Sugar-based peptidomimetics as potential inhibitors of the vascular endothelium growth factor binding to neuropilin-1

Novoa, Alexandre; Pellegrini‐Moise, Nadia; Béchet, Denise; Barberi‐Heyob, Muriel; Chapleur, Yves

doi:10.1016/j.bmc.2010.03.012

Cited by 35 publications

(27 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is possible that other ligands containing a C-terminal arginine will also bind in a similar fashion [15]. Although protein-protein interactions have been considered challenging targets in drug discovery [16], a number of small molecules and peptides have been identified as inhibitors of the VEGF-A 165 -NRP1 interaction [17][18][19][20][21][22][23][24][25][26][27][28][29]. In some cases, it has been demonstrated that the inhibitors act through direct binding to the b1 domain of NRP1.…”

Section: Introductionmentioning

confidence: 99%

Architecture and hydration of the arginine‐binding site of neuropilin‐1

Mota¹,

Fotinou²,

Rana³

et al. 2018

The FEBS Journal

View full text Add to dashboard Cite

Neuropilin‐1 (NRP1) is a transmembrane co‐receptor involved in binding interactions with variety of ligands and receptors, including receptor tyrosine kinases. Expression of NRP1 in several cancers correlates with cancer stages and poor prognosis. Thus, NRP1 has been considered a therapeutic target and is the focus of multiple drug discovery initiatives. Vascular endothelial growth factor (VEGF) binds to the b1 domain of NRP1 through interactions between the C‐terminal arginine of VEGF and residues in the NRP1‐binding site including Tyr297, Tyr353, Asp320, Ser346 and Thr349. We obtained several complexes of the synthetic ligands and the NRP1‐b1 domain and used X‐ray crystallography and computational methods to analyse atomic details and hydration profile of this binding site. We observed side chain flexibility for Tyr297 and Asp320 in the six new high‐resolution crystal structures of arginine analogues bound to NRP1. In addition, we identified conserved water molecules in binding site regions which can be targeted for drug design. The computational prediction of the VEGF ligand‐binding site hydration map of NRP1 was in agreement with the experimentally derived, conserved hydration structure. Displacement of certain conserved water molecules by a ligand's functional groups may contribute to binding affinity, whilst other water molecules perform as protein–ligand bridges. Our report provides a comprehensive description of the binding site for the peptidic ligands’ C‐terminal arginines in the b1 domain of NRP1, highlights the importance of conserved structural waters in drug design and validates the utility of the computational hydration map prediction method in the context of neuropilin.DatabaseThe structures were deposited to the PDB with accession numbers PDB ID: 5IJR, 5IYY, 5JHK, 5J1X, 5JGQ, 5JGI.

show abstract

Section: Introductionmentioning

confidence: 99%

Architecture and hydration of the arginine‐binding site of neuropilin‐1

Mota¹,

Fotinou²,

Rana³

et al. 2018

The FEBS Journal

View full text Add to dashboard Cite

show abstract

“…One of them relies on the VEGF 165 trapping agents such as soluble NRP-1 isoforms [17] and anti-VEGF antibodies [18]. Others utilize the NRP-1 binding site blockers for instance: anti-NRP-1 antibodies [19], small molecules [20][21][22][23][24], cyclic [25][26][27] and linear peptides, e.g. heptapeptide ATWLPPR (A7R) [28] and tuftsin or VEGF related [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Conformational latitude – activity relationship of KPPR tetrapeptide analogues toward their ability to inhibit binding of vascular endothelial growth factor 165 to neuropilin‐1

Fedorczyk

Lipiński

Tymecka

et al. 2017

Journal of Peptide Science

View full text Add to dashboard Cite

Neuropilin-1 has been found to be overexpressed in several kinds of malignant tumors, and it is postulated that its interaction with the vascular endothelial growth factor 165 leads to progression of tumor vascularization and growth. Several analogues (KxxR) with various conformational latitudes have been synthesized and found as inhibitors of NRP-1. Detailed insight provided by molecular dynamics simulation allowed forming a clear relationship between flexibility of xx part of the molecule and its inhibitory activity.

show abstract

“…Interesting compounds were obtained and one hit compound was identified (compound 1, Chart 1a). 25 Simultaneously, a paper by Jarvis et al described compound EG00229 as small molecule inhibitor of the NRP-1/VEGF-A165 binding and this molecule has recently shown in vivo activity towards cancer models (Chart 1a). 26 More recently, a fully nonpeptidic compound comprising phenylbenzimidazole and benzodioxane moieties linked by a stable carboxythiourea spacer was identified.…”

Section: Introductionmentioning

confidence: 99%

“…29 The objective of the present work was the molecular design and synthesis of new NRP-1 ligands inspired by compound 1. 25 The use of carbohydrates as scaffolds to construct bioactive compounds and peptidomimetics is a well-accepted concept since the pioneering works related to peptidomimetics of somatostatin. 30,31,32 We wanted to take advantage of functionalities and stereodiversities of sugar derivatives to develop new analogs of carbohydrate-based peptidomimetics.…”

Section: Introductionmentioning

confidence: 99%

Carbohydrate-based peptidomimetics targeting neuropilin-1: Synthesis, molecular docking study and in vitro biological activities

Richard

Chateau

Jelsch

et al. 2016

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Neuropilin-1 (NRP-1), a transmembrane glycoprotein acting as a co-receptor of VEGF-A, is expressed by cancer and angiogenic endothelial cells and is involved in the angiogenesis process. Taking advantage of functionalities and stereodiversities of sugar derivatives, the design and the synthesis of carbohydrate based peptidomimetics are here described. One of these compounds (56) demonstrated inhibition of VEGF-A165 binding to NRP-1 (IC50 = 39 µM) and specificity for NRP-1 over VEGF-R2. Biological evaluations were performed on human umbilical vein endothelial cells (HUVECs) through activation of downstream proteins (AKT and ERK phosphorylation), viability/proliferation assays and in vitro measurements of anti-angiogenic abilities.

show abstract

Sugar-based peptidomimetics as potential inhibitors of the vascular endothelium growth factor binding to neuropilin-1

Cited by 35 publications

References 57 publications

Architecture and hydration of the arginine‐binding site of neuropilin‐1

Architecture and hydration of the arginine‐binding site of neuropilin‐1

Conformational latitude – activity relationship of KPPR tetrapeptide analogues toward their ability to inhibit binding of vascular endothelial growth factor 165 to neuropilin‐1

Carbohydrate-based peptidomimetics targeting neuropilin-1: Synthesis, molecular docking study and in vitro biological activities

Contact Info

Product

Resources

About