IndraLab
Statements
sparser
"The well-documented NRP1/VEGF-A blocker EG00229 ( xref ) was also studied to compare its NRP1 interaction with that of VEGF-A. Thus, in this study, to explore the stability and binding interactions of CendR peptides, seventeen systems were studied – VEGF-A, 13 peptides, a lone arginine, an arginine analogue and an NRP1 inhibitor ( xref and xref C)."
sparser
"Though TKPR has been reported to disrupt the NRP1-VEGF interface ( xref ), the results of the present study cannot conclusively support that finding given the inconsistency of binding affinity scores across the three simulations of NRP1-TKPR (-23.67 ± 11.80 kcal/mol, -67.33 ± 5.31 kcal/mol, -51.48 ± 19.13 kcal/mol) and NRP1-VEGF-A (-85.81 ± 18.66 kcal/mol, -67.34 ± 11.27 kcal/mol, -82.07 ± 18.59 kcal/mol)."
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"No information on the spontaneous mutations of the amino-acid residues in the CendR binding pocket of NRP1 could also be found.Disrupting the key protein-protein interactions between NRP1 and VEGF-A at the b1 CendR binding site has long been the focus of drug discovery efforts, particularly for cancer therapy."
sparser
"Blocking of Vegf binding to Nrp1 using a specific antibody that leaves Vegf binding to Vegfr2 intact xref does not phenocopy the retinal angiogenesis defects in Nrp1 mutants described here, and Nrp1 promotes activation of intracellular c-abl activation in a VEGF-independent manner xref , further supporting the idea that Nrp1 may affect other pathways that trigger tip cell formation."
reach
"Thus, all the isoforms can bind the two main VEGFA tyrosine kinase receptors, VEGFR1 (FLT1) and VEGFR2 (KDR, previously also known as FLK1), while NRP1 binds with higher affinity the larger VEGFA isoforms, such as VEGFA165 and VEGFA189, compared to VEGFA121 by interacting with the heparin binding domain encoded by exon 7, even though the interaction between VEGFA and NRP1 also involves the exon 8 encoded epitope, which is common to all the isoforms [58,59,60,61]."
sparser
"In 2006, von Wronski et al demonstrated that Tuftsin, a naturally occurring short peptide antagonist mimicking the C-terminal sequence of VEGF-A (Tuftsin: TKPR; exon 8a: CDKPRR), blocks VEGF-A binding to NRP1 without blocking VEGF-A binding to VEGFR2. xref The peptide competed with VEGF-A165a on NRP1 and NRP2, and displaced VEGF-A165a from endothelial cells."
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"Aiming to improve the H-bonding network, the benzothiadiazole heteroaryl moiety of EG00229 was replaced with methylaminoaryl-substituted dihydrobenzofuran, providing the compound EG01377 (compound 2 in Table 4) with an improved inhibition of VEGF-A binding to NRP1 with IC = 0.6 µM. Crystallographic studies revealed two crystal complexes in higher and lower resolutions, which differ in the binding conformation of the bulky aromatic moiety."
sparser
"NRP1 binding to VEGF-A is isolated to C-terminal portion of VEGF-A165a and VEGF-A165a exon 8a encoded residues are indispensible for NRP1 binding. xref , xref , xref , xref , xref Crystallographic studies are not yet available for intact VEGF-A121a, but this ligand has the entire exon 5 and exon 8a encoded sequence intact and is shown by the SPR technique (cell-free) to bind NRP1, with lower affinity compared to VEGF-A165a xref , xref and to NRP2 with similar affinity as NRP1. xref Modulation of VEGF-A121a-VEGFR2 signaling by the expression of (or interference with) NRP1 on cells in vitro suggests that these components are interacting (or at least interdependent), although it is also established that VEGF-A121a cannot form the extracellular VEGFR2-VEGF-NRP1 bridge that VEGF-A165a is capable of forming (or if a weak extracellular VEGFR2-VEGF-A121a-NRP1 bridge exists, it can not be measured experimentally)."
