New Peptide Stapling Chemistry Creates More Stable Drug-Like Helical Peptides Resistant to Digestion | Research

The takeaway

A new i,i+7 amine-containing hydrocarbon staple — spanning two helical turns — significantly enhanced α-helical stability and proteolytic resistance of peptides, with a surprising finding that reversing the staple orientation dramatically improved helicity.

Orientation reversal dramatically enhanced helicity
Reversing the i,i+7 ACH staple orientation significantly improved α-helical stability beyond the canonical arrangement — a transferable design principle for stapled peptide therapeutics

What the researchers found

A 13-atom butylaminoalkenyl tether with SS configuration was identified as the most effective i,i+7 ACH staple. Orientation reversal substantially enhanced helicity and this effect transferred across helical registers. The optimized staple conferred significant proteolytic resistance, linking structural preorganization to biochemical resilience.

Why it matters

Expanding the ACH stapling toolkit to i,i+7 topology enables longer-range helical control for therapeutic peptides targeting protein-protein interactions, with improved aqueous compatibility over conventional staples.

The numbers in context

13-atom optimal tether length; SS stereochemistry; i,i+7 topology spanning 2 helical turns

How the study worked

Systematic variation of cross-link length, stereochemistry, and orientation in model peptides. Helicity measured by circular dichroism spectroscopy. Proteolytic resistance tested against enzymatic degradation. Transferability confirmed across different helical register positions.

What this study cannot tell us

This is a purely chemical study without biological activity data. The helicity measurements and proteolytic resistance were demonstrated in model peptides, not therapeutic candidates. Translation to specific disease-relevant peptides needs further validation. The study does not address cell permeability, in vivo stability, or pharmacokinetics of the stapled peptides.

How to read the evidence

This is a peptide chemistry study focused on conformational analysis and proteolytic stability. While the chemical findings are well-characterized, no biological activity or therapeutic efficacy data was presented.

When this study was published

Published in 2026, this study advances the cutting-edge field of peptide stapling chemistry, building on the growing clinical pipeline of stapled peptide drugs.

The bigger picture

Stapled peptides are one of the most commercially advanced peptide drug technologies, with several candidates in clinical trials. The original all-hydrocarbon (AHC) staples pioneered by the Verdine lab are hydrophobic and can limit water solubility. These amine-containing hydrocarbon (ACH) staples offer improved aqueous compatibility — critical for drug formulation — while maintaining the conformational lock that makes stapled peptides effective. Expanding from i,i+4 to i,i+7 provides longer-range structural control, enabling researchers to stabilize larger helical segments and potentially target protein-protein interactions that require extended helical surfaces.

Questions still open

Do i,i+7 ACH-stapled peptides show improved cell permeability compared to conventional AHC staples?
Can the orientation-reversal helicity enhancement be applied to therapeutic peptides targeting specific protein-protein interactions?
How do ACH staples perform in vivo compared to all-hydrocarbon staples in terms of pharmacokinetics and efficacy?

Common questions

What is peptide stapling?

Peptide stapling is a chemical technique that locks a peptide into its bioactive shape (usually a helix) by adding a covalent crosslink between two amino acids. Think of it like adding a rivet to hold a coiled spring in place. This makes the peptide more stable, more resistant to enzymes that would normally destroy it, and often better at entering cells — all critical properties for turning peptides into effective drugs.

Why does spanning two helical turns matter?

The i,i+7 staple spans two complete turns of the helix, providing stronger structural reinforcement than shorter staples (like i,i+4 which spans one turn). This longer-range control is important for stabilizing larger protein-interacting surfaces and for targeting protein-protein interactions where extended helical contacts are needed — a major class of 'undruggable' disease targets.

Read the original research

Helix stabilization by i,i + 7 amine-containing hydrocarbon Staples: Effects of length, stereochemistry, and orientation.

Bioorganic & medicinal chemistry, 132, 118443

View on PubMed ↗Publisher’s paper ↗

Citation

Nguyen, Ha T N; Lee, Su-Yeon; Tran, Duc V H; Kim, Young-Woo. (2026). Helix stabilization by i,i + 7 amine-containing hydrocarbon Staples: Effects of length, stereochemistry, and orientation.. Bioorganic & medicinal chemistry, 132, 118443. https://doi.org/10.1016/j.bmc.2025.118443