382 Neuropeptides as Drugs. Glycosylation-Promoted Drug Delivery

Friday, November 6, 2009: 2:00 PM
Angus (Camino Real Hotel)
Charles M. Keyari , Chemistry, University of Arizona, Tucson, AZ
Yingxue Li , Chemistry, University of Arizona, Tucson, AZ
Dhanasekaran Muthu , University of Arizona
Lajos Z. Szabo , Chemistry, University of Arizona, Tucson, AZ
Larisa Yeomans , Chemistry, University of Arizona, Tucson, AZ
Richard D. Egleton, Ph.D. , Department of Pharmacology, Marshall University School of Medicine, Huntington, WV
Jean M. Bidlack , Department of Pharmacology, University of Rochester, Rochester, NY
Edward J. Bilsky , Pharmacology Department, University of New England, Biddeford, ME
Robin Polt , Department of Chemistry & Biochemistry, and BIO5, University of Arizona, Tucson, AZ
Neuropeptides influence nearly every aspect of human behavior, and are capable of extremely potent and selective receptor binding. Because peptides are unstable in serum and do not cross the blood-brain barrier (BBB), they have not made good drugs, but have served as starting points for drug design. The incorporation of glycosides has provided glycopeptides that are more stable and readily penetrate the BBB without interfering with binding or selectivity. Moreover, since the glycopeptides are synthesized from amino acids and carbohydrates that are naturally found in the body, the degradation of this class of drugs does not lead to a cascade of toxic metabolites, providing potent and safe drugs. This technology has been extended to much larger glycopeptides related to β-endorphin (16-18 residues), which penetrate the BBB and produce antinociception in mice. Studies show that the helices bind to membrane bilayers with μM to low nM KD's. Multiple lines of evidence show that the BBB transport is driven by absorptive endocytosis. The presence of more than 250 endogenous neuropeptide transmitters and neuromodulators in the human brain suggests that glycosylation may be applicable to the treatment of a wide range of behavioral disorders. This work was supported by the NSF, the NIH, and ONR.