🔗 Constrained Peptide Technology

Stapled Peptide Synthesis

Hydrocarbon-Stapled Alpha-Helical Peptides for Targeting Undruggable PPIs

Boston Molecules offers custom synthesis of hydrocarbon-stapled peptides using olefin metathesis chemistry. Our platform supports i,i+4 and i,i+7 staples, double-stapled, and stitched peptide architectures — enabling researchers to target protein-protein interactions previously considered undruggable.

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Why Stapled Peptides?

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Target Undruggable PPIs

~80% of disease-relevant protein interactions lack small-molecule binding pockets. Stapled peptides bridge the gap between small molecules and biologics, engaging large, flat PPI interfaces.

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Enhanced Stability

Hydrocarbon crosslinks increase protease resistance by 10–100×, extend serum half-life, and lock the peptide in its bioactive alpha-helical conformation.

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Cell Permeability

Stapling imparts cell-penetrating properties through enhanced amphipathicity, enabling intracellular targets like p53–MDM2, BCL-2 family, and transcription factors.

Staple Architectures We Offer

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i, i+4 Hydrocarbon Staple

Single-turn alpha-helix stabilization using S5 (S-pentenylalanine) residues. Crosslinks one helical turn (~6 Å span). Ideal for short helical motifs (8–12 residues).

S5 Olefin 1-Turn Helix RCM
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i, i+7 Hydrocarbon Staple

Two-turn alpha-helix stabilization using S5 + R8 (R-octenylalanine) residues. Spans two helical turns (~11 Å). Greater conformational constraint for longer helices.

S5 + R8 2-Turn Helix Extended
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Double-Stapled Peptides

Two independent hydrocarbon staples on the same peptide. Maximum helical stabilization and protease resistance. Used for long PPI interfaces (>15 residues).

Dual Constraint Maximum Stability 🔥 Advanced
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Stitched Peptides

Multi-component staple where a single residue participates in two crosslinks, creating a continuous "stitch" along the helix. Pioneered by Verdine lab at Harvard.

Multi-Crosslink Verdine Novel

Synthesis Chemistry

Olefin Metathesis Stapling Platform

Key Building Blocks

  • • Fmoc-S5-OH — (S)-2-(4'-pentenyl)alanine
  • • Fmoc-R8-OH — (R)-2-(7'-octenyl)alanine
  • • Grubbs Catalyst — Ring-closing metathesis (RCM)

Our Capabilities

  • ✅ On-resin olefin metathesis
  • ✅ Both i,i+4 and i,i+7 geometries
  • ✅ Double-stapled & stitched designs
  • ✅ CD spectroscopy for helicity confirmation
  • ✅ mg to gram scale

Therapeutic Applications of Stapled Peptides

Target PPI Disease Area Example Stage
p53–MDM2/MDMX 🔥 Hot
Reactivates p53 tumor suppressor by disrupting MDM2 binding 		Cancer (multiple solid tumors) ALRN-6924 (Aileron Therapeutics) Phase 2 clinical
BCL-2 Family (BH3)
Mimics BH3 domain to trigger apoptosis in cancer cells 		Hematological malignancies SAHB (Stabilized Alpha-Helix of BCL-2) Preclinical
Estrogen Receptor (ER)
Blocks ER-coactivator interaction to suppress ER signaling 		Breast cancer Stapled ER coactivator peptides Preclinical
β-Catenin/TCF 🔥 Hot
Disrupts β-catenin/BCL9 complex in Wnt signaling 		Colorectal cancer, Wnt-driven tumors SAH-BCL9 stapled peptides Preclinical
Notch Signaling
Inhibits Notch transcription complex assembly 		T-ALL, solid tumors SAHM1 (Stapled Alpha-Helical peptide from MAML1) Preclinical
RAS–Effector PPI 🔥 Hot
Targets "undruggable" RAS protein-protein interactions 		KRAS-driven cancers Stapled SOS1 / RAF peptides Early discovery

Custom Peptide Synthesis Quote

Design your custom peptide and get an instant quote with our online configurator.

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For research use only. Not for diagnostic or therapeutic use.