Biousian glycopeptides penetrate the blood-brain barrier

Richard D. Egleton, Edward J. Bilsky, Gordon Tollin, Muthu Dhanasekaran, John Lowery, Isabel Alves, Peg Davis, Frank Porreca, Henry I. Yamamura, Larisa Yeomans, Charles M. Keyari, Robin Polt

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Clinicians have long desired the ability to introduce either exogenous or endogenous neuropeptides directly into the brain in order to alter brain chemistry, but have been thwarted by the blood-brain barrier (BBB). The BBB blocks the introduction of most peptides and proteins into the brain. Glycosylation can be employed as an effective and practical strategy that allows the systemic use of neuropeptides in vivo. A series of glycopeptides based on the Leu-enkephalin analogue YtGFS*-CONH2 led to greatly enhanced stability in vivo and effective penetration of the BBB. Transport through the BBB hinges on the biousian nature of the glycopeptides. That is, the amphipathic glycopeptides possess two conflicting solubility states; one state that is completely water soluble, and another at water-membrane phase boundaries. Multiple lines of evidence suggest that the BBB transport is absorptive endocytosis. Several Leu-enkephalin analogues studied showed antinociceptive potencies greater than morphine. Moreover, these δ-selective glycopeptides lacked many of the μ-opioid side effects generally associated with classical opiate analgesics. The biousian design was extended to much larger glycopeptides (16-17 residues) related to β-endorphin, which also penetrated the BBB and produced antinociception in mice. Plasmon-waveguide resonance (PWR) studies showed that the amphipathic helices bound to membrane bilayers with micromolar to low nanomolar K D's. The presence of diverse endogenous neuropeptide transmitters and neuromodulators in the human brain is potentially applicable to the treatment of a wide range of behavioral disorders.

Original languageEnglish (US)
Pages (from-to)65-75
Number of pages11
JournalTetrahedron Asymmetry
Volume16
Issue number1
DOIs
StatePublished - Jan 10 2005

ASJC Scopus subject areas

  • Catalysis
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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    Egleton, R. D., Bilsky, E. J., Tollin, G., Dhanasekaran, M., Lowery, J., Alves, I., Davis, P., Porreca, F., Yamamura, H. I., Yeomans, L., Keyari, C. M., & Polt, R. (2005). Biousian glycopeptides penetrate the blood-brain barrier. Tetrahedron Asymmetry, 16(1), 65-75. https://doi.org/10.1016/j.tetasy.2004.11.038