Synthesis and receptor binding affinity of carboxylate analogues of the mannose 6-phosphate recognition marker

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is involved in multiple physiological pathways including targeting of lysosomal enzymes, degradation of IGF2, and cicatrization through TGFbeta activation. To target potential therapeutics to this membrane receptor, four carb...

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Bibliographic Details
Published inBioorganic & medicinal chemistry Vol. 14; no. 10; pp. 3575 - 82
Main Authors Jeanjean, Audrey, Garcia, Marcel Mg, Leydet, Alain, Montero, Jean-Louis, Morère, Alain
Format Journal Article
LanguageEnglish
Published Elsevier 15.05.2006
Subjects
Binding, Competitive
Biological Markers
Cancer
Carbohydrate Sequence
Carboxylic Acids
Cell Line
Cell Proliferation
Cells, Cultured
Humans
Life Sciences
Mannosephosphates
Molecular Sequence Data
Pharmaceutical sciences
Protein Binding
Receptor, IGF Type 2
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Summary:The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is involved in multiple physiological pathways including targeting of lysosomal enzymes, degradation of IGF2, and cicatrization through TGFbeta activation. To target potential therapeutics to this membrane receptor, four carboxylate analogues of mannose 6-phosphate (M6P) were synthesized. Three of them, two isosteric carboxylate analogues and a malonate derivative, showed a binding affinity for the M6P/IGF2R equivalent to or higher than that of M6P. Contrary to M6P, all these analogues were particularly stable in human serum. Moreover, these derivatives did not present any cytotoxic activity against two human cell lines. These analogues represent a new potential for the lysosomal targeting of enzyme replacement therapy in lysosomal diseases or to prevent the membrane-associated activities of the M6P/IGF2R.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2006.01.024