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

By Aubin Moutal, Laurent F. Martin, Lisa Boinon, Kimberly Gomez, Dongzhi Ran, Yuan Zhou, Harrison J. Stratton, Song Cai, Shizhen Luo, Kerry Beth Gonzalez, Samantha Perez-Miller, Amol Patwardhan, Mohab M. Ibrahim, Rajesh Khanna

Posted 18 Jul 2020
bioRxiv DOI: 10.1101/2020.07.17.209288 (published DOI: 10.1097/j.pain.0000000000002097)

Global 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. ### Competing Interest Statement R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids drugs for chronic pain. In addition, R. Khanna has patents US10287334 and US10441586 issued to Regulonix LLC. The other authors declare no competing financial interests. * ACE2 : Angiotensin converting enzyme 2 AUC : area under the curve CaV2.2 : N-type voltage-gated calcium channel COVID-19 : coronavirus disease 2019 DRG : dorsal root ganglia MEA : multi-well microelectrode array NaV1.7 : voltage-gated sodium channel isoform 7 NRP-1 : Neuropilin-1 PWTs : paw withdrawal thresholds SARS-CoV-2 : Severe acute respiratory syndrome coronavirus 2 sEPSCs : spontaneous excitatory postsynaptic currents SNI : spared nerve injury VEGF-A : vascular endothelial growth factor-A

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