Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1

Starzec, Anna; Vassy, Roger; Martin, Antoine; Lecouvey, Marc; Benedetto, Mélanie Di; Crépin, Michel; Perret, G

doi:10.1016/j.lfs.2006.08.005

Cited by 148 publications

(130 citation statements)

References 37 publications

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“…The coagulation factor domains of Nrp are responsible for binding basic regions of both VEGF and semaphorin (24,25). Additionally, peptide inhibitors of Nrp are currently in development for use as antiangiogenic agents, all of which are basic in character and function by competing for ligand binding (18,(34)(35)(36). Tuftsin, an immunostimulatory tetrapeptide (TKPR), is very similar to the VEGF165 C terminus (DKPRR) and competes with VEGF165 for Nrp binding (34).…”

Section: Resultsmentioning

confidence: 99%

“…Nrp expression is observed in tumor vasculature, and overexpression promotes tumorigenesis in vivo for a variety of solid tumors including pituitary, prostate, breast, and colon cancers (12)(13)(14)(15). In contrast, a soluble splice form containing only part of the extracellular domain of Nrp inhibits tumorigenesis (16) as do a number of peptides that block VEGF binding to Nrp (17,18). Recent evidence has also demonstrated a role for Nrp in hematological malignancies.…”

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confidence: 99%

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Structural basis for ligand and heparin binding to neuropilin B domains

Kooi

Jusino

Perman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

211

259

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Neuropilin (Nrp) is a cell surface receptor with essential roles in angiogenesis and axon guidance. Interactions between Nrp and the positively charged C termini of its ligands, VEGF and semaphorin, are mediated by Nrp domains b1 and b2, which share homology to coagulation factor domains. We report here the crystal structure of the tandem b1 and b2 domains of Nrp-1 (N1b1b2) and show that they form a single structural unit. Cocrystallization of N1b1b2 with Tuftsin, a peptide mimic of the VEGF C terminus, reveals the site of interaction with the basic tail of VEGF on the b1 domain. We also show that heparin promotes N1b1b2 dimerization and map the heparin binding site on N1b1b2. These results provide a detailed picture of interactions at the core of the Nrp signaling complex and establish a molecular basis for the synergistic effects of heparin on Nrp-mediated signaling.semaphorin ͉ Tuftsin ͉ VEGF N europilins (Nrps) are essential cell surface receptors with central roles in both angiogenesis and axon guidance (1-3). During angiogenesis, Nrp directly binds VEGF and functions as a coreceptor for VEGF along with VEGF receptor (VEGFR)-2, one of the three VEGFR tyrosine kinases (3, 4). During neural development, Nrp directly binds semaphorin and functions as a semaphorin coreceptor with members of the plexin family (5). Additionally, interactions with both neural adhesion protein L1 and Nrp-interacting protein (NIP), have been shown to be involved in a variety of other cellular processes (6-8).Nrp plays a stimulatory role in angiogenesis, a process critical for growth of solid tumors (reviewed in refs. 4 and 9-11). Nrp expression is observed in tumor vasculature, and overexpression promotes tumorigenesis in vivo for a variety of solid tumors including pituitary, prostate, breast, and colon cancers (12-15). In contrast, a soluble splice form containing only part of the extracellular domain of Nrp inhibits tumorigenesis (16) as do a number of peptides that block VEGF binding to Nrp (17,18). Recent evidence has also demonstrated a role for Nrp in hematological malignancies. Nrp overexpression is observed in both multiple myeloma and acute myeloid leukemia and, in the latter case, is associated with significantly reduced survival (19,20). Strategies to inhibit Nrp activity are thus being developed as potential antitumor therapies (reviewed in ref. 11).Higher eukaryotes possess two Nrp homologs, Nrp-1 and Nrp-2, which share 44% amino acid sequence identity (1). Nrp extracellular regions are composed of two complement binding CUB domains (a1 and a2) followed by two coagulation factor domains (b1 and b2), a MAM (meprin, A5, ) domain (c1), a single membrane-spanning region, and a short cytoplasmic tail (Fig. 1A) (21, 22). The a1 and a2 domains of Nrp are essential for binding to the core seven-bladed Sema domain of semaphorin as well as contributing to interactions with VEGF (23, 24). The coagulation factor domains b1 and b2 contain the high-affinity binding site for the basic heparin binding domain (HBD) of VEGF165 as well a...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Structural basis for ligand and heparin binding to neuropilin B domains

