Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

Journal of Enzyme Inhibition and Medicinal Chemistry

Kyle L. Hoehn¹  Frances L. Byrne¹  Marwa N. Rahimi²  Shelli R. McAlpine²  Jack L. Bennett²  Laura K. Buckton²  Yuantao Huo²  Eloise C. Smith² 

[1] School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australi;School of Chemistry, University of New South Wales, Sydney, Australia;

关键词: Peptide drug delivery;    protein-protein interactions;    prodrugs;    heat shock protein 90;    cell permeability;   

DOI  :  10.1080/14756366.2019.1580276

来源: publisher

【 摘 要 】

The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O-alkyl, (b) N-alkyl, and (c) acetyl groups, and their binding affinity for Hsp90. Alkyl moieties increased compound permeability, Papp, from 3.3 to 5.6, however alkyls could not be removed by liver microsomes or in-vivo and their presence decreased target binding affinity (IC50 of ≥10 µM). Thus, unlike small molecules, peptide masking groups cannot be predictably removed; their removal is related to the 3-D conformation. O-acetyl groups were cleaved but are labile, increasing challenges during synthesis. Utilising acetyl groups coupled with mono-methylated amines may decrease the polarity of a peptide, while maintaining binding affinity.

【 授权许可】

CC BY