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

Fedorczyk, Bartlomiej; Lipiński, Piotr F. J.; Tymecka, Dagmara; Puszko, Anna K.; Wileńska, Beata; Perret, G; Misicka, Aleksandra

doi:10.1002/psc.3009

Cited by 17 publications

(28 citation statements)

References 47 publications

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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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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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“…These include small molecules [16,17,18,19,20,21], VEGF 165 derived peptides [22,23], or cyclic peptides [24,25,26]. Another set of the inhibitors proposed so far consists of the peptide A7R (ATWLPPR) [27] and derivatives inspired by this sequence [28,29,30]. A7R exhibits a relatively good inhibition in in vitro tests with an IC 50 of 5.86 μM [24].…”

Section: Introductionmentioning

confidence: 99%

Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165

et al. 2019

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Inhibiting the interaction of neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has become an interesting mechanism for potential anticancer therapies. In our previous works, we have obtained several submicromolar inhibitors of this interaction, including branched pentapeptides of general structure Lys(Har)-Xxx-Xxx-Arg. With the intent to improve the proteolytic stability of our inhibitors, we turned our attention to 1,4-disubstituted 1,2,3-triazoles as peptide bond isosteres. In the present contribution, we report the synthesis of 23 novel triazolopeptides along with their inhibitory activity. The compounds were synthesized using typical peptide chemistry methods, but with a conversion of amine into azide completely on solid support. The inhibitory activity of the synthesized derivatives spans from 9.2% to 58.1% at 10 μM concentration (the best compound Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg, 3, IC50 = 8.39 μM). Synthesized peptidotriazoles were tested for stability in human plasma and showed remarkable resistance toward proteolysis, with half-life times far exceeding 48 h. In vitro cell survival test resulted in no significant impact on bone marrow derived murine cells 32D viability. By means of molecular dynamics, we were able to propose a binding mode for compound 3 and discuss the observed structure–activity relationships.

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“…Conformational latitude -inhibitory activity relationship of KPPR tetrapeptide analogues (KxxR) [5] 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 the -xx-part (positions 2 and 3) of the molecules and their inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%