Neuropilin-1 Assists SARS-CoV-2 Infection by Stimulating the Separation of Spike Protein Domains S1 and S2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated inflammasome diseases. Moreover, its pathophysiology involves the angiotensin-converting enzyme 2 (ACE2) receptor, Toll-like receptor 4 (TLR4) pathway, neuropilin‑1 pathway, inflammasome activation pathway, sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization pathway, cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, spike protein/inflammasome-genetic pathway, and immunological memory engram pathway. Therefore, it is necessary to prescribe anticatalytic treatments to alleviate the SARS-CoV-2 inflammasome, immunologic engram, and spike protein levels.

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Spread of Mink SARS-CoV-2 Variants in Humans: A Model of Sarbecovirus Interspecies Evolution

Frontiers in Microbiology ◽

10.3389/fmicb.2021.675528 ◽

2021 ◽

Vol 12 ◽

Author(s):

Christian A. Devaux ◽

Lucile Pinault ◽

Jérémy Delerce ◽

Didier Raoult ◽

Anthony Levasseur ◽

...

Keyword(s):

Neutralizing Antibodies ◽

3D Structure ◽

Spike Protein ◽

Linear Epitope ◽

Angiotensin I ◽

Vaccine Protection ◽

Angiotensin I Converting Enzyme ◽

Neuropilin 1 ◽

Rapid Spread ◽

The Impact

The rapid spread of SARS-CoV-2 variants has quickly spanned doubts and the fear about their ability escape vaccine protection. Some of these variants initially identified in caged were also found in humans. The claim that these variants exhibited lower susceptibility to antibody neutralization led to the slaughter of 17 million minks in Denmark. SARS-CoV-2 prevalence tests led to the discovery of infected farmed minks worldwide. In this study, we revisit the issue of the circulation of SARS-CoV-2 variants in minks as a model of sarbecovirus interspecies evolution by: (1) comparing human and mink angiotensin I converting enzyme 2 (ACE2) and neuropilin 1 (NRP-1) receptors; (2) comparing SARS-CoV-2 sequences from humans and minks; (3) analyzing the impact of mutations on the 3D structure of the spike protein; and (4) predicting linear epitope targets for immune response. Mink-selected SARS-CoV-2 variants carrying the Y453F/D614G mutations display an increased affinity for human ACE2 and can escape neutralization by one monoclonal antibody. However, they are unlikely to lose most of the major epitopes predicted to be targets for neutralizing antibodies. We discuss the consequences of these results for the rational use of SARS-CoV-2 vaccines.

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Faculty Opinions recommendation of SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738773272.793579818 ◽

2020 ◽

Author(s):

Gerald Zamponi

Keyword(s):

Spike Protein ◽

Receptor Signaling ◽

Neuropilin 1

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Mutating novel interaction sites in NRP1 reduces SARS-CoV-2 spike protein internalization

10.1101/2021.10.11.463689 ◽

2021 ◽

Author(s):

Debjani Pal ◽

Kuntal De ◽

Tomithy Yates ◽

Wellington Muchero

Keyword(s):

Angiotensin Converting Enzyme ◽

Ribosomal Protein ◽

Protein S ◽

Spike Protein ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Interaction Sites ◽

Viral Binding ◽

Expression Of Genes ◽

Neuropilin 1

The global pandemic of Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 has become a severe global health problem because of its rapid spread. Both angiotensin-converting enzyme 2 and neuropilin 1 provide initial viral binding sites for SARS-CoV-2. Here, we show that three cysteine residues located in a1/a2 and b1 domains of neuropilin 1 are necessary for SARS-CoV-2 spike protein internalization in human cells. Mutating cysteines C82, C104, and C147 altered neuropilin 1 stability and binding ability as well as cellular internalization and lysosomal translocation of the spike protein. This resulted in up to 4 times reduction in spike protein load in cells for the original, alpha, and delta SARS-CoV-2 variants even in the presence of the endogenous angiotensin-converting enzyme 2 receptors. Transcriptome analysis of cells transfected with mutated NRP1 revealed significantly reduced expression of genes involved in viral infection and replication, including eight members of the ribosomal protein L, ten members of ribosomal protein S, and five members of the proteasome β subunit family proteins. We also observed higher expression of genes involved in the suppression of inflammation and endoplasmic reticulum-associated degradation. These observations suggest that these cysteines offer viable targets for therapies against COVID-19.

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SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia

10.1101/2020.07.17.209288 ◽

2020 ◽

Cited By ~ 2

Author(s):

Aubin Moutal ◽

Laurent F. Martin ◽

Lisa Boinon ◽

Kimberly Gomez ◽

Dongzhi Ran ◽

...

