Glycosylation has proven to be an effective method to convert endogenous peptide neurotransmitters (highly amphipathic peptides that interact with GPCRs) into glycopeptide drugs capable of <i>"membrane hopping"</i> and penetration of the blood-brain barrier (BBB). Generally speaking, these are WYSIWYG drugs— the binding affinities of the original peptides are mirrored by the glycopeptides, but the PK/PD properties have been greatly altered. Several examples will be presented, ranging from small peptides such as enkephalins and angiotensins (6-mers, 7-mers), to much larger peptides such as endorphins, dynorphins (18-mers), PACAP and VIP (27-mers, 28mers), as well as cyclic peptides. All of the resulting glycopeptide drug candidates have potent central activity in mice and/or rats. Quantification of the glycopeptides <i>in vivo,</i> and factors affecting stability and BBB penetration will be discussed. The increased lifetime and BBB penetration of the glycosides show great promise for the world of pharmaceutical development.

Glycopeptide drugs from endogenous peptides violate all of Lipinski's rules and penetrate the BBB

2019 Fall National Meeting

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