Membrane Permeability

Therapeutic peptides are predicted to go from a $21 billion to a $46.6 billion dollar industry by 2024. The revenue increase is anticipated to come from the discovery of new peptide drugs. Cyclic peptides are a highly promising class of molecules, because they are stabile to proteases, have well-defined 3-D structures, and have restricted conformational movement.

These properties provide energetic binding and steric advantages for cyclic peptides over small molecules and linear peptides inhibitors of protein–protein interactions. For these reasons cyclic peptides are anticipated to be at forefront of new peptide drug development.

Published in Peptide Science, researchers in Shelli McAlpine's lab describe the design, synthesis, and biological evaluation of 5 N-methylated analogs that are based on a lead drug structure LB51. LB51 is a cyclic pentapeptide that inhibits heat shock protein 90 and although a potent inhibitor of the protein function, it has poor cell permeability. 

Introduction of an N-methyl moiety at each amino acid produces 5 analogs of LB51, where all 5 show significantly improved membrane permeability over the lead molecule despite the presence of 4 highly polar side chains.

The McAlpine lab members have also recently reported a prodrug strategy where including masked polar side chains, with no N-methylation of the backbone produces relatively permeable molecules, with 4–5 fold decrease in potency. Studies aimed at maintaining activity while examining the synergistic effects of N-methylation, inverting stereochemistry, and modification of side chains will be reported here in due course.

Converting Polar Cyclic Peptides into Membrane Permeable Molecules using N‐Methylation
Leo L. H. Lee, Laura K. Buckton, Shelli R. McAlpine
Peptide Science, Volume 110, Issue 3