Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are "More Equal" than Others.

Glycosaminoglycan (GAG) mimetics are synthetic or semi-synthetic analogues of heparin or heparan sulfate, which are designed to interact with GAG binding sites on proteins. The preclinical stages of drug development rely on efficacy and toxicity assessment in animals and aim to apply these findings to clinical studies. However, such data may not always reflect the human situation possibly because the GAG binding site on the protein ligand in animals and humans could differ. Possible inter-species differences in the GAG-binding sites on antithrombin III, heparanase, and chemokines of the CCL and CXCL families were examined by sequence alignments, molecular modelling and assessment of surface electrostatic potentials to determine if one species of laboratory animal is likely to result in more clinically relevant data than another. For each protein, current understanding of GAG binding is reviewed from a protein structure and function perspective. This combinatorial analysis shows chemokine dimers and oligomers can present different GAG binding surfaces for the same target protein, whereas a cleft-like GAG binding site will differently influence the types of GAG structures that bind and the species preferable for preclinical work. Such analyses will allow an informed choice of animal(s) for preclinical studies of GAG mimetic drugs.