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"Correspondingly, all molecular descriptors were calculated for these compounds and they were considered part of the small molecule set.Since one objective of inhibiting the VEGF-A/NRP-1 interaction is disruption of pain signals, the full therapeutic effect will require drug exposure in the central nervous system (CNS)."
sparser
"While investigating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), two studies reported that the virus’s Spike protein — responsible for viral entry through interactions with the Angiotensin-converting enzyme 2 receptor — could also bind NRP1 [ xref ] and interrupt VEGF-A binding to NRP1 [ xref ]."
sparser
"The docked pose of the lead compound from this series, 4’-methyl-2’-morpholino-2-(phenylamino)-[4,5’-bipyrimidin]-6(1H)-one, (designated herein as NRP1–4) predicts interactions with key NRP1 residues responsible for stabilizing the interaction with VEGF-A, including T349, and Y353 [ xref ; xref ] ( xref , xref )."
sparser
"These findings were consistent with our previous results using EG00229 or Spike protein [ xref ] and support the conclusion that blocking the interaction of VEGF-A with NRP1 following central administration of NRP1–4 is sufficient to reverse experimental neuropathic pain induced by spared nerve injury in rats."
sparser
"In the peptides group, the significant achievement was the identification (by a mutated phage library screening) of heptapeptide Ala-Thr-Trp-Leu-Pro-Pro-Arg (A7R) which selectively inhibits VEGF-A 165 binding to NRP-1 and decreases breast cancer angiogenesis and growth in vivo (Starzec et al. xref , xref )."
reach
"Correspondingly, all molecular descriptors were calculated for these compounds
and they were considered part of the small molecule set.Since one objective of inhibiting the VEGF-A/NRP-1 interaction is disruption of pain
signals, the full therapeutic effect will require drug exposure in the central nervous
system (CNS)."
sparser
"Aiming to improve the H-bonding network, the benzothiadiazole heteroaryl moiety of EG00229 was replaced with methylaminoaryl-substituted dihydrobenzofuran, providing the compound EG01377 (compound 2 in xref ) with an improved inhibition of VEGF-A binding to NRP1 with IC 50 = 0.6 µM. Crystallographic studies revealed two crystal complexes in higher and lower resolutions, which differ in the binding conformation of the bulky aromatic moiety."
sparser
"Thus, all the isoforms can bind the two main VEGFA tyrosine kinase receptors, VEGFR1 (FLT1) and VEGFR2 (KDR, previously also known as FLK1), while NRP1 binds with higher affinity the larger VEGFA isoforms, such as VEGFA165 and VEGFA189, compared to VEGFA121 by interacting with the heparin binding domain encoded by exon 7, even though the interaction between VEGFA and NRP1 also involves the exon 8 encoded epitope, which is common to all the isoforms [ xref , xref , xref , xref ]."
sparser
"NRP1 binding to VEGF-A, R-x-x-R carboxyl-terminal motif-containing peptides (CendR) ( xref ), or a NRP1-targeting ligand-blocking antibody promotes lateral NRP1 delocalization at cell-cell contacts and increased permeability in a manner dependent on NRP1 cytoplasmic domain but independent of VEGFR2 activity ( xref )."
sparser
"Biochemical and functional studies have demonstrated that Asp-320 and Tyr-297 are critical for VEGFA binding to NRP1 with mutations of Asp-320 to Lys (D320K) or Tyr-297 to Ala (Y297A) abrogating VEGFA binding to NRP1 ( xref ) without affecting NRP1 binding to class 3 semaphorins [ xref , xref , xref ]."
sparser
"In this article, we have identified residues essential for VEGF-A 165 binding to NRP1, which constitute part of the putative binding pocket for VEGF-A 165 in the NRP1 b1 domain, defined by computational analysis of the b1 domain structure, and inferred from the crystal structure of the b1 domain."
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"Blocking of Vegf binding to Nrp1 using a specific antibody that leaves Vegf binding to Vegfr2 intact XREF_BIBR does not phenocopy the retinal angiogenesis defects in Nrp1 mutants described here, and Nrp1 promotes activation of intracellular c-abl activation in a VEGF independent manner XREF_BIBR, further supporting the idea that Nrp1 may affect other pathways that trigger tip cell formation."
sparser
"The suitability of the binding pocket to accommodate different ligands with the CendR terminals is evident from the comparison of the crystal complexes of VEGF-A 164 -NRP1 and SARS-CoV-2-NRP1 ( xref A), which show remarkable similarities in the binding mode of their CendR sequences."
