Helical Peptide Design & Synthesis

Precision stabilization of α-helical peptide architectures—built to preserve conformation, improve binding, and enhance functional durability.

Overview

Conformation-first synthesis for helix-stabilized peptides

Helical peptides are conformationally controlled peptides engineered to adopt and maintain α-helical secondary structure under experimental or physiological conditions. Because many biologically critical interactions—especially protein–protein interactions (PPIs)—are mediated by α-helices, stabilizing a helix often improves potency, selectivity, and functional durability.

Unlike linear peptides that frequently lose helicity in solution, helix-stabilized peptides incorporate structural constraints (crosslinks, helix-promoting residues, or backbone modifications) that bias the peptide toward a defined conformation. We help select a stabilization strategy that fits your sequence, target interface, and downstream assay or delivery constraints.

Stapling / lactam / disulfide options Helix-promoting residues (e.g., Aib) Backbone modifications (project-dependent) 45+ Years of Expertise U.S. Facilities - Texas
Helical peptide design and synthesis: helix stabilization strategies including hydrocarbon stapling, lactam bridges, disulfide/thioether constraints, helix-promoting residues, and backbone N-methylation.
Figure: Different α-helix-stabilization methods used to control α-helix formation and retention. for small peptides. For cross-linked peptides, all are between residues i and (i + 4). (a) Triazole stapled helix; (b) Hydrocarbon stapled helix; (c) di-sulfide cross-linked helix; (d) Lactam cross-linked helix; (e) Aib substituted helix.

Related constrained peptide services: Stapled Peptide Synthesis, Cyclic Peptide Synthesis, Macrocyclic Peptide Synthesis, Bicyclic Peptide Synthesis. For ready-made options, browse Catalog Peptides.

What defines a helical peptide?

Definition

A helical peptide is defined by functionally relevant α-helix stabilization—not by a single synthetic method.

  • Enforced or biased α-helical secondary structure
  • Reduced conformational entropy
  • Improved binding to helix-recognition sites
  • Enhanced stability vs linear analogs
Why helicity matters

Helix stabilization is most useful when activity depends on presenting key side chains in a defined helical geometry.

  • Protein–protein interaction (PPI) modulation
  • Receptor/ligand binding interfaces
  • Transcriptional and signaling complexes
What is (and isn’t) stapling

Stapled peptides are a subset of helical peptides that use hydrocarbon crosslinks. Other chemistries can stabilize helices without hydrocarbon stapling.

  • Stapling: i,i+4 or i,i+7 hydrocarbon crosslink
  • Non-staple options: lactam, disulfide/thioether, Aib, N-methylation
Design inputs that speed up feasibility

If you provide these details, we can recommend a stabilization strategy and QC plan faster.

  • Target interface and known hot-spot residues
  • Desired helix span (e.g., 8–20 residues)
  • Required functional handles (cysteine, azide/alkyne, biotin, fluorophores)
  • Solubility constraints and assay buffer conditions
  • Preferred stabilization method (or ask us to recommend)
  • Purity/quantity targets and turnaround expectations

Helical stabilization strategies

Hydrocarbon stapling

Side-chain crosslinking (commonly i,i+4 or i,i+7) to strongly enforce α-helicity; widely used for PPI targets.

  • Helix enforcement for intracellular targets
  • Sequence-dependent placement and feasibility
  • Often improves protease resistance
Lactam bridges

Amide crosslinks between side chains to stabilize helix without hydrocarbon chemistry; useful for aqueous compatibility.

  • Side-chain to side-chain constraints
  • Good for polar/charged designs
  • Orthogonal protection planning matters
Disulfide / thioether constraints

Cysteine-based constraints that can stabilize local structure; thioether options add redox stability vs disulfides.

  • Disulfides: reversible/redox-sensitive
  • Thioethers: more chemically robust
  • Works well with cysteine-specific workflows
Helix-promoting residues

α,α-disubstituted residues (e.g., Aib) and strategic substitutions to bias helix formation without crosslinks.

  • Supports short helices and helix caps
  • Maintains smaller molecular footprint
  • Useful when crosslinking is undesirable
Backbone N-methylation

Backbone modification to tune conformation, permeability, and protease resistance (project-dependent feasibility).

  • Conformational tuning and stability
  • Often requires careful SPPS optimization
  • Best for design-led projects
Short-range cyclization motifs

Local constraints (including small rings or tethered motifs) to stabilize partial helices or turn/helix boundaries.

  • Helix caps and local structure control
  • Can improve reproducibility vs linear peptides
  • Often pairs well with labels/conjugation
How we choose a strategy
  • Conformation goal: full helix vs partial helix vs local stabilization
  • Sequence behavior: aggregation, hydrophobicity, and solubility constraints
  • Compatibility: labels, conjugations, and downstream assay conditions
  • Manufacturability: SPPS feasibility, orthogonality, and side reactions
  • Analytical plan: what data you need to confirm identity/purity/conformation
  • Risk control: staged synthesis/QC when complexity is high

Helical peptides vs stapled peptides

This distinction matters: helical peptides are a conformation-defined class, while stapled peptides are a chemistry-defined subset.

