Chemistry and Biology of Heparin Mimetics that Bind to Fibroblast Growth Factors

Abstract

We aim from this review to stimulate further research in this area by providing a description of the different types of inhibitors containing heparin mimetic molecules that have recently been reported and data on their biological activity. Molecules that mimic heparin and bind to heparin-binding growth factors are important building blocks for synthetic biomaterials. Different types of synthetic mimics of the biological properties of heparin have been prepared inclu-ding high molecular weight compounds or small molecule mimics. Peptide-based mimics of heparin functionality are limited and because of their low degree of sulfation, they are natural targets as heparin mimics. Aromatic sulfonamide derivatives exhibit a range of bioactivities and a novel angiogenesis inhibitor (E 7820) is used as a TF model for screening assay. The anticoagulant activity of the known heparin pentasaccharide sequence prompted synthetic efforts aimed at the procurement of this structure as well as a host of related sequences. Chemical modification of the natural or synthetic heparin increased factor activation of AT III Xa affinity. A variety of non-peptide non-saccharides inhibitors as anti-angiogenesis therapies directed against the VEGFR kinase are a promising and well-validated therapeutic approach under active evaluation of their safety and efficacy in multiple clinical trials. These low molecular weight modulators could be useful tools for biologists and may have potential as drugs or as leads for drug development.

Effects on in vitro and in vivo angiogenesis induced by small peptides carrying adhesion sequences

“…Moreover, HSPGs promote FGF-2 internalization and are required for a correct presentation of FGF-2 to its receptors [28]. Consequently, molecules, such as heparin-like anionic molecules [35,36], able to counteract the HSPGs/FGF-2 interaction may function as anti-angiogenic agents. In this context, HVP possesses the heparin-binding sequence present in human vitronectin and can interact with cell membrane HSPGs.…”

Heparin-Like Drugs with Antiangiogenic Activity

“…All the suramin derivatives contain the amido-N-methylpyrrolnaphthalenesulfonic acid group and are generally called suradistas. Suradistas present a higher inhibition of bFGF-induced mitogenesis on fibroblasts and a higher inhibition of the neovascularization of the CAM than suramins (Hassan, 2007).…”

Engineered Sulfated Polysaccharides for Biomedical Applications

“…More recently, an LMW variant of the above glycol‐split heparin derivative with negligible anticoagulant and strong antiangiogenic properties was reported. [ 478 ] Finally, various sulfated oligosaccharide derivatives have been shown to inhibit angiogenesis, e.g., sulfated mannopentaose phosphate (PI‐88), [ 479,480 ] maltotetraose and maltohexaose sulfate, [ 481 ] or the heparanase inhibitor oligomannurarate sulfate. [ 414,479,480 ] maltotetraose and maltohexaose sulfate, [ 481 ] or the heparanase inhibitor oligomannurarate sulfate.…”