Structure–function analysis of the antiangiogenic ATWLPPR peptide inhibiting VEGF165 binding to neuropilin-1 and molecular dynamics simulations of the ATWLPPR/neuropilin-1 complex

Starzec, Anna; Ladam, Patrick; Vassy, Roger; Badache, Sabah; Bouchemal, Nadia; Navaza, A.; Penhoat, C. Hervé Du; Perret, G

doi:10.1016/j.peptides.2007.09.013

Cited by 96 publications

(70 citation statements)

References 38 publications

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“…Exon 8-related peptides, which also bind to NRP-1, 28 Tuftsin (TKPR), and Tuftsin analog (TKPPR), are also highly homologous to the HTLV-1 SU 90-94 region. Strikingly, the KPxR consensus motif that can be deduced from these 4 sequences contains the 3 residues of VEGF 165 previously shown to be critical for direct interaction with NRP-1 24,26 ( Figure 5A). …”

Section: The Htlv Sus Contain a Conserved Vegf 165 Exon 8-like Motifmentioning

confidence: 98%

“…18,23 Both exon 7 and exon 8 peptides interfere with the VEGF 165 /NRP-1 interaction. [24][25][26][27][28][29] Moreover, in contrast to VEGF 165 , VEGF 121 (which lacks exon 7) and VEGF 165b (which lacks exon 8) bind poorly to NRP-1 and are not capable of bridging NRP-1 and VEGF-R2. 23 This suggests that HSPG-mediated and direct interactions function cooperatively in forming an extended surface that allows stable binding of VEGF 165 to NRP-1 ( Figure 3A).…”

Section: Introductionmentioning

confidence: 99%

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HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165

Lambert

Bouttier

Vassy

et al. 2009

Blood

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138

134

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Section: The Htlv Sus Contain a Conserved Vegf 165 Exon 8-like Motifmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165

Lambert

Bouttier

Vassy

et al. 2009

Blood

Self Cite

138

134

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“…These results show that the C terminus of VEGF contains an active CendR element. Several peptides with C-terminal arginine, such as tuftsin (TKPR), enhanced tuftsin (TKPPR), and A7R (ATWLPPR), are known to compete with VEGF for NRP-1 interaction (31,32). T7 phage clones displaying these peptides also bound to PPC1 cells, and the binding was inhibited by the free RPARPAR peptide (Fig.…”

Section: A165mentioning

confidence: 99%

C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration

Teesalu

Sugahara

Kotamraju

et al. 2009

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

697

807

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Screening of phage libraries expressing random peptides for binding to prostate cancer cells primarily yielded peptides that had a Cterminal arginine (or rarely lysine) residue, usually in a consensus context R/KXXR/K. Phage expressing these sequences and synthetic nanoparticles coated with them bound to and were internalized into cells. The C-terminal arginine (or lysine) was essential to the activity; adding another amino acid, or even blocking the free carboxyl group of this arginine residue by amidation, eliminated the binding and internalizing activity. An internal R/KXXR/K can be exposed and switched on by a cleavage by a protease. The strict requirement for C-terminal exposure of the motif prompted us to term the phenomenon the C-end rule (CendR). Affinity chromatography showed that the CendR peptides bind to neuropilin-1 (NRP-1) on the target cells. NRP-1 is a cell-surface receptor that plays an essential role in angiogenesis, regulation of vascular permeability, and the development of the nervous system. VEGF-A165 and other ligands of NRP-1 possess a C-terminal CendR sequence that interacts with the b1 domain of NRP-1 and causes cellular internalization and vascular leakage. Our CendR peptides have similar effects, particularly when made multivalent through coupling to a particle. We also noted a unique and important activity of these peptides: penetration and transportation through tissues. The peptides were able to take payloads up to the nanoparticle size scale deep into extravascular tissue. Our observations have implications in drug delivery and penetration of tissue barriers and tumors.homing peptides ͉ vascular permeability ͉ VEGF ͉ cell penetrating peptides

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“…Therefore, to determine whether NRP1 contributed differently to VEGF-mediated angiogenesis in wild-type (WT) versus ␤3 integrin-deficient (␤3-null) mice, we performed growth factor-dependent subcutaneous sponge implant angiogenesis assays (24). Briefly, synthetic sponges were implanted subcutaneously into WT or ␤3-null mice and then injected either with VEGF-A164 or VEGF in combination with an NRP1-directed peptide (ATWLPPR, nrp1) that was designed to inhibit VEGF-NRP1 binding (13,25). A scrambled peptide (LWRPTPA, scr) was used as a control.…”

Section: Nrp1 Inhibition Reduces Vegf-induced Angiogenesis In ␤3-nullmentioning

confidence: 99%

αvβ3 Integrin Limits the Contribution of Neuropilin-1 to Vascular Endothelial Growth Factor-induced Angiogenesis

Robinson

Reynolds

Kostourou

et al. 2009

Journal of Biological Chemistry

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Both vascular endothelial growth factor receptors (VEGFR) and integrins are major regulators of VEGF-induced angiogenesis. Previous work has shown that ␤3 integrin can regulate negatively VEGFR2 expression. Here we show that ␤3 integrin can regulate negatively VEGF-mediated angiogenesis by limiting the interaction of the co-receptor NRP1 (neuropilin-1) with VEGFR2. In the presence of ␣v␤3 integrin, NRP1 contributed minimally to VEGF-induced angiogenic processes in vivo, ex vivo, and in vitro. Conversely, when ␤3 integrin expression is absent or low or its function is blocked with RGD-mimetic inhibitors, VEGF-mediated responses became NRP1-dependent. Indeed, combined inhibition of ␤3 integrin and NRP1 decreased VEGF-mediated angiogenic responses further than individual inhibition of these receptors. We also show that ␣v␤3 integrin can associate with NRP1 in a VEGF-dependent fashion. Our data suggest that ␤3 integrin may, in part, negatively regulate VEGF signaling by sequestering NRP1 and preventing it from interacting with VEGFR2.

show abstract

Structure–function analysis of the antiangiogenic ATWLPPR peptide inhibiting VEGF165 binding to neuropilin-1 and molecular dynamics simulations of the ATWLPPR/neuropilin-1 complex

Cited by 96 publications

References 38 publications

HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165

HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165

C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration

αvβ3 Integrin Limits the Contribution of Neuropilin-1 to Vascular Endothelial Growth Factor-induced Angiogenesis

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