Feature Helical Peptides Stapled Peptides
Definition Peptides engineered to maintain α-helical structure Subset of helical peptides using hydrocarbon crosslinks
Stabilization methods Multiple (lactam, disulfide/thioether, Aib, N-methylation, stapling) Primarily hydrocarbon stapling (i,i+4 or i,i+7)
Chemical flexibility High (strategy chosen to fit sequence/assay) Moderate (restricted to staple-compatible placements)
Primary goal Helix formation and retention Strong helix enforcement; often improved stability
Best use cases Broad research & discovery across targets and conditions Intracellular PPIs and drug-lead style designs

If you already know you need stapling, go directly to Stapled Peptide Synthesis. If you want the best helix strategy for your sequence, this helical peptide service is the right starting point.

Applications of helical peptides

Common research uses
  • Protein–protein interaction (PPI) inhibition or stabilization
  • Transcription factor and cofactor modulation
  • Signal transduction and pathway studies
  • Structural biology and biophysics workflows
Discovery & development contexts
  • Helix-mimetic therapeutic leads
  • Tool compounds for target validation
  • Cell-penetrating or intracellular designs (sequence-dependent)
  • Conjugation-ready helices for imaging or pull-down
Where helical peptides fail (and what we do about it)
  • Low helicity in solution: add crosslinking or helix-promoting residues
  • Poor solubility: sequence edits, charge balancing, or formulation guidance
  • Proteolysis: constraint selection and targeted substitutions
  • Synthesis difficulty: orthogonal protecting group design and staged workflows
  • Analytical ambiguity: fit-for-purpose QC + optional characterization
  • Scale needs: planning around purification and yield expectations

Quality control & characterization

Standard QC
  • Mass spectrometry (MS) identity confirmation
  • Analytical HPLC profile / purity (where feasible)
  • COA + supporting documentation
Helpful add-ons
  • Additional HPLC methods (project-dependent)
  • Custom documentation bundles
  • Stability-oriented handling recommendations
Optional helicity assessment
  • CD spectroscopy (for helicity trend assessment)
  • Comparative testing across analog series
  • Interpretation aligned to your conditions

Tell us what decision you need the data to support (screening, SAR, biophysics, or assay validation) and we’ll recommend a QC/characterization package that matches.

Specifications & typical deliverables

Use this as a practical checklist for quote requests. If you’re unsure, send your sequence(s) and goal—we’ll propose options.

Parameter Typical options Notes for helical peptide projects
Sequence length Commonly 8–30 aa (project-dependent) Helix span and stabilization placements influence feasibility and conformation.
Stabilization strategy Stapling, lactam bridges, disulfide/thioether, Aib/helix-promoting residues, N-methylation We recommend a fit-for-sequence strategy based on target, solubility, and manufacturability.
Quantity µg–g scale (project-dependent) Constraint chemistry and purification requirements affect yield expectations.
Purity Crude to higher purity upon request Purity targets should match downstream use; some constrained formats require method tuning.
Optional modifications Labels, biotin, PEG/linkers, functional handles Plan orthogonality early to avoid conflicts with helix stabilization chemistries.
Standard QC deliverables MS + HPLC profile, COA Additional methods can be added as needed for complex constraints.
Optional characterization CD spectroscopy (trend assessment) Useful to compare analogs and confirm that stabilization is delivering the intended effect.

FAQ

Are helical peptides always stapled peptides?

No. Stapled peptides are one subset that use hydrocarbon crosslinks. Helical peptides may also be stabilized with lactam bridges, disulfide/thioether constraints, helix-promoting residues (e.g., Aib), or backbone modifications.

When should I choose helical peptides instead of cyclic or macrocyclic peptides?

Choose helical peptides when activity depends on presenting residues in an α-helical geometry (common in PPIs). Cyclic/macrocyclic formats can constrain peptides too, but they do not automatically produce an α-helix unless designed for it.

What information do you need to recommend a stabilization strategy?

Sequence(s), target or interface (if known), preferred helix span, required labels/handles, solubility/assay conditions, and your desired quantity/purity/QC. If you don’t know the strategy, send your goal and we’ll propose options.

Can you make multiple analogs for SAR?

Yes. Helical peptide programs commonly use analog series to tune helicity, affinity, and stability while keeping the binding epitope consistent.

Do you offer helicity measurement?

We provide standard analytical QC (HPLC/MS). Optional CD spectroscopy can be added for helicity trend assessment when that data supports your decisions.

Can you add functional handles for conjugation?

Yes. We can incorporate cysteine, azide/alkyne, linkers, and labels—planned to remain compatible with the selected helix stabilization chemistry.

Contact & quote request

What to send for a fast quote
  • Sequence(s) and target application (PPI, assay type, biophysics, etc.)
  • Preferred stabilization method (or “recommend”) and any required handles/labels
  • Quantity, purity target, and delivery timeline
  • Any known solubility constraints or buffer conditions
Need help choosing the strategy?

Send your sequence and the interaction you’re targeting. We’ll recommend a stabilization path and a practical synthesis/QC plan aligned to your goals.

  • Strategy selection (staple vs lactam vs cysteine-based vs substitutions)
  • Purification planning and yield expectations
  • QC package aligned to your downstream decision

Also available: Catalog Peptides   for ready-made, on-demand options.

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