sparser
"NRP1 has also been implicated in tumor growth and angiogenesis; inhibition by a blocking antibody that prevents VEGF-A binding to NRP1 enhanced the antitumor effects of the inhibitory anti-VEGF-A antibody, bevacizumab, in mouse xenograft models.( xref ) As an alternative to biological therapeutics, small molecule inhibitors of NRP1 function would be desirable, but development of protein−protein interaction inhibitors is not a trivial task. xref , xref We utilized the bicyclic peptide 1 , corresponding to the C-terminal 28 amino acids of VEGF-A 165 (Figure xref ) as a starting point for small molecule design."
sparser
"The potency of compound 2 in inhibiting VEGF-A binding to NRP1 was thus very similar to that of the bicyclic peptide compound 1 , which inhibits 125 I-VEGF-A binding to PAE/NRP1 and tumor cells with IC 50 values of 2−3 μM and inhibits 125 I-VEGF-A binding to HUVECs with an IC 50 of 20 μM.( xref )"
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"While investigating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), two studies reported that the virus’s Spike protein — responsible for viral entry through interactions with the Angiotensin-converting enzyme 2 receptor — could also bind NRP1 [8] and interrupt VEGF-A binding to NRP1 [15]."
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"Here we have shown that disrupting the binding between VEGF-A and NRP1 (i) decreases sensory neuron excitability (ii) decreases surface expression and function of NaV1.7 and Cav2.2 in DRGs; (iii) decreases nociceptive spinal neurotransmission; and (iv) reverses experimental neuropathic pain in two different preclinical pain models without causing toxicity (Figure 5, 6)."
sparser
"In contrast, a study in chick revealed that VEGFR2 and Nrp1 are expressed in cranial NCCs while VEGF-A is expressed in the surface ectoderm adjacent to the rhombomere 4 NCC migratory route, and furthermore, that the VEGF-A-Nrp1 interaction was required for proper cranial NCC invasion from the rhombomere 4 migratory stream into branchial arch 2 ( xref )."
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"To assess whether inhibiting Nrp1/Vegfa interaction can be of therapeutic relevance for the treatment of psoriasis, we administrated to K14-Vegfa mice an anti-Nrp1 antibody that blocks the binding of Vegfa (Nrp1b antibody) or the binding of semaphorins (Nrp1a antibody) (Fig. 3, A to C) (25, 26)."
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"The rapid improvement of psoriatic-like disease following the administration of anti-Nrp1 blocking antibodies that specifically target the interaction between Nrp1 and Vegfa demonstrates the therapeutic potential of blocking the Nrp1/Vegfa interaction in psoriasis.In conclusion, our study demonstrates a keratinocyte autonomous function of Nrp1 and Flt1 in mediating Vegfa signaling in the epidermis and the development of psoriatic-like disease in mice."
sparser
"In our study, as shown in Figure xref A-C, NRP-1 was highly expressed in both MDA-MB-231 and SUM159 cells, while nearly no NRP-1 was detected in other molecular subtype cell lines, indicating that VEGFA may interact with NRP-1 and further activate intracellular signaling pathways in TNBC cells."
sparser
"VEGFR-1 (also known as Flt1 ) is considered to be a decoy receptor that limits VEGF-A availability for VEGFR-2 and therefore activation and signaling of the VEGF-A/VEGFR-2 axis (decoy - or - sink hypothesis). xref , xref VEGF-A also binds to semaphorin receptor NRP1, xref a single spanning non–tyrosine kinase transmembrane protein that functions as a VEGFR-2 co-receptor."
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"While the expression of NRP-1 ligands in microglia and VEGFA receptors in astrocytes decreased after CCI, NRP-1/VEGFA interactions between Microglia-8 and astrocytes were enhanced as compared with that observed in the CON group.To verify that CADM1/CADM1 and NRP-1/VEGFA interactions among the three glial cell types after CCI were consistent with that of scRNA-seq results, we used IF staining to assess the expression and localization of CADM1, NRP-1 and VEGFA in spinal cord tissue (Fig. 10K-M)."
sparser
"Here, we demonstrated that both regorafenib and SC-78 could decrease the endogenous level of VEGF-A and the inhibition of secreted VEGF-A would further reduce the binding of VEGF-A to receptor NRP-1, which might lead to increased binding of SEMA3A and NRP-1 and reduce the migration of breast cancer cells."
