Antisense Oligoamides as Antiinfectives: Strategies and Tactics in Monomer Synthesis and in Oligomer Syntheses and Bioassays

Dr. Mark - Eugene Duban

Mark-Eugene Duban, Department of Chemistry and Physics

The antisense approach attempts therapeutic intervention via purine/pyrimidine sequence-specific interception of cellular components that interact with DNA or RNA elements in vivo. The approach entered a new era in 1998 with the first FDA approval of an antisense therapeutic, fomivirsen sodium (lsis/Novartis CIBA Vision), for the treatment of cytomegaloviral retinitis in AIDS patients. There are currently at least 10 more antisense therapies in Phase II or III clinical trials. Each of the areas of Phase II/Phase III clinical antisense research requires efficient methods for the synthesis, purification, and characterization of the oligomeric antisense agent, and of four or more monomeric nucleoside analog precursors. The research of this NIH MBRS laboratory for antisense research now focuses on the development of such efficient methods, including broadening the stereoselective, radical-mediated Chu-Tam approach to 3'-C-substituted nucleotide analogs, developing general, convergent syntheses of antisense precursor monomers (e.g., via adaptations of the Stork-Just approach to 3',5'-substituted ribofuranose analogs), identifying and designing potential new first generation antisense therapeutics in the antiinfectives area, and developing methodologies to effectively rank the potencies of antisense agents via in vitro assay.

Recent Publications

Maresso, AW; Wu, R; Kern, JW; Zhang, R; Janik, D; Missiakas, D; Duban, M-E; Joachimiak, A; and Schneewind, O. Activation of inhibitors by sortase triggers irreversible modification of the active site, J Biol Chem 2007,accepted for publications.

Recent Presentations

Duban, M-E; Maresso, AW; Wu, R; Kern, JW; Zhang, R; Janik, D; Missiakas, D; Joachimiak, A; and Schneewind, O. Discovery aimed at Gram-positive antibacterials, 1. Mannich base mechanism-based inactivation of sortase via an apparent E1cb elimination. Abstr 234th Natl Mtg Amer Chem Soc, Boston, MA, 19-23 August 2007, accepted.

Duban, M-E; Lee, SP; Janik, D; Ma, C. Balannik, V; Kempf, D; Pinto, LH.  Novel blockers of the M2 channel of influenza virus, 1. Inhibitor design, and first active agents. Abstr 234th Natl Mtg Amer Chem Soc, Boston, MA, 19-23 August 2007, accepted.

Maresso, AW; Kern, JW; Wu, R; A Joachimiak; Duban, M-E; Missiakas, D; and Schneewind, O. Identification of aromatic Mannich bases as sortase inhibitors, 4th Annual GLRCE Conf Biodefense Emerging Infect Disease, Hilton Head, SC, 30 November-2 December 2006.

Duban, M-E; Janik, D; Wilmes, JS; Varma-O'Brien, S; Kern, JW; Maresso, AW; and Schneewind, O. What are the odds…? Improving HTS outcomes through early-stage medicinal chemistry (computations and synthesis), 4th Annual GLRCE Conf Biodefense Emerging Infect Disease, Hilton Head, SC, 30 November-2 December 2006.

M-E. Duban, R.E. Glowinski, P.E. Guzman, M. DiPierro, & F.M. Rivas. Synthesis of glycosamino acids and antisense nucleosides, I: Progress in radical-based total synthesis and FGI approaches. 227th National Meeting. American. Chemical Society Abstr. ORGN 500, 28 March – 1 April 2004.

Pablo Guzman presents his research

RISE student Pablo Guzman presents his research

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