Geometrically Diverse Lariat Peptide Scaffolds Reveal an Untapped Chemical Space of High Membrane Permeability

Constrained,
membrane-permeable peptides offer the possibility
of engaging challenging intracellular targets. Structure-permeability
relationships have been extensively studied in cyclic peptides whose
backbones are cyclized from head to tail, like the membrane permeable
and orally bioavailable natural product cyclosporine A. In contrast,
the physicochemical properties of lariat peptides, which are cyclized
from one of the termini onto a side chain, have received little attention.
Many lariat peptide natural products exhibit interesting biological
activities, and some, such as griselimycin and didemnin B, are membrane
permeable and have intracellular targets. To investigate the structure-permeability
relationships in the chemical space exemplified by these natural products,
we generated a library of scaffolds using stable isotopes to encode
stereochemistry and determined the passive membrane permeability of
over 1000 novel lariat peptide scaffolds with molecular weights around
1000. Many lariats were surprisingly permeable, comparable to many
known orally bioavailable drugs. Passive permeability was strongly
dependent on N-methylation, stereochemistry, and
ring topology. A variety of structure-permeability trends were observed
including a relationship between alternating stereochemistry and high
permeability, as well as a set of highly permeable consensus sequences.
For the first time, robust structure-permeability relationships are
established in synthetic lariat peptides exceeding 1000 compounds.