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 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.
Jeanjean
Audrey
A
Laboratoire de Chimie Biomoléculaire, Université Montpellier II Ecole Nationale Supérieure de Chimie de Montpellier, 8 Rue de l'Ecole Normale F-34296 Montpellier Cedex 05, France.
Garcia
Marcel
M
Leydet
Alain
A
Montero
Jean-Louis
JL
Morère
Alain
A
D001667:Binding, Competitive; D015415:Biomarkers / Q000737:chemistry; D002240:Carbohydrate Sequence; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008360:Mannosephosphates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D011485:Protein Binding; D017527:Receptor, IGF Type 2 / Q000378:metabolism*
D015415:Biomarkers; D002264:Carboxylic Acids; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate