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

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Hexosamines
Volatile Fatty Acids
Drug Discovery
Gene Expression
Butyrates
Genes
Acetates
Polymerase Chain Reaction
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Elmouelhi, N., Aich, U., Paruchuri, V. D. P., Meledeo, M. A., Campbell, C. T., Wang, J. J., ... 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

Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery. / Elmouelhi, Noha; Aich, Udayanath; Paruchuri, Venkata D P; Meledeo, M. Adam; Campbell, Christopher T.; Wang, Jean J.; SriNivas, Raja; Khanna, Hargun S.; Yarema, Kevin J.

In: Journal of Medicinal Chemistry, Vol. 52, No. 8, 23.04.2009, p. 2515-2530.

Research output: Contribution to journalArticle

Elmouelhi, N, Aich, U, Paruchuri, VDP, Meledeo, MA, Campbell, CT, Wang, JJ, SriNivas, R, Khanna, HS & Yarema, KJ 2009, 'Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery', Journal of Medicinal Chemistry, vol. 52, no. 8, pp. 2515-2530. https://doi.org/10.1021/jm801661m
Elmouelhi N, Aich U, Paruchuri VDP, Meledeo MA, Campbell CT, Wang JJ et al. Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery. Journal of Medicinal Chemistry. 2009 Apr 23;52(8):2515-2530. https://doi.org/10.1021/jm801661m
Elmouelhi, Noha ; Aich, Udayanath ; Paruchuri, Venkata D P ; Meledeo, M. Adam ; Campbell, Christopher T. ; Wang, Jean J. ; SriNivas, Raja ; Khanna, Hargun S. ; Yarema, Kevin J. / Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 8. pp. 2515-2530.
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