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.