title: Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery.
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-kappaB pathway. Together, these results establish the SCFA-hexosamine template as a versatile platform for modulating biological activity and developing new therapeutics.
authors.affiliation: The Department of Biomedical Engineering, 106A Clark Hall, 3400 North Charles Street, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Noha
authors.initials: N
authors.lastname: Elmouelhi
authors.forename: Udayanath
authors.initials: U
authors.lastname: Aich
authors.forename: Venkata D P
authors.initials: VD
authors.lastname: Paruchuri
authors.forename: M Adam
authors.initials: MA
authors.lastname: Meledeo
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Campbell
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Wang
authors.forename: Raja
authors.initials: R
authors.lastname: Srinivas
authors.forename: Hargun S
authors.initials: HS
authors.lastname: Khanna
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Yarema