Login / Register Order My Items
Contact Us
800.227.0627
Contact Us Quote Order Login / Register

D-Amino Acid Peptide Synthesis

Custom D-amino acid peptide synthesis for research and preclinical programs, with defined specifications and analytical verification.

Request a Quote View D-amino acid list
Talk to a chemist Request a quote
Overview Capabilities Retro-inverso Mirror-image Decision guide Services D-AA list Workflow QC FAQ Recommended reading Contact

Overview

D-amino acid peptide synthesis is a stereochemical amino acid substitution strategy in which one or more natural L-amino acids in a peptide sequence are replaced with their mirror-image D-enantiomers. This approach is widely used to improve protease resistance, increase metabolic stability, and generate stereochemical controls for mechanism and SAR studies [1].

Mechanistically, D-substitution changes the configuration at the α-carbon while leaving the peptide bond connectivity intact. In other words, it is typically classified as an amino acid substitution (stereochemical modification), not a backbone connectivity modification. This distinction matters in practice: D-residues often disrupt protease recognition and can modulate local conformation without requiring new backbone chemistries [2].

D-residues are commonly introduced in hotspot positions (e.g., known cleavage sites) to reduce enzymatic degradation, or used as single-point variants to test stereochemical dependence of activity. In more advanced formats, entire sequences can be synthesized as full D-peptides (“mirror-image peptides”) to maximize resistance to many naturally occurring proteases [1].

For projects that require functional mimicry with increased stability, retro-inverso peptide design may be used. Retro-inverso analogs reverse the sequence direction and substitute D-residues to approximate the side-chain topography of the parent peptide (context-dependent), offering a practical route to stability-enhanced mimetics in selected systems [3].

We provide site-defined D-amino acid incorporation at the N-terminus, internal positions, and C-terminus, including standard D-residues and specialty D-building blocks (see the available list below). Deliverables are supported by fit-for-purpose purification and analytical verification to match downstream use (assay controls, stability studies, binding experiments, or peptide engineering workflows) [1], [4].

Site-specific D-substitution Full or Partial D-peptide synthesis Protease-resistant peptides Mirror-image peptides Retro-inverso peptides

Mirror-Image & Retro-Inverso Peptides

Mirror-image peptides (Full D-peptides)

Full D-peptides are composed entirely of D-amino acids and are frequently used when the primary goal is maximum protease resistance and enhanced stability in biological matrices. [1]

These are often selected for long-incubation assays or environments with high protease activity.

Retro-inverso peptide synthesis

Retro-inverso (RI) peptides reverse sequence direction while substituting D-amino acids to approximate aspects of the parent peptide’s side-chain topology. Structural and functional similarity should be validated experimentally, as retro-inverso analogs may not fully replicate the parent L-peptide’s conformational or binding characteristics. [3]

RI peptides are commonly evaluated when stability enhancement is desired while attempting to retain functional characteristics.

Decision guide: when to use D-amino acids

Use D-substitution when you need…
  • Protease resistance (protect known cleavage sites)
  • Longer incubation stability (serum, lysates, cell media)
  • Stereochemical controls (L vs D matched variants)
  • Conformational tuning (turn/loop changes via D-Pro)

Tip: start with single-point D-substitutions near cleavage sites before redesigning the entire sequence [1].

Common trade-offs to plan for
  • Changes in potency if D-residues are placed inside a critical binding motif
  • Local conformational shifts (helpful or harmful depending on target)
  • Altered solubility/aggregation if multiple hydrophobics are introduced

For mimicry-focused stability design, retro-inverso may be appropriate (case-dependent) [3].

Quick decision guide

Compare common D-amino acid design strategies based on project goals.

Goal Recommended Strategy Considerations
Reduce protease cleavage D-substitute known cleavage hotspots (often termini or flanks) Activity may change if substitution occurs in binding motif
Improve stability while