sparser
"VEGF-A interacts with NRP-1 and this leads to enhanced VEGF-A interaction with VEGFR, leading to enhanced angiogenesis. xref – xref Consistent with this role, NRP-1 overexpression increases blood vessel formation, xref and inactivation causes abnormal vasculature formation leading to embryonic lethality. xref NRP-1 is expressed in various human tumors, including prostate cancer, breast cancer, melanoma and pancreatic adenocarcinoma. xref – xref In some model systems, NRP-1 expression increases angiogenesis and tumor formation; xref , xref however, how NRP-1 regulates tumor formation is not well understood."
sparser
"Conversely, blocking NRP1 binding to VEGF-A with anti-NRP1 blocking antibodies abrogating VEGF-A binding to NRP1 but not to VEGFR2, reduces VEGF-induced EC migration, proliferation, vessel sprouting and neovascularisation in the eye, although to a lesser extent compared to VEGF blocking antibodies [ xref ]."
sparser
"Furthermore, treatment with anti-NRP1 blocking antibodies preventing NRP1 binding to VEGF-A, partially decreases VEGF-A-induced EC proliferation and AKT, ERK1/2 and p38 MAPK phosphorylation compared to treatment with an anti-VEGF-A antibody which completely abrogated these VEGF-A-induced responses [ xref ] ( xref )."
sparser
"Although these data support the role of NRP1 as a positive modulator of VEGF-A signalling, the fact that VEGF-A binding to NRP1 is dispensable for vascular permeability in vivo and that combining anti-NRP1 with anti-VEGF-A blocking antibodies has a synergistic effect on tumour angiogenesis and growth, suggests that NRP1 also promotes VEGF-A independent signalling [ xref ]."
sparser
"Based on the structure of A7R and our previous study [ xref ], the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg (K4R) was designed, which according to the ELISA (enzyme-linked immunosorbent assay) test is a stronger inhibitor of VEGF-A 165 binding to NRP-1, and at the same time, is more stable in human serum compared to A7R in micro-scale research [ xref ]."
sparser
"Inhibition studies of VEGF-A 165 binding to NRP-1 performed using the competitive ELISA test were carried out for two series of compounds, i.e., the parent peptides A7R, D R7A and parent branched peptidomimetic K4R, and the compounds Sc-1 , Sc-1bis , Sc-2 , Sc-3 and Ga-3 listed above."
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"The finding that expression of the Y297A and D320A NRP1 mutants reduced high-affinity VEGF-A 165 binding to endothelial cells and VEGF-A 165 stimulation of endothelial cell migration and tubulogenesis in a coculture model provides strong evidence that VEGF-A 165 binding to NRP1 plays an important role in migratory responses important for angiogenesis."
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"Our data further showed that expression of the Y297A NRP1 mutant prevented VEGF-A 165 -induced complex formation between NRP1 and KDR, indicating that VEGF-A 165 binding to NRP1 is essential for formation of NRP1 and KDR heterodimers either alone or as homodimers or oligomers with WT NRP1, and that these heterocomplexes may be rapidly destabilized by subsequent VEGF-A 165 binding to KDR."
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"The potency of compound 2 in inhibiting VEGF-A binding to NRP1 was thus very similar to that of the bicyclic peptide compound 1, which inhibits 125 I-VEGF-A binding to PAE and NRP1 and tumor cells with IC 50 values of 2-3 muM and inhibits 125 I-VEGF-A binding to HUVECs with an IC 50 of 20 muM."
reach
"Biochemical and functional studies have demonstrated that Asp-320 and Tyr-297 are critical for VEGFA binding to NRP1 with mutations of Asp-320 to Lys (D320K) or Tyr-297 to Ala (Y297A) abrogating VEGFA binding to NRP1 (Figure 1) without affecting NRP1 binding to class 3 semaphorins [7,8,25]."
sparser
"Further studies of the shortest active fragment of A7R led to a more elaborate branched peptidomimetic, Lys(hArg)-Dab-Pro-Arg, which was a stronger inhibitor of VEGF-A 165 binding with NRP-1, as determined by an in vitro ELISA assay, and was more stable in human serum compared to A7R [ xref ]."
sparser
"According to the literature data, the heptapeptide A7R is known to be an effective antagonist of the VEGF-A 165 binding with NRP-1 and to show in vivo anti-angiogenic properties [ xref ], whereas the Lys(hArg)-Dab-Pro-Arg peptidomimetic is much more active (IC 50 = 0.2 μM) than the heptapeptide A7R (IC 50 = 5.9 μM [ xref ]), with a stability half-life in human serum that is nearly 2 days [ xref , xref ]."
