Improving Membrane Permeation in the Beyond Rule-of-Five Space by Using Prodrugs to Mask Hydrogen Bond Donors

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

A wide range of drug targets can be effectively modulated by peptides and macrocycles. Unfortunately, the size and polarity of these compounds prevents them from crossing the cell membrane to reach target sites in the cell cytosol. As such, these compounds do not conform to standard measures of drug-likeness and exist in beyond the rule-of-five space. In this work, we investigate whether prodrug moieties that mask hydrogen bond donors can be applied in the beyond rule-of-five domain to improve the permeation of macrocyclic compounds. Using a cyclic peptide model, we show that masking hydrogen bond donors in the natural polar amino acid residues (His, Ser, Gln, Asn, Glu, Asp, Lys, and Arg) imparts membrane permeability to the otherwise impermeable parent molecules, even though the addition of the masking group increases the overall compound molecular weight and the number of hydrogen bond acceptors. We demonstrate this strategy in PAMPA and Caco2 membrane permeability assays and show that masking with groups that reduce the number of hydrogen-bond donors at the cost of additional mass and hydrogen bond acceptors, a donor-acceptor swap, is effective.

Original languageEnglish
Pages (from-to)2070-2078
Number of pages9
JournalACS Chemical Biology
Volume15
Issue number8
DOIs
Publication statusPublished - 21 Aug 2020

Cite this