Extracellular and intracellular esterase processing of SCFA-hexosamine analogs: Implications for metabolic glycoengineering and drug delivery

Mohit P. Mathew, Elaine Tan, Shivam Shah, Rahul Bhattacharya, M. Adam Meledeo, Jun Huang, Freddy A. Espinoza, Kevin J. Yarema

Research output: Contribution to journalArticle

Abstract

This report provides a synopsis of the esterase processing of short chain fatty acid (SCFA)-derivatized hexosamine analogs used in metabolic glycoengineering by demonstrating that the extracellular hydrolysis of these compounds is comparatively slow (e.g.; with a t1/2 of ∼4 h to several days) in normal cell culture as well as in high serum concentrations intended to mimic in vivo conditions. Structure-activity relationship (SAR) analysis of common sugar analogs revealed that O-acetylated and N-azido ManNAc derivatives were more refractory against extracellular inactivation by FBS than their butanoylated counterparts consistent with in silico docking simulations of Ac4ManNAc and Bu4ManNAc to human carboxylesterase 1 (hCE1). By contrast, all analogs tested supported increased intracellular sialic acid production within 2 h establishing that esterase processing once the analogs are taken up by cells is not rate limiting.

Original languageEnglish (US)
Pages (from-to)6929-6933
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2012

Keywords

  • Drug metabolism
  • Esterase
  • ManNAc analogs
  • Metabolic oligosaccharide engineering
  • Prodrugs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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