C O M M U N I C A T I O N S
in which the exchangeable amide N-H groups of D-Leu2, Leu3,
and Tyr6 point toward solvent, with the more slowly exchanging
amides of Leu1 and Leu4 involved in transannular hydrogen bonds
(see Supporting Information). Significant population of this con-
former in water, in which three out of five amide N-H groups
point toward solvent, may contribute to the low membrane
permeability of compound 9.
We have identified a novel cyclic peptide scaffold whose
backbone contains none of the modifications (e.g., N-methylation)
commonly found in cyclic peptide natural products, yet whose
passive membrane diffusion rate parallels that of cyclosporine A.
Detailed structural analysis suggests that membrane permeability
in cyclic peptides may be governed by a combination of factors:
intramolecular hydrogen bonding, steric protection of amide NH
groups from solvation, and the relative stability of impermeable
“open” conformers in water. Future studies aimed at elucidating
the relative importance and control of these factors may advance
our understanding and design of membrane-permeable cyclic
peptides. Regardless of the detailed mechanism, synthetic scaffolds,
such as 1, promise to extend the application of cyclic peptides to
include a greater share of intracellular targets.
Acknowledgment. We gratefully acknowledge the National
Institutes of Health (CA104569-01, DK064265) for its generous
support. M.P.J. was supported by start-up funds provided by HHMI
Biomedical Research Support Program Grant No. 5300246 to the
UCSF School of Medicine, and by NIH Grant AI35707. We also
thank Jack Taunton for stimulating discussions.
Figure 2. NMR solution structures of 1 and 9 in CDCl3. Above: Schematic
structures of 1 and 9 illustrating their hydrogen bonding networks. Below:
Stereoviews of 1 and 9.
Supporting Information Available: NMR data for 1 and 9, detailed
experimental procedures on compound synthesis, PAMPA assay, H/D
exchange, and details of computational methods and calculated structure
of 9 in water. This material is available free of charge via the Internet
the i + 1 position of a type II′ â-turn, which is followed by a type
I â-turn centered on Tyr6 and Leu1 at the i + 1 and i + 2 positions,
respectively. The amide N-H of Tyr6 points away from the ring
into solvent, while the amide N-H of Leu4 points inward, toward
the γ-turn centered on D-Leu2.
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D2O. Only one amide N-H in 1, that of D-Leu2, exchanged with
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