title: The high-affinity maltose switch MBP317-347 has low affinity for glucose: implications for targeting tumors with metabolically directed enzyme prodrug therapy.
abstract: Development of agents with high affinity and specificity for tumor-specific markers is an important goal of molecular-targeted therapy. Here, we propose a shift in paradigm using a strategy that relies on low affinity for fundamental metabolites found in different concentrations in cancerous and non-cancerous tissues: glucose and lactate. A molecular switch, MBP317-347, originally designed to be a high-affinity switch for maltose and maltose-like polysaccharides, was demonstrated to be a low-affinity switch for glucose, that is, able to be activated by high concentrations (tens of millimolar) of glucose. We propose that such a low-affinity glucose switch could be used as a proof of concept for a new prodrug therapy strategy denominated metabolically directed enzyme prodrug therapy (MDEPT) where glucose or, preferably, lactate serves as the activator. Accordingly, considering the typical differential concentrations of lactate found in tumors and in healthy tissues, a low-affinity lactate-binding switch analogous to the low-affinity glucose-binding switch MBP317-347 would be an order of magnitude more active in tumors than in normal tissues and therefore can work as a differential activator of anticancer drugs in tumors.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 LeConte Ave., Los Angeles, CA, 90095-1714, USA.
authors.forename: Gilmer
authors.initials: G
authors.lastname: Valdes
authors.forename: Reinhard W
authors.initials: RW
authors.lastname: Schulte
authors.forename: Marc
authors.initials: M
authors.lastname: Ostermeier
authors.forename: Keisuke S
authors.initials: KS
authors.lastname: Iwamoto
mesh_terms: D005947:Glucose / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008320:Maltose / Q000378:metabolism*; D058619:Maltose-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011355:Prodrugs / Q000627:therapeutic use*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000627:therapeutic use; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D058619:Maltose-Binding Proteins; D010455:Peptides; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D019344:Lactic Acid; D008320:Maltose; D001618:beta-Lactamases; D005947:Glucose
keywords: allosteric protein; enzyme prodrug therapy; glucose; lactate; low-affinity switch