个人简介

NSF Rotator, 2002-2003 Public Health Service Postdoctoral Fellow, 1986-1988 National Science Foundation Predoctoral Fellow, 1981-1984

研究领域

Biochemistry/Organic/""Metabolism/Signaling/and Regulation""/Bioorganic/Chemical Biology/Protein and Membrane Biochemistry/Synthesis/Synthetic Methods Development"//Biochemistry/Educational and Teacher Preparation/""Metabolism/Signaling/and Regulation""“

New Methods for Organic Synthesis. Cell-surface carbohydrates (glycoproteins & glycolipids) have achieved a prominent place during the past decade, giving rise to the new discipline of "glycobiology." Cell-surface carbohydrates play decisive roles during mammalian fertilization, embryogenesis, normal cellular differentiation and regulation, as well as critical roles in malignancy, tumor growth, and tumor cell metastasis. The vertebrate nervous system seems to be a special beneficiary of the cell-cell communication afforded by glycoconjugates, and we are especially interested in the synthesis of ganglioside analogues which may be useful in probing neuronal development, the formation of synapses, and tumor cell metastasis. The influence of the carbohydrate moiety on glycoprotein structure and function is an area of interest to the "Polt Group." Using synthetic methods developed in our laboratory, the preferred conformations of various glycopeptide model systems are being determined using state-of-the-art 2-D NMR techniques. This data will permit glycobiologists to understand intracellular trafficking and intercellular transport of glycoproteins at the molecular level. Work done by the "Polt Group" in collaboration with the "Hruby Group" has produced glycopeptide analogues of neurotransmitters which are capable of crossing the blood-brain barrier. These are the first glycopeptide-based neurotransmitters to function as drugs in vivo. New synthetic methodology developed in the "Polt Group" is focused on the use of metal-ligand interactions to direct C-C and C-O bond formations starting from amino acids, such as L-alanine and D-serine. These new methods are being applied to the synthesis of highly-functionalized natural products such as castanospermine which functions as a glycosidase inhibitor, or to unnatural substrate analogues designed to inhibit glycoprotein processing enzymes (glycosyltransferases).

