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neuropilin 1

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2998

Nomenclature: neuropilin 1

Family: Neuropilins and Plexins

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 923 10p11.22 NRP1 neuropilin 1
Mouse 1 923 8 75.78 cM Nrp1 neuropilin 1
Rat 1 922 19q12 Nrp1 neuropilin 1
Gene and Protein Information Comments
Several alternatively spliced transcript variants that encode different protein isoforms originating from the human and mouse genes have been identified.
Previous and Unofficial Names Click here for help
Npn-1 | CD304 | NRP | VEGF165R
Database Links Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Neuropilin1-b1 domain in complex with EG01377.
PDB Id:  6FMC
Ligand:  EG01377
Resolution:  0.9Å
Species:  Human
References:  7
Natural/Endogenous Ligands Click here for help
semaphorin 3A {Sp: Human}

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Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
EG01377 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist 5.9 pKd 7
pKd 5.9 (Kd 1.32x10-6 M) [7]
Description: Evaluated using a SPR binding assay (Biacore), measuring competitive displacement of biotinylated VEGF from immobilised recombinant NRP1 b1b2 protein.
EG01377 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist 6.2 pIC50 7
pIC50 6.2 (IC50 6.09x10-7 M) [7]
Description: In a cell free assay.
Immunopharmacology Comments
NRP1 is expressed on several types of immune cells (e.g. T cells, dendritic cells) [8,10], and it is involved in potentiating the function and survival of regulatory T cells (Tregs) [4]. In the tumour microenvironment NRP1-mediated regulation of Tregs acts as a barrier to effective anti-tumour immunity. Subsequently, pharmacological inhibition of NRP1 function is being examined via the development of selective antagonists that are predicted to offer anti-angiogenic, anti-tumour and immunomodulatory activities that may be applicable in immuno-oncology [7]. It is hoped that targeting NRP1 will limit Treg-mediated tumour-induced tolerance without inducing autoimmunity.
Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   regulatory T cell (CL:0000815)
Comment:  Neuropilin 1 is expressed by Treg cells and promotes their function and survival.
References:  4
Immuno Cell Type:  Dendritic cells
References:  8,10
General Comments
Neuropilin 1 (NRP1) is a type I transmembrane protein that is a co-receptor for a number of different growth factors (TGFβ1, PLGF, HGF and class 3 secreted semaphorin ligands), which plays crucial roles in vascular and neuronal development. The semaphorins were originally identified for their roles in repulsive axon guidance during development of the central and peripheral nervous systems [5]. NRP1 is also a receptor for the mitogenic, heparin-binding form or VEGF, VEGF165, on endothelial and tumour cells. VEGF165 competes with semaphorin 3A for NRP1 binding sites on endothelial cells [6].

SARS-CoV-2 and COVID-19: NRP1 has been identified as a host protein with potentiating activity as an entry co-factor for SARS-CoV-2 infection [1-3], and this suggests NRP1 as a novel therapeutic target whose modulation could be exploited for COVID-19. A C-terminal sequence in the spike S1 domain that is generated by furin-mediated cleavage (CendR [9]) directly binds to NRP1, and this interaction (and SARS-CoV-2 infection) is blocked in vitro by a mAb that binds to the CendR-binding pocket of NRP1 [2].

References

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1. Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K, Kaya T, Anastasina M et al.. (2020) Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science, [Epub ahead of print]. DOI: 10.1126/science.abd2985

2. Daly JL, Simonetti B, Klein K, Chen K-E, Williamson MK, Antón-Plágaro C, Shoemark DK, Simón-Gracia L, Bauer M, Hollandi R et al.. (2020) Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science, [Epub ahead of print]. DOI: 10.1126/science.abd3072

3. Davies J, Randeva HS, Chatha K, Hall M, Spandidos DA, Karteris E, Kyrou I. (2020) Neuropilin‑1 as a new potential SARS‑CoV‑2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID‑19. Mol Med Rep, 22 (5): 4221-4226. [PMID:33000221]

4. Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J et al.. (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature, 501 (7466): 252-6. [PMID:23913274]

5. Kolodkin AL, Matthes DJ, Goodman CS. (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell, 75 (7): 1389-99. [PMID:8269517]

6. Narazaki M, Tosato G. (2006) Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF165 and semaphorin3A. Blood, 107 (10): 3892-901. [PMID:16424390]

7. Powell J, Mota F, Steadman D, Soudy C, Miyauchi JT, Crosby S, Jarvis A, Reisinger T, Winfield N, Evans G et al.. (2018) Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells. J. Med. Chem., 61 (9): 4135-4154. [PMID:29648813]

8. Roy S, Bag AK, Singh RK, Talmadge JE, Batra SK, Datta K. (2017) Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy. Front Immunol, 8: 1228. [PMID:29067024]

9. Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E. (2009) C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci U S A, 106 (38): 16157-62. [PMID:19805273]

10. Tordjman R, Lepelletier Y, Lemarchandel V, Cambot M, Gaulard P, Hermine O, Roméo PH. (2002) A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat. Immunol., 3 (5): 477-82. [PMID:11953749]

How to cite this page

Neuropilins and Plexins: neuropilin 1. Last modified on 21/10/2020. Accessed on 30/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2998.