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"VEGF-A binds VEGFR1 and VEGFR2 homodimers, VEGFR1/2 and VEGFR2/3 heterodimers, as well as Nrp1 homodimers; VEGF-B and PGF bind VEGFR1 homodimers, VEGFR1/2 heterodimers and Nrp1 homodimers; and VEGF-C and VEGF-D bind VEGFR2 and VEGFR3 homodimers, VEGFR2/3 heterodimers and Nrp2 homodimers."
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"Treatment of mice in utero (E12.5-E16.5) with an antibody that blocks Sema3A binding to Nrp-1, but not with an antibody that blocks VEGF-A binding to Nrp-1, resulted in a complex phenotype of impaired lymphatic vessel function, enhanced perivascular cell coverage and abnormal lymphatic vessel and valve morphology."
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"Treatment of mice in utero with an antibody that blocks Sema3A binding to Nrp-1, but not with an antibody that blocks VEGF-A binding to Nrp-1, resulted in reduced lymphatic vessel function, abnormal morphology of the collecting lymphatic vessels and valves, and aberrant SMC coverage of lymphatic vessels."
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"17 Novel drug compounds which act as NRP1 antagonists could therefore exhibit their anticancer effects in three different ways : blocking tumor angiogenesis by blocking the NRP1 and VEGF-A interaction, 18 preventing tumor cell migration by binding to NRP1, 19 and reducing Treg or macrophage mediated suppression of the immune response."
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"NRP1 binding to VEGF-A, R-x-x-R carboxyl-terminal motif-containing peptides (CendR) (36), or a NRP1-targeting ligand-blocking antibody promotes lateral NRP1 delocalization at cell-cell contacts and increased permeability in a manner dependent on NRP1 cytoplasmic domain but independent of VEGFR2 activity (36)."
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"It is of interest that we found fewer blood vessel capillaries in anti-Nrp-1B treated pups at day P5.5 (XREF_SUPPLEMENTARY), indicating that the formation of smaller blood vessels is impaired when VEGF-A binding to Nrp-1 is blocked, in line with previously reported effects of this antibody 24."
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"Importantly, although inhibition of the VEGF-A binding to Nrp-1 did not influence lymphatic vessel development, the formation of small blood vessels was impaired, in agreement with the previously reported effects of this antibody 24 - therefore confirming the activity of the antibody."
sparser
"Blocking VEGFA 165 binding to NRP1 using a selective NRP1 inhibitor, ATWLPPR Peptide TFA (trifluoroacetic acid) ( xref ), inhibited migration, although this effect did not reach statistical significance and NRP1 inhibition did not significantly affect VEGFA 165 -induced proliferation (fig."
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"Alternatively, the interaction of NRP-1, VEGF-A, and SARS-CoV2 may be responsible for part of the presented symptoms11: blocking the binding site of VEGF-A to NRP-1, as described for SARS-CoV2 spike protein, could ameliorate or prevent proper pain sensation in affected patients.11Obviously, we cannot completely rule out other reasons for the observed hypoalgesia, abnormal QST, and reduced intraepidermal fiber density."
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"Effects of Semaphorins and Neuropilin -1 17, however, involve a more complicated process and have been shown to function as pro - angiogenesis stimuli (VEGF-A 165 binding to NRP-1 and VEGFR-2 and Plexin-A1 or 2) or facilitate migration (Np-1/Np-2/VEGFR-1/Plexin-A1/2 when bound by VEGF-A (165, 145, 121), VEGF-B and PlGF-2)."
sparser
"To further analyse its role in arthritis-induced angiogenesis, we investigated whether NRP-1 function is required for the induction of endothelial cell migration by arthritic paw homogenates applying a neutralising antibody that specifically blocks the binding of VEGF121 and VEGF164 to NRP-1 [ xref , xref ]."