Keyword(s):

Viral Entry ◽

Disease Transmission ◽

Neuronal Firing ◽

Synaptic Activity ◽

Spike Protein ◽

Angiogenic Factor ◽

Neuropilin 1 ◽

Neuropathic Pain Model ◽

Asymptomatic Individuals ◽

Endothelial Growth Factor

AbstractGlobal spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2’s Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) – a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A–triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A ‘silencing’ of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.

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In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein

10.1101/2020.09.22.308783 ◽

2020 ◽

Cited By ~ 1

Author(s):

Samantha Perez-Miller ◽

Marcel Patek ◽

Aubin Moutal ◽

Carly R. Cabel ◽

Curtis A. Thorne ◽

...

Keyword(s):

Neuropathic Pain ◽

Binding Site ◽

Small Molecule ◽

Chemical Properties ◽

Cancer Therapeutics ◽

Spike Protein ◽

Virus Protein ◽

Furin Cleavage ◽

Neuropilin 1 ◽

Almost All

AbstractNeuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain and hypothesize that interference of this pathway by SARS-CoV-2 spike protein interferes with pain signaling. Here, we report hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physico-chemical properties. Using an ELISA, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that almost all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Two compounds displayed robust inhibition of a recombinant vesicular stomatitis virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain and cancer with the added potential of inhibiting SARS-CoV-2 virus entry.

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Alternate mechanisms of SARS-CoV-2–induced analgesia and additional pathological significance of SARS-CoV-2 spike protein interaction with vascular endothelial growth factor-A/neuropilin-1 receptor signaling

Pain ◽

10.1097/j.pain.0000000000002447 ◽

2021 ◽

Vol 162 (12) ◽

pp. 2956-2957

Author(s):

Amit Jain ◽

Reda Tolba ◽

Amar Salti ◽

Massimo Lamperti

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Protein Interaction ◽

Spike Protein ◽

Vascular Endothelial ◽

Receptor Signaling ◽

Neuropilin 1 ◽

Endothelial Growth Factor

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Myxobacterial Depsipeptide Chondramides Interrupt SARS-CoV-2 Entry by Targeting Its Broad, Cell Tropic Spike Protein: Antagonistic Prospects for Anti-COVID-19 Drug Discovery

10.26434/chemrxiv.14043641 ◽

2021 ◽

Author(s):

Rey Arturo T. Fernandez ◽

Mark Tristan J. Quimque ◽

Kin Israel Notarte ◽

Joe Anthony Manzano ◽

Delfin Yñigo H. Pilapil ◽

...

Keyword(s):

Host Cell ◽

In Silico ◽

Protein Docking ◽

Spike Protein ◽

Viral Agent ◽

Viral Attachment ◽

Cell Receptors ◽

Binding Domains ◽

Neuropilin 1 ◽

The Uk

The severity of the COVID-19 pandemic necessitated the search for drugs against the causative viral agent, SARS-CoV-2. Among the promising targets is the viral surface of SARS-CoV-2 adorned by spike proteins appearing as crown-like structures known for their function in viral attachment and entry mechanisms. To exploit the potential of previously reported antiviral microbial metabolites, we explored the antagonistic prospects of myxobacterial secondary metabolites against receptor-binding domains (RBD) to host cell receptors namely angiotensin-converting enzyme 2 (ACE2), basigin (CD147) and glucose-regulated protein 78 (GRP78) as well as the binding site of neuropilin-1 (NRP1) in the SARS-CoV-2 spike protein using in silico molecular interaction based approaches such as molecular and protein-protein docking along with an investigation of their pharmacokinetic profiles. Thus, the cyclic depsipeptide chondramides in general conferred high affinity and demonstrated strong binding to true viral hot spots in the spike protein such as Arg403, Gln493 and Gln498 with high selectivity compared to most of the host cell receptors studied. The binding energy (BE) of chondramide C3 (1), being the top ligand against ACE2 and CD147 RBD, remained relatively constant when docked against most of the spike variants such as A475V, L452R, V483A, S477N, F490L and V439K. On the other hand, the parent congener chondramide C (2) exhibited strong affinity against the UK variant (N501Y), the South African variant (E484K) and the globally prevalent D614G along with its co-occurring mutation in the RBD, I472V. Meanwhile, chondramide C6 (29) showed highest BE towards GRP78 RBD. To study the effect of complexed chondramide ligands, protein-protein binding experiments were carried out using high-ambiguity driven docking (HADDOCK) which showed weaker binding affinity between spike and the target host receptors. The in silico active chondramides in general conferred favourable pharmacokinetic properties illustrating their potential to be developed as anti-COVID-19 drugs that limit viral attachment and minimize infection.

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