Abstract
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.
Highlights
Glycosaminoglycans (GAGs) are natural heteropolysaccharides that are composed of repeating disaccharide units consisting of a uronic acid linked to an amino sugar, either of which can be sulfated or non-sulfated [1]
It is being understood that the choice of animal species to use for preclinical testing of drug candidates is of critical importance, as an inappropriate choice can have a major impact on the relevance of the data to the clinical situation
This is true for the development of GAG mimetics as drugs as it is for the development of small molecules as drugs
Summary
Glycosaminoglycans (GAGs) are natural heteropolysaccharides that are composed of repeating disaccharide units consisting of a uronic acid linked to an amino sugar, either of which can be sulfated or non-sulfated [1]. PECAM-1 from these rodents will not bind heparin with the same affinity as human PECAM-1 From these examples, we suggest that understanding how the heparin binding motifs in proteins being targeted for the development of GAG mimetic drugs differ, between humans and the animal species commonly used for pre-clinical studies, will be essential to avoid misinterpretation of the data generated. We suggest that understanding how the heparin binding motifs in proteins being targeted for the development of GAG mimetic drugs differ, between humans and the animal species commonly used for pre-clinical studies, will be essential to avoid misinterpretation of the data generated Experiments such as mutagenesis, X-ray crystallography, and NMR spectroscopy coupled with molecular modelling studies have revealed the amino acids comprising the heparin binding sites on our selected proteins (Table 1).
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