Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery

Noha Elmouelhi, Udayanath Aich, Venkata D.P. Paruchuri, M. Adam Meledeo, Christopher T. Campbell, Jean J. Wang, Raja SriNivas, Hargun S. Khanna, Kevin J. Yarema

Research output: Contribution to journalArticle

Abstract

This study investigates the breadth of cellular responses engendered by short chain fatty acid (SCFA)-hexosamine hybrid molecules, a class of compounds long used in "metabolic glycoengineering" that are now emerging as drug candidates. First, a "mix and match" strategy showed that different SCFA (n-butyrate and acetate) appended to the same core sugar altered biological activity, complementing previous results [Campbell et al. J. Med. Chem. 2008, 51, 8135-8147] where a single type of SCFA elicited distinct responses. Microarray profiling then compared transcriptional responses engendered by regioisomerically modified ManNAc, GlcNAc, and GalNAc analogues in MDA-MB-231 cells. These data, which were validated by qRT-PCR or Western analysis for ID1, TP53, HPSE, NQO1, EGR1, and VEGFA, showed a two-pronged response where a core set of genes was coordinately regulated by all analogues while each analogue simultaneously uniquely regulated a larger number of genes. Finally, AutoDock modeling supported a mechanism where the analogues directly interact with elements of the NF-κB pathway. Together, these results establish the SCFA-hexosamine template as a versatile platform for modulating biological activity and developing new therapeutics.

Original languageEnglish (US)
Pages (from-to)2515-2530
Number of pages16
JournalJournal of medicinal chemistry
Volume52
Issue number8
DOIs
StatePublished - Apr 23 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Elmouelhi, N., Aich, U., Paruchuri, V. D. P., Meledeo, M. A., Campbell, C. T., Wang, J. J., SriNivas, R., Khanna, H. S., & Yarema, K. J. (2009). Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery. Journal of medicinal chemistry, 52(8), 2515-2530. https://doi.org/10.1021/jm801661m