Abstract
The interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFR) has important implications in angiogenesis and cancer, which moved us to search for peptide derivatives able to block this protein–protein interaction. In a previous work we had described a collection of linear 13-mer peptides specially designed to adopt helical conformations (Ac-SSEEX5ARNX9AAX12N-NH2), as well as the evaluation of seven library components for the inhibition of the interaction of VEGF with its Receptor 1 (VEGFR1). This study led to the discovery of some new, quite potent inhibitors of this protein–protein system. The results we found prompted us to extend the study to other peptides of the library. We describe here the evaluation of a new selection of peptides from the initial library that allow us to identify new VEGF-VEGFR1 inhibitors. Among them, the peptide sequence containing F, W, and I residues at the 5, 9, and 12 positions, show a very significant nanomolar IC50 value, competing with VEGF for its receptor 1, VEGFR1 (Flt-1), which could represent a new tool within the therapeutic arsenal for cancer detection and therapy.
Highlights
Protein–protein interactions (PPIs) play essential roles in multiple biological functions mediating both in physiological and pathological processes and constitute important targets in biological and medicinal chemistry
2 (FYW) and 3 (FWY), showed good IC50 values (29 ± 3 μM and 23 ± 4 μM, respectively), comparable to that of model peptide QK (Table 1). These results already suggested that the single substitution of Tyr9 and Tyr12 residues by Trp, has some advantages leading to better inhibitors of the vascular endothelial growth factor (VEGF)-VEGF with its Receptor 1 (VEGFR1) interaction
The binding studies were performed on VEGF isoform VEGF-A (VEGF165) that is the most commonly involved in pathological angiogenesis
Summary
Protein–protein interactions (PPIs) play essential roles in multiple biological functions mediating both in physiological and pathological processes and constitute important targets in biological and medicinal chemistry. 2 (FYW) and 3 (FWY), showed good IC50 values (29 ± 3 μM and 23 ± 4 μM, respectively), comparable to that of model peptide QK (Table 1).
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