A New Amino Acid for Improving Permeability and Solubility in Macrocyclic Peptides through Side Chain-to-Backbone Hydrogen Bonding

Despite the notoriously poor membrane
permeability of peptides,
many cyclic peptide natural products show high passive membrane permeability
and potently inhibit a variety of “undruggable” intracellular
targets. A major impediment to the design of cyclic peptides with
good permeability is the high desolvation energy associated with the
peptide backbone amide NH groups. While several strategies have been
proposed to mitigate this deleterious effect, only few studies have
used polar side chains to sequester backbone NH groups. We investigated
the ability of N,N-pyrrolidinylglutamine
(Pye), whose side chain contains a powerful hydrogen-bond-accepting
CO amide group but no hydrogen-bond donors, to sequester exposed
backbone NH groups in a series of cyclic hexapeptide diastereomers.
Analyses revealed that specific Leu-to-Pye substitutions conferred
dramatic improvements in aqueous solubility and permeability in a
scaffold- and position-dependent manner. Therefore, this approach
offers a complementary tool for improving membrane permeability and
solubility in cyclic peptides.