Non-Proteinogenic (Unnatural) Amino Acid Peptide Synthesis

Custom incorporation of non-proteinogenic residues for SAR optimization, stability engineering, and advanced peptide design.

Overview

Non-proteinogenic (unnatural) amino acids are residues beyond the 20 canonical amino acids. In peptide design, they enable precise tuning of sterics, polarity, charge, hydrogen bonding, and chemical functionality to meet specific performance goals (e.g., stability, binding, selectivity, permeability).

In practice, unnatural amino acid incorporation is a core strategy for structure–activity relationship (SAR) optimization and stability engineering. Substitutions can improve protease resistance, stabilize or disrupt secondary structure, and introduce functional handles for downstream conjugation or detection.

Non-proteinogenic AAs SAR panels & libraries Protease resistance Permeability tuning HPLC / LC-MS QC

Related: D-amino acid peptides · N-methyl peptides · Peptide cyclization · Macrocyclic peptides

Applications

Protease resistance & stability

Reduce enzymatic recognition and improve stability in serum, lysates, or long incubations.

cleavage-site protection serum stability
SAR optimization

Analog substitutions to map tolerance and tune potency/selectivity at key positions.

single-position scan multi-variant panel
Conformational control

Stabilize or disrupt helices/turns using constrained residues and backbone variants.

helix/turn tuning rigidity
Permeability tuning

Selected substitutions can support physicochemical optimization in suitable scaffolds.

lipophilicity backbone tuning
Macrocycles & constrained peptides

Combine non-proteinogenic residues with cyclization strategies for constrained scaffolds.

macrocycles constrained scaffolds
Probes & functional handles

Introduce clickable/reactive residues for labeling, enrichment, and engagement studies.

azide/alkyne photo-reactive
Typical project formats
  • Single substitutions: quick hypothesis testing
  • Analog panels: scan one position with multiple residues for SAR
  • Multi-position designs: stability and binding optimization (project-defined)
  • Combination builds: unnatural residues + cyclization, labels, conjugation

Capabilities (service specs)

Purity targets

Crude to high-purity options (e.g., ≥ 95% / ≥ 98%) depending on sequence and use case.

Analytical verification

HPLC/UPLC purity profile plus LC-MS intact mass confirmation (when feasible).

Panels & libraries

Single-position scans, multi-variant SAR panels, and project-defined libraries.

If you need specific length/scale/QC specs listed on-page, add your exact ranges and we’ll format them to match this template.

Services we provide

Single substitutions

Site-specific analog insertion to test tolerance, improve stability, or tune binding at key positions.

SAR panels & libraries

Multi-variant panels (single position or multi-position) designed for efficient iteration.

Advanced integration

Unnatural residues combined with cyclization, conjugation, or labels (feasibility confirmed during review).

Unnatural amino acid categories for peptide synthesis

Category Examples Primary purpose
Aliphatic analogs Norleucine (Nle), Norvaline (Nva) Hydrophobic tuning, oxidation resistance (project-dependent)
Charged analogs Ornithine (Orn), Citrulline (Cit) Charge modulation, binding/selectivity tuning
Constrained residues α-methyl amino acids, Aib Helix/turn control, conformational restriction
Bulky aromatics Cyclohexylalanine (Cha), β-naphthylalanine Binding interface optimization, hydrophobic packing
β-amino acids β-alanine, β-homoleucine Backbone tuning and stability (scaffold-dependent)
Functional handles Azido / alkyne residues, photo-reactive residues Click chemistry, labeling, capture workflows
Additional residues (available upon request)

Fluorinated amino acids, N-methylated residues, lipid-like analogs, proprietary building blocks, and project-specific residues can be evaluated upon request. Provide your residue name (or structure), position(s), and intended use.

Workflow

Typical workflow
  1. Sequence review + substitution goal (SAR, stability, binding, probes)
  2. Route planning (building block, protecting groups, coupling strategy)
  3. SPPS synthesis + cleavage
  4. Purification (prep HPLC as required)
  5. Analytical verification + documentation
What to send for a fast quote
  • Sequence(s) + terminal state (free/capped)
  • Residue(s) and position(s), or “recommend”
  • Quantity and purity target
  • Intended use (assay type, stability matrix, binding target)
  • Any combination requirements (cyclization, labels, conjugation)

Quality control & deliverables

Standard QC

Analytical HPLC/UPLC purity profile and LC-MS intact mass confirmation (when feasible).

Panels & comparatives

SAR substitution panels, matched controls, and multi-variant sets for iteration.

Optional add-ons

Additional characterization and custom documentation (project-defined).

FAQ

What counts as a non-proteinogenic amino acid?

Any residue beyond the 20 canonical amino acids, including constrained residues, side-chain analogs, backbone variants, and functional handles.

Can these be combined with cyclization or labels?

Often yes. Compatibility depends on residue chemistry and sequence context; feasibility is confirmed during quote review.

Can you make SAR panels with multiple substitutions?

Yes. We support single-position and multi-position panels. Share your design intent and constraints so we can propose a practical set.

What is the difference between D-amino acids and unnatural amino acids?

D-amino acids are stereochemical variants (L→D). Unnatural amino acids are non-proteinogenic residues used to tune stability, conformation, and functionality.

Contact & quote request

For the fastest quote, send your peptide sequence(s), the substitution(s) and positions (or “recommend”), desired quantity/purity, and intended use (therapeutic discovery, assay standard, probe, etc.). We’ll recommend a practical synthesis route plus purification/QC aligned to your application.

Send project details

If you’re unsure which residues to use, share the goal (e.g., “increase stability” or “optimize affinity”) and any constraints. We’ll propose practical substitution options and a synthesis + QC plan.


Email: sales@biosyn.com
Phone: +1 (800) 227-0627 | +1 (972) 420-8505

Fast quote checklist
  • Sequence(s) + terminal state (free/capped)
  • Unnatural residue(s) + position(s), or “recommend”
  • Quantity and purity target
  • Intended use (SAR, stability, binding, probes)
  • Any combo needs (cyclization, labels, conjugation)

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