro studies demonstrate efficacy in Calu-3L,50, A549M,42, A549-ATN,32, 293TO,8, HEK293-hACE2P,24,40 , 293T/hACE2/TMPRSS2Q,41, Vero E6R,2,14,18,28,40,42,44,46,48,50 , and SH-SY5YS,39 cells.
Curcumin decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells48, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress8, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts36, is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants15, lowers ACE2 and STAT3, curbing lung inflammation and ARDS in preclinical COVID-19 models33, inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity43, has direct virucidal action by disrupting viral envelope integrity45, may inhibit viral replication and modulate inflammatory pathways like NF-κB via SIRT1 activation53, and can function as a photosensitizer in photodynamic therapy to generate reactive oxygen species that damage the virus45.
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a.
The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
b.
The receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.
c.
The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
d.
RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
e.
The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.
f.
The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.
g.
The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
h.
Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.
i.
The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.
j.
The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.
k.
Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
l.
Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.
m.
A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.
n.
A549-AT is a human lung carcinoma cell line stably transfected with ACE2 and TMPRSS2 receptors. Unlike the parental line, this overexpression ensures stable infection and enhanced viral entry, allowing for the evaluation of antiviral efficacy against various SARS-CoV-2 variants.
o.
293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.
p.
HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.
q.
293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.
r.
Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.
s.
SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.
Ataya et al., 23 Mar 2026, peer-reviewed, 4 authors.
Contact: fataya@ksu.edu.sa.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
Abstract:
Citation: Ataya F , Alamro A, Alghamdi A, Fouad D (2026) Identification of polyphenols as novel neuropilin-1 cendR pocket inhibitors to block SARS-CoV-2 entry and enhance variant resistance. PLoS One 21(3): e0345051. https:// doi.org/10.1371/journal.pone.0345051
Editor: Yusuf Oloruntoyin Ayipo, Kwara State University, NIGERIA
Received:
November 10, 2025
Accepted:
February 12, 2026
Published:
March 23, 2026
Copyright: © 2026 Ataya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data availability statement : All relevant data are included within the paper and its supplementary file. No additional datasets were generated or deposited in external repositories.
Funding: FA received funding from King Abdulaziz City for Science and Technology (KACST) - Projects, grant number
RESEARCH ARTICLE
Identification of polyphenols as novel neuropilin-1 cendR pocket inhibitors to block SARS-CoV-2 entry and enhance variant resistance
Farid Ataya 1 * , Abir Alamro 1 , Amani Alghamdi 1 , Dalia Fouad 2
- 1 Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia,
- 2 Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
[* fataya@ksu.edu.sa](mailto:fataya@ksu.edu.sa)
Abstract
Neuropilin-1 (NRP-1) functions as an essential co-receptor for SARS-CoV-2, facilitating viral entry by binding the spike protein's C-end rule (CendR) motif in its b1 domain, yet it has received less attention than ACE2 in therapeutic development. This in silico study evaluates plant-derived polyphenols as potential selective inhibitors of the NRP-1 CendR pocket to disrupt SARS-CoV-2 engagement, addressing limitations of synthetic inhibitors like EG01377, which exhibit modest affinity (-5.83 kcal/mol) and potential off-target risks. High-throughput molecular docking of 10,000 phytochemicals using AutoDock Vina identified 10 polyphenols with binding affinities ranging from -9.87 to -6.63 kcal/mol, led by 6'-O-acetyldaidzin (-9.87 kcal/mol) and phloretin (-8.64 kcal/mol), forming stable hydrogen bonds and π-cation interactions with critical residues (e.g., THR-401, GLU-367 for 6'-O-acetyldaidzin; PRO-311, ILE400 for phloretin), as visualized in Discovery Studio. Notably, four of the top inhibitors are isoflavonoid derivatives, highlighting a chemical class enrichment. Molecular dynamics simulations over 100 ns using Desmond indicated moderate complex stability (RMSD: 0.6-3.8 Å; RMSF <0.5 Å at binding site ). ADMET-Tox profiling via SwissADME and ProTox-II revealed drug-like properties, including high gastrointestinal absorption (>70% for leads) and low toxicity (classes 4-5), though 6'-Oacetyldaidzin shows limited bioavailability due to its high H-bond acceptor count (10) and large size, suggesting need for formulation optimization. The NRP-1 b1 homology model, built with SWISS-MODEL, exhibited high fidelity (GMQE: 0.79; Ramachandran favored regions: 90.3% ). This focused computational screening of polyphenols against NRP-1 complements prior studies and identifies candidates for experimental validation as potential SARS-CoV-2 inhibitors. Limitations include the in silico nature, and lack of membrane/sialic acid models, necessitating in vitro and in vivo testing against SARS-CoV-2..
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"abstract": "<jats:p>\n Neuropilin-1 (NRP-1) functions as an essential co-receptor for SARS-CoV-2, facilitating viral entry by binding the spike protein’s C-end rule (CendR) motif in its b1 domain, yet it has received less attention than ACE2 in therapeutic development. This\n <jats:italic>in silico</jats:italic>\n study evaluates plant-derived polyphenols as potential selective inhibitors of the NRP-1 CendR pocket to disrupt SARS-CoV-2 engagement, addressing limitations of synthetic inhibitors like EG01377, which exhibit modest affinity (−5.83 kcal/mol) and potential off-target risks. High-throughput molecular docking of 10,000 phytochemicals using AutoDock Vina identified 10 polyphenols with binding affinities ranging from −9.87 to −6.63 kcal/mol, led by 6“-O-acetyldaidzin (-9.87 kcal/mol) and phloretin (-8.64 kcal/mol), forming stable hydrogen bonds and π-cation interactions with critical residues (e.g., THR-401, GLU-367 for 6”-O-acetyldaidzin; PRO-311, ILE-400 for phloretin), as visualized in Discovery Studio. Notably, four of the top inhibitors are isoflavonoid derivatives, highlighting a chemical class enrichment. Molecular dynamics simulations over 100 ns using Desmond indicated moderate complex stability (RMSD: 0.6–3.8 Å; RMSF <0.5 Å at binding site\n <jats:bold>).</jats:bold>\n ADMET-Tox profiling via SwissADME and ProTox-II revealed drug-like properties, including high gastrointestinal absorption (>70% for leads) and low toxicity (classes 4–5), though 6”-O-acetyldaidzin shows limited bioavailability due to its high H-bond acceptor count (10) and large size, suggesting need for formulation optimization. The NRP-1 b1 homology model, built with SWISS-MODEL, exhibited high fidelity (GMQE: 0.79; Ramachandran favored regions: 90.3%\n <jats:bold>).</jats:bold>\n This focused computational screening of polyphenols against NRP-1 complements prior studies and identifies candidates for experimental validation as potential SARS-CoV-2 inhibitors. Limitations include the\n <jats:italic>in silico</jats:italic>\n nature, and lack of membrane/sialic acid models, necessitating\n <jats:italic>in vitro</jats:italic>\n and\n <jats:italic>in vivo</jats:italic>\n testing against SARS-CoV-2 variants.\n </jats:p>",
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