Premium
Towards a systematic design of novel endogenous peptide‐based antiangiogenic approaches
Author(s) -
Karagiannis Emmanouil,
Popel Aleksander S.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.925.15
Subject(s) - angiogenesis , in vitro , proteases , in vivo , receptor , chemistry , in vitro toxicology , computational biology , peptide , peptidomimetic , microbiology and biotechnology , biology , biochemistry , cancer research , pharmacology , enzyme
To date the quest for the experimental identification of angiogenesis inhibitors has been an empirical time‐consuming process. Selected proteins were proteolytically processed by proteases and the cleaved fragments were tested for their antiangiogenic potency. In this study we introduced a systematic computational and experimental methodology that enabled us to identify and classify novel putative endogenous inhibitors of angiogenesis. The novels peptides are derived from various protein families including thrombospondins, and CXC chemokines, type IV collagen fibrils, as well as coagulation factors, and various kringle‐containing proteins. Testing their activity in vitro in suppressing the proliferation and migration of endothelial cells provided proof of principle for the validity of the computational method. By performing receptor neutralization studies we identified receptors that the novel peptides bind. Using the receptor binding information we designed peptide combinatorial therapeutic strategies. In some cases the combinatorial targeting of specific receptors identified strong synergism. Based on the results from the in vitro screening, we tested the ability of the peptides to suppress angiogenesis in in vivo assays including the subcutaneous basement‐membrane‐extract filled angioreactors assay, the corneal micro‐pocket angiogenesis assay and tumor xenograft models.