近期论文

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Kriss C, Lou B-H, Szabó LZ, Mitchell SA, Hruby VJ, Polt RL. Enkephalin-based drug design: Conformational analysis of O-linked glycopeptides by NMR and molecular modeling. Tetrahedron: Asymmetry 2000, 11, 9-25 Razavi H, Polt RL. Asymmetric syntheses of (-)-8-epi-swainsonine and (+)-1,2-Di-epi-swainsonine. Carbonyl addition thwarted by an unprecedented aza-pinacol rearrangement. J Org Chem 2000, 65, 5693-5706 Elmagbari NO, Sdimid WR, Palian MM, Polt RL, Bilsky EJ. Structure-activity studies with novel opioid glycopeptides: Antinociception and blood-brain barrier penetration. FASEB J 2000, 14, 44 Bilsky EJ, Polt RL, Lipkowski AW, Misicka A, Porreca F, Hruby VJ. Pharmacological strategies for developing opioid peptides as therapeutic agents. FASEB J 2000, 14, 45 Dangel BD, Polt RL. Catalysis by amino acid-derived tetra-coordinate complexes: Enantioselective addition of dialkylzincs to aliphatic and aromatic aldehydes. Org Lett 2000, 2, 3003-3006 Egleton RD, Mitchell SA, Polt RL, Hruby VJ, Davis TP. Glycosylation improves the brain delivery of Met-Enkephalin analogs. Brain Res 2000, 881, 37-46 Bilsky EJ, Egleton RD, Mitchell SA, Huber JD, Jones H, Yamamura HI, Janders J, Davis TP, Davis P, Porreca F, Hruby VJ, Palian MM, Polt RL. Enkephalin glycopeptide analogs produce analgesia with reduced dependence liability. J Med Chem 2000, 43, 2586-2590 Mitchell SA, Pratt MR, Hruby VJ, Polt RL. Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin. J Org Chem 2001, 66, 2327-2342 Palian MM, Jacobsen NE, Polt RL. O-linked glycopeptides retain helicity in water. J Peptide Res 2001, 58, 180-189 Palian MM, Polt RL. Lipo alpha-amino-beta-Hydroxy acids and O-linked glycosides: Building blocks for ceramyl and glycosphingoyl peptides. J Org Chem 2001, 66, 7178-7183 Palian MM, Polt RL. Glycopeptide Analgesics. Drugs of the Future 2001, 26, 561-576 Egleton RD, Mitchell SA, Huber JD, Palian MM, Polt RL, Davis TP. Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. J Pharm Exp Ther 2001, 299, 967-972 Polt RL, Kelly BD, Dangel BD, Tadikonda UB, Ross RE, Raisimring AM, Astashkin AV. Optically active 4- and 5-coordinate transition metal complexes of bifurcated dipeptide Schiff bases. Inorg Chem 2003, 42, 566-574 Palian MM, Boguslavsky VI, O’Brien DF, Polt RL. Glycopeptide-membrane interactions: Glycosyl enkephalin analogs adopt turn conformations by NMR and CD in amphipathic media. J Am Chem Soc 2003, 125, 5823-5831 Abeytunga DTU, Glick JJ, Gibson NJ, Oland LA, Somogyi A, Wysocki VH, Polt RL. Presence of unsaturated sphingomyelins and changes in their composition during the life cycle of the moth Manduca sexta. J Lipid Res 2004, 45, 1221-1231 Slavish J, Oland LA, Friel D, Polt RL. New PDMP analogues inhibit process outgrowth in an insect cell line. Biorg Med Chem Lett 2004, 14, 1487-1490 Elmagbari NO, Egleton RD, Palian MM, Lowery JJ, Schmid WR, Davis P, Navratilova E, Dhanasekaran M, Keyari CM, Yamamura HI, Porreca F, Hruby VJ, Polt RL, Bilsky EJ. Antinociceptive structure-activity studies with enkephalin-based opioid glycopeptides. J Pharm Exp Therap 2004, 311, 290-297 Egleton RD, Bilsky EJ, Tollin G, Dhanasekaran M, Lowery JJ, Alves I, Davis P, Porreca F, Yamamura HI, Yeomans L, Keyari CM, Polt RL. Biousian glycopeptides penetrate the blood-brain barrier. Tetrahedron: Asymmetry 2005, 16, 65-75 Dhanasekaran M, Polt RL. New prospects for glycopeptide-based analgesia: Glycoside-induced penetration of the blood-brain barrier. Current Drug Delivery 2005, 2, 59-73 Dhanasekaran M, Palian MM, Alves I, Yeomans L, Keyari CM, Davis P, Bilsky EJ, Egleton RD, Yamamura HI, Jacobsen NE, Tollin G, Hruby VJ, Porreca F, Polt RL. Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers. J Am Chem Soc 2005, 127, 5435-5448 Dhanasekaran M, Keyari CM, Polt RL. Glycosylated neuropeptides: A new vista for neuropsychopharmacology? Med Res Rev 2005, 25, 557-585 Egleton RD, Hawkins BT, Bilsky EJ, Yeomans L, Dhanasekaran M, Polt RL. The role of blood brain barrier transport in the enhanced analgesia of glycopeptide opioids. FASEB J 2006, 20, A240-A241 abstract only Lowery JJ, Raymond T, Yeomans L, Polt RL, Bilsky EJ. In vivo pharmacology of MMP2200 a delta/mu opioid glycopeptides. FASEB J 2006, 20, A241 abstract only Lowery JJ, Yeomans L, Keyari CM, Davis P, Porreca F, Knapp BI, Bidlack JM, Bilsky EJ, Polt RL. Glycosylation improves the central effects of DAMGO. Chem Biol Drug Des 2007, 69, 41-47