Antiangiogenic potential of small polypeptide sequences: In vivo assays, cytotoxicity, synthetic approaches and influence of C-terminal carboxyamidation

The search for new inhibitors of tyrosine kinase receptors involved in angiogenesis is a frequent topic in the design of antiangiogenic drugs. Michaloski and coworkers have obtained the peptide sequences PCAIWF-OH and PSAIWF-OH that showed potential inhibition of VEGF receptors. The present work describes the obtention of these peptides and their carboxyamidated analogues, which are prepared by a more efficient method. Their antiangiogenic activities were evaluated in vivo using the chicken embryo chorioallantoic membrane model. Assays with ARPE-19 cells were carried out to evaluate toxicity. PSAIWF-NH2 showed the higher inhibition of angiogenesis, at levels comparable to the bevacizumab. This carboxyamidated analogue carrying a serine has the advantage of not undergoing dimerization and it can be obtained by a more efficient and cheaper synthetic method. Retinal cells displayed in general high cell viability in the presence of the four peptides. PSAIWF-NH2 presented the highest angiogenic inhibition and the lowest toxicity. To evaluate the feasibility of prolonged and controlled release, PSAIWF-NH2 was incorporated into PLGA implants. The delivery profile was characterized by two phases, initially marked by a burst of release, followed by the sustained release of lower quantities during 36 days. Peptide concentrations were kept at levels that showed angiogenic inhibition.(C) 2022 Published by Elsevier B.V.

Automated summary

The study describes the synthesis and evaluation of peptide sequences and their carboxyamidated analogues as inhibitors of VEGF receptors involved in angiogenesis. Among them, PSAIWF-NH2 showed the highest inhibition of angiogenesis, comparable to bevacizumab. It has the advantage of not undergoing dimerization and can be obtained by a more efficient and cheaper synthetic method. In terms of cytotoxicity, all four peptides exhibited high cell viability in retinal cells.