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

Richard, Mylène; Chateau, Alicia; Jelsch, Christian; Didierjean, Claude; Manival, Xavier; Charron, Christophe; Maigret, Bernard; Barberi‐Heyob, Muriel; Chapleur, Yves; Boura, Cédric; Pellegrini‐Moise, Nadia

doi:10.1016/j.bmc.2016.08.052

Cited by 29 publications

(26 citation statements)

References 88 publications

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“…However, Tuftsin is not an ideal agent for use in clinical practice because of several limiting points including size, stability (susceptible to degradation by peptidases), lack of effective methods for delivery, low oral bioavailability, rapid excretion and poor transport properties through biologic membranes [ 26 , 27 ]. Thus, we developed a novel peptidomimetic named MR438 which has been built by molecular modeling based on well-known A7R peptide [ 16 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous work focused on the development of peptides for targeting NRP-1 and we have proposed to use peptidomimetics for their theoretical stability [ 14 , 15 ]. We have recently designed and assessed some new sugar-based peptidomimetics targeting NRP-1 and one of them named MR438 presented a relevant in vitro affinity for NRP-1 (IC 50 of 88 μM) [ 16 ]. Tuftsin (TKPR: Thr-Lys-Pro-Arg) is a natural ligand of NRP-1 with a IC 50 of 25 μM [ 17 , 18 ] and it was used in our work as reference compound.…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1

et al. 2018

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Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears as an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283-Med and D341-Med), classified in the more pejorative molecular subgroups, were obtained by in vitro enrichment. These models were characterized by an increase of NRP-1 and cancer stem cell markers (CD15, CD133 and Sox2), meanwhile a decrease of the differentiated cell marker Neurofilament-M (NF-M) was observed. Our previous work investigated potential innovative peptidomimetics that specifically target NRP-1 and showed that MR438 had a good affinity for NRP-1. This small molecule decreased the self-renewal capacity of MB stem cells for the 3 cell lines and reduced the invasive ability of DAOY and D283 stem cells while NRP-1 expression and cancer stem cell markers decreased at the same time. Possible molecular mechanisms were explored and showed that the activation of PI3K/AKT and MAPK pathways significantly decreased for DAOY cells after treatment. Finally, our results highlighted that targeting NRP-1 with MR438 could be a potential new strategy to differentiate MB stem cells and could limit medulloblastoma progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1

et al. 2018

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“…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

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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.

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“…Figure 4E). Thus, all of compounds are able to partially mimic the terminal carboxyl contacts that are considered to be critical for anchoring the terminal Arg of CendR peptides 12,31,[38][39][40][41][42][44][45][46][47][48][49][50][51][52][53] (Figure 1C) or known small molecule mimetics and inhibitors that contain a terminal guanidyl from Arg moiety and carboxylic group 54,61,62 . Figure 4F).…”

Section: Series Analysis and Docked Binding Modesmentioning

confidence: 99%

“…Due to its role in cancer, NRP-1 has been a target for drug design for over 20 years. During this time, discovery efforts have focused on development of NRP-1 antibody therapies 9,[28][29][30][31][32][33] , including a recent dual-specificity antibody to VEGFA and NRP-1 32,33 , peptides that target transmembrane domain interactions 11,[34][35][36][37] or the CendR interaction site 12,31,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] , as well as small-molecules that target the CendR site [54][55][56][57][58][59][60][61] . With one exception 43 , the CendR site targeting peptides contain a CendR motif, even those which are cyclical 39,45,46,49 or branched 51,53 .…”

Section: Introductionmentioning

confidence: 99%

In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein

Perez‐Miller

Pátek²,

Moutal

et al. 2020

Preprint

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Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain and hypothesize that interference of this pathway by SARS-CoV-2 spike protein interferes with pain signaling. Here, we report hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physico-chemical properties. Using an ELISA, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that almost all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Two compounds displayed robust inhibition of a recombinant vesicular stomatitis virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain and cancer with the added potential of inhibiting SARS-CoV-2 virus entry.

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

Cited by 29 publications

References 88 publications

Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1

Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1

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

In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein

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