New Peptide Stapling Methods From Mushroom Toxin Chemistry Enable Sub-Nanomolar Drug Candidates | Research

The takeaway

Tryptathionine and 2,2'-bis-indole staples — natural motifs from amatoxins and staurosporine — were efficiently applied to staple peptide drugs, yielding sub-nanomolar binding affinity for melanocortin receptors.

Sub-nanomolar Ki
binding affinity achieved with natural product-inspired peptide staple

What the researchers found

Both tryptathionine and 2,2'-bis-indole stapling of α-MSH produced nanomolar Ki values, with one stapled variant achieving sub-nanomolar affinity for melanocortin receptors.

Why it matters

Peptide stapling is key to making peptide drugs more stable and cell-penetrating. These new staple types from natural product chemistry expand the peptide drug designer's toolkit and could enable development of more potent, stable therapeutic peptides.

The numbers in context

Two new staple types developed: tryptathionine (from amatoxins/phallotoxins) and 2,2'-bis-indole (from staurosporine). Applied to melanotan-II.

How the study worked

Chemical synthesis using 5-hydroxypyrroloindoline condensation with cysteine-thiol or tryptophan-indole, applied to α-MSH as a model peptide, with binding affinity measured against melanocortin receptors.

Who was studied

Synthetic peptide chemistry (melanotan-II as model peptide)

What this study cannot tell us

Demonstrated on only one model peptide (α-MSH); binding affinity measured but not cellular activity or in vivo efficacy; metabolic stability of stapled peptides not assessed; limited exploration of staple position effects; no comparison to existing stapling methods.

How to read the evidence

Preliminary proof-of-concept for new peptide chemistry. Demonstrates feasibility and high binding affinity but lacks biological validation and drug-like property assessment.

When this study was published

Published in 2024, contributing novel peptide stapling methods to the growing field of constrained peptide therapeutics.

The bigger picture

As peptides become increasingly important as drugs, finding new ways to stabilize their three-dimensional structures is crucial. Drawing inspiration from toxic natural products to create drug-like stapled peptides represents a creative convergence of natural product chemistry and drug design.

Questions still open

Do these natural product staples improve peptide cell permeability and metabolic stability?
Can these stapling methods be applied to therapeutic peptides targeting disease-relevant receptors?
How does the conformational constraint compare to established staple types like hydrocarbon staples?

Common questions

What is peptide stapling?

It's a technique to lock a peptide drug into a specific 3D shape by adding a chemical bridge (staple) between two points. This makes the peptide more stable, more likely to enter cells, and often more potent at binding its target.

Why use mushroom toxin chemistry for drug design?

The deadly amatoxins in mushrooms are incredibly potent precisely because their peptide structure is rigidly stapled. By borrowing these natural stapling motifs, chemists can create similarly rigid and potent — but non-toxic — therapeutic peptides.

Read the original research

5-Hydroxypyrroloindoline Affords Tryptathionine and 2,2'-bis-Indole Peptide Staples: Application to Melanotan-II.

Chemistry (Weinheim an der Bergstrasse, Germany), 30(19), e202304270

View on PubMed ↗Publisher’s paper ↗

Citation

Todorovic, Mihajlo; Blanc, Antoine; Wang, Zhou; Lozada, Jerome; Froelich, Juliette; Zeisler, Jutta; Zhang, Chengcheng; Merkens, Helen; Benard, Francois; Perrin, David M. (2024). 5-Hydroxypyrroloindoline Affords Tryptathionine and 2,2'-bis-Indole Peptide Staples: Application to Melanotan-II.. Chemistry (Weinheim an der Bergstrasse, Germany), 30(19), e202304270. https://doi.org/10.1002/chem.202304270