Kooi

Jusino

Perman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

211

259

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“…We then seeded the chamber with ∼10 4 PPC-1 human prostate carcinoma cells in 2 mL of culture medium. PPC-1 cells were selected as a model because they express high levels of NRP-1, a well characterized receptor that binds and internalizes peptides with C-terminal arginine residues, typically within a consensus context of R/KXXR/K (the C-end Rule or CendR motif) (29)(30)(31). As a negative control, we used phage expressing hepta-glycine (G7), which exhibits negligible binding to PPC-1 cells (28).…”

Section: Resultsmentioning

confidence: 99%

Selection of phage-displayed peptides on live adherent cells in microfluidic channels

Wang

Teesalu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Affinity reagents that bind to specific molecular targets are an essential tool for both diagnostics and targeted therapeutics. There is a particular need for advanced technologies for the generation of reagents that specifically target cell-surface markers, because transmembrane proteins are notoriously difficult to express in recombinant form. We have previously shown that microfluidics offers many advantages for generating affinity reagents against purified protein targets, and we have now significantly extended this approach to achieve successful in vitro selection of T7 phagedisplayed peptides that recognize markers expressed on live, adherent cells within a microfluidic channel. As a model, we have targeted neuropilin-1 (NRP-1), a membrane-bound receptor expressed at the surface of human prostate carcinoma cells that plays central roles in angiogenesis, cell migration, and invasion. We show that, compared to conventional biopanning methods, microfluidic selection enables more efficient discovery of peptides with higher affinity and specificity by providing controllable and reproducible means for applying stringent selection conditions against minimal amounts of target cells without loss. Using our microfluidic system, we isolate peptide sequences with superior binding affinity and specificity relative to the well known NRP-1-binding RPARPAR peptide. As such microfluidic systems can be used with a wide range of biocombinatorial libraries and tissue types, we believe that our method represents an effective approach toward efficient biomarker discovery from patient samples.

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“…Another hepta-peptide binding to Neuropilin-1 (NRP), a vascular endothelial growth factor (VEGF) receptor, has been evaluated in vitro [124] and more recently in vivo [125]. The peptide used against circulating VEGF was initially identified by phage display (see next section), and then a linear 20-mer peptide was further studied by X-rays crystallography to improve its binding properties to VEGF.…”

Section: Structure-activity Relationship Of Ligandsmentioning

confidence: 99%

Cell-penetrating and cell-targeting peptides in drug delivery

Vivès

Schmidt

Pèlegrin

2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

315

272

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During the last decade, the potential of peptides for drug delivery into cells has been highlighted by the discovery of several cell-penetrating peptides (CPPs). CPPs are very efficient in delivering various molecules into cells. However, except in some specific cases, their lack of cell specificity remains the major drawback for their clinical development. At the same time, various peptides with specific binding activity for a given cell line (cell-targeting peptides) have also been reported in the literature. One of the goals of the next years will be to optimize the tissue and cell delivery of therapeutic molecules by means of peptides which combine both targeting and internalization advantages. In this review, we describe the main strategies that are currently in use or likely to be employed in the near future to associate both targeting and delivery properties.

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Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1

Cited by 148 publications

References 37 publications

Structural basis for ligand and heparin binding to neuropilin B domains

Structural basis for ligand and heparin binding to neuropilin B domains

Selection of phage-displayed peptides on live adherent cells in microfluidic channels

Cell-penetrating and cell-targeting peptides in drug delivery

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