RT Journal Article
SR Electronic
T1 Vector-Mediated Transport Producing Drug-Like Peptides
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 507434
DO 10.1101/507434
A1 Kenneth A. Gruber
A1 James A. Cowan
A1 Ada Cowan
A1 Wenbin Qi
A1 Stephen Pearson
A1 Martin J. Ross
A1 Christine Wachnowsky
A1 Fabio Gallazzi
A1 Shaokai Jiang
A1 Steve R. Van Doren
A1 Michael F. Callahan
YR 2018
UL http://biorxiv.org/content/early/2018/12/28/507434.abstract
AB Drugs that are structural mimetics of peptides (e.g. small molecules) have been plagued by problems associated with oral availability and transcellular movement. Vector-mediated transport, where a potentially therapeutic drug is covalently linked to another molecule that is a ligand for an active transport or transcytosis system, was developed as an approach for moving a drug across the blood-brain-barrier. We now report a vector approach that produced peptides with oral activity, blood-brain-barrier transport, and extended in vivo half-life. Generating these properties requires secondary structure stabilization into a β hairpin, and the addition of a C-terminal dipeptide sequence composed of non-polar residues. Peptides with biological activity incompatible with these derivatizations were covalently linked to a model transport vector, producing a chimera with the therapeutic activity of the peptide and the transport properties of the vector. Our platform technology may be a general approach for the design of drug-like peptides.