sparser
"M. W. Parker et al. reported the first detailed picture of the structural basis for the binding of NRP-1 and VEGF-A. The binding interface involved regions encoded by both exons 7 and 8 of VEGF-A. Exon 7 encoded residues primarily govern selectivity, whereas exon 8 encoded residues mainly mediate high-affinity binding [ xref ]."
| PMC
sparser
"Jarvis, A.; Allerston, C. K.; Jia, H.; Herzog, B.; Garza-Garcia, A.; Winfield, N.; 675 Ellard, K.; Aqil, R.; Lynch, R.; Chapman, C.; Hartzoulakis, B.; Nally, J.; Stewart, M.; Cheng, L.; Menon, M.; Tickner, M.; Djordjevic, S.; Driscoll, P. C.; Zachary, I.; Selwood, D. L., Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction."
| DOI
sparser
"A library of 5 × 10 5 compounds was screened for specifically targeting this site; nine chemical series were reported with lead- or drug-like physical and chemical properties, out of which six compounds effectively disrupted VEGF-A–NRP-1 interaction, and all nine inhibited VEGF-A triggered VEGFR2 phosphorylation."
sparser
"As it was mentioned already, the amino acid Asp320 is very important for NRP1 to interact with different ligands and VEGF-A xref , xref , as well as for the CendR region in the SARS-CoV-2 xref , xref , therefore, the region between the amino acids Thr316, Asp320, Ser346, Thr349 and Tyr353 has a very important role for the S1 region of SARS-CoV-2 to interact with NRP1; in this study was carried out a docking directed to amino acids in the b1 region reported in the NRP1 (Thr316, Asp320, Ser346, Thr349 and Tyr353) xref , that is important to interact with the S-Protein (S1 region) of SARS-CoV-2 xref , since it has been shown that by preventing this interaction, the infectious process caused by this virus could be reduced xref , xref , xref ."
| PMC
sparser
"To
clarify the nature of these interaction results on cross-sectional cognition,
stratified analyses showed that in APOE -ε4 carriers,
higher expression of NRP1 (β=−0.176, p=0.034) and VEGFA (β=−0.027, p=0.019) were associated
with worse global cognition scores; whereas in APOE -ε4
non-carriers, higher NRP1 (β=0.112, p=0.003) expression
predicted better global cognition scores."
sparser
"To exclude that impaired VEGFR2 phosphorylation simply reflects a reduced affinity of NRP1 cyto for VEGF-A 165 , we used an established method that tests binding of NRP1 ligands such as alkaline phosphatase-conjugated VEGF-A 165 to NRP1-expressing axons and vessels in vivo ( xref )."
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"Based on the structure of A7R and our previous study [34], the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg (K4R) was designed, which according to the ELISA (enzyme-linked immunosorbent assay) test is a stronger inhibitor of VEGF-A binding to NRP-1, and at the same time, is more stable in human serum compared to A7R in micro-scale research [38]."
reach
"Inhibition studies of VEGF-A binding to NRP-1 performed using the competitive ELISA test were carried out for two series of compounds, i.e., the parent peptides A7R, R7A and parent branched peptidomimetic K4R, and the compounds Sc-1, Sc-1bis, Sc-2, Sc-3 and Ga-3 listed above.The previous study performed by our research group indicated that the K4R peptidomimetic shows high affinity to NRP-1 due to the introduction of the hArg via the side chain (ε amine group) of Lys at the N-terminus and the unnatural Dab at the second position, which together result in the adoption of the optimal conformation of K4R molecule for binding to NRP-1 [38]."
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"One of the main stages of the angiogenesis process is the interaction between the pro-angiogenic vascular endothelial growth factor (VEGF-A ), its receptor (VEGFR-2), and the neuropilin-1 (NRP-1) co-receptor [10,11,12,13,14,15], resulting in formation of ternary VEGF-A /VEGFR-2/NRP-1 complex."
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"The application of a theranostic radiopharmaceutical pair is the basis of the personalized therapy that is more and more often used in nuclear medicine.Studies of the crystallographic structure of the VEGF-A /NRP-1 complex showed that NRP-1 binds to VEGF-A through the b1 and b2 subdomains of neuropilin, as a result of which the binding of VEGF-A to VEGFR-2 is enhanced [18,28,29,30,31]."