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

Moutal, Aubin; Martin, Laurent; Boinon, Lisa; Gómez, Kimberly; Ran, Dongzhi; Zhou, Yuan; Stratton, Harrison J.; Cai, Sanjun; Luo, Shizhen; Gonzalez, Kerry Beth; Perez‐Miller, Samantha; Patwardhan, Amol; Ibrahim, Mohab; Khanna, Rajesh

doi:10.1101/2020.07.17.209288

Cited by 40 publications

(56 citation statements)

References 70 publications

(85 reference statements)

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“…In addition, NRP1 is up-regulated in clinical tumor samples (72). Recent studies also indicate that SARS-CoV-2 spike protein can also bind NRP1 in pulmonary vagal neurons, blocking nociceptive signaling and thereby potentially contributing to "asymptomatic" virus spread (73). Our data demonstrate that COUP-TF2 drives NRP1 expression, facilitating lung vascular repair, although the body of literature suggests that COUP-TF2-mediated NRP1 signaling may promote pathologic angiogenesis in other lung disease contexts, possibly pulmonary hypertension or lung tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2

et al. 2020

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Acute respiratory distress syndrome is associated with a robust inflammatory response that damages the vascular endothelium, impairing gas exchange. While restoration of microcapillaries is critical to avoid mortality, therapeutic targeting of this process requires a greater understanding of endothelial repair mechanisms. Here, we demonstrate that lung endothelium possesses substantial regenerative capacity and lineage tracing reveals that native endothelium is the source of vascular repair after influenza injury. Ablation of chicken ovalbumin upstream promoter–transcription factor 2 (COUP-TF2) (Nr2f2), a transcription factor implicated in developmental angiogenesis, reduced endothelial proliferation, exacerbating viral lung injury in vivo. In vitro, COUP-TF2 regulates proliferation and migration through activation of cyclin D1 and neuropilin 1. Upon influenza injury, nuclear factor κB suppresses COUP-TF2, but surviving endothelial cells ultimately reestablish vascular homeostasis dependent on restoration of COUP-TF2. Therefore, stabilization of COUP-TF2 may represent a therapeutic strategy to enhance recovery from pathogens, including H1N1 influenza and SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2

et al. 2020

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“…What is crucial here is to understand the molecular basis that allows for such disruption to ACE2 to occur and investigate whether synthetic NPs could cause similar effects on certain proteins? Moreover, there is a growing evidence that the SARS-CoV-2 can cause analgesia through its effects on the VEGF-A/Neuropilin-1 receptor signaling pathway (Moutal et al, 2020). It was found that SARS-CoV-2 not only binds to ACE2 protein but also to neuropilin-1, which is a transmembrane glycoprotein highly expressed in the respiratory and olfactory epithelium, vasculature and has several roles within the nervous system (Cantuti-Castelvetri et al, 2020).…”

Section: Trafficking Of Sars-cov2 Within Cellsmentioning

confidence: 99%

Nanomedicine & Nanotoxicology Future Could Be Reshaped Post-COVID-19 Pandemic

Al-Ahmady

Ali‐Boucetta

2020

Front. Nanotechnol.

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Since its first emergence in December 2019, the coronavirus-2 infection has quickly spread around the world and the severity of the pandemic has already re-shaped our lives. This review highlights the role of nanotechnology in the fight against this pandemic with a focus on the design of effective nano-based prevention and treatment options that overcome the limitations associated with conventional vaccines and other therapies. How nanotechnology could be utilized to understand the pathology of the ongoing pandemic is also discussed as well as how our knowledge about SARS-CoV-2 cellular uptake and toxicity could influence future nanotoxicological considerations and nanomedicine design of safe yet effective nanomaterials.

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“…These connections raise an interesting question: does interference with the VEGF-A/NRP-1 signaling pathway by SARS-CoV-2 result in dampened pain? This question has been examined by our laboratory; we recently showed that SARS-CoV-2 Spike protein binding to NRP-1 prevents VEGF-A signaling and reduces neuropathic pain in an animal model 27 . Thus, NRP-1 represents a novel target for treating neuropathic pain 27 .…”

Section: Introductionmentioning

confidence: 99%

“…This question has been examined by our laboratory; we recently showed that SARS-CoV-2 Spike protein binding to NRP-1 prevents VEGF-A signaling and reduces neuropathic pain in an animal model 27 . Thus, NRP-1 represents a novel target for treating neuropathic pain 27 . Furthermore, targeting NRP-1 also presents a unique approach to inhibiting viral entry and/or re-entry into cells to reduce viral load.…”

Section: Introductionmentioning

confidence: 99%

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

Perez‐Miller

Pátek²,

Moutal

et al. 2020

Preprint

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

Cited by 40 publications

References 70 publications

Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2

Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2

Nanomedicine & Nanotoxicology Future Could Be Reshaped Post-COVID-19 Pandemic

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

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