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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-03-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/24/5/924 |
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| author | Eric D. Boittier Neha S. Gandhi Vito Ferro Deirdre R. Coombe |
| author_facet | Eric D. Boittier Neha S. Gandhi Vito Ferro Deirdre R. Coombe |
| author_sort | Eric D. Boittier |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T22:28:51Z |
| format | Article |
| id | doaj.art-a5fa1276b30447d4bcdd270d883d7582 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T22:28:51Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a5fa1276b30447d4bcdd270d883d75822022-12-22T00:48:12ZengMDPI AGMolecules1420-30492019-03-0124592410.3390/molecules24050924molecules24050924Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than OthersEric D. Boittier0Neha S. Gandhi1Vito Ferro2Deirdre R. Coombe3School of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Mathematical Sciences and Institute for Health and Biomedical Innovation, Faculty of Science and Engineering, Queensland University of Technology, Brisbane, QLD 4000, AustraliaSchool of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA 6102, AustraliaGlycosaminoglycan (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.http://www.mdpi.com/1420-3049/24/5/924antithrombinglycosaminoglycanschemokinesheparin binding proteinseotaxinIL-8molecular modelling |
| spellingShingle | Eric D. Boittier Neha S. Gandhi Vito Ferro Deirdre R. Coombe Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than Others Molecules antithrombin glycosaminoglycans chemokines heparin binding proteins eotaxin IL-8 molecular modelling |
| title | Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than Others |
| title_full | Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than Others |
| title_fullStr | Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than Others |
| title_full_unstemmed | Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than Others |
| title_short | Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than Others |
| title_sort | cross species analysis of glycosaminoglycan binding proteins reveals some animal models are more equal than others |
| topic | antithrombin glycosaminoglycans chemokines heparin binding proteins eotaxin IL-8 molecular modelling |
| url | http://www.mdpi.com/1420-3049/24/5/924 |
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