Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1568, Issue 2, Pages 147-154Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S0304-4165(01)00211-2
Keywords
metabolic engineering; cancer; drug delivery; sialic acid; glycosylation
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Funding
- NIGMS NIH HHS [R01 GM 58867-01] Funding Source: Medline
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Human cells incubated with N-levulinoylmannosamine ManLev) process this unnatural metabolic precursor into N-levulinoyl sialic acid (SiaLev), which is incorporated into cell surface glycoconjugates. A key feature of SiaLev is the presence of a ketone group that can be exploited in chemoselective ligation reactions to deliver small-molecule probes to the cell surface. A mathematical model was developed and tested experimentally to evaluate the prospects of using cell surface ketones as targets for covalent small-molecule drug delivery. We quantified the absolute number of ketone groups displayed on cell surfaces as a function of the concentration of ManLev in the medium. The apparent rate constants for the hydrolysis and disappearance of the cell surface conjugates were determined, as well as the apparent rate constant for the formation of covalent bonds with cell surface ketones. These values and the mathematical model confirm that chemoselective reactions on the cell surface can deliver to cells similar numbers of molecules as antibodies. Thus, cell surface ketones are a potential vehicle for a metabolically controlled small-molecule drug delivery system. (C) 2001 Elsevier Science B.V. All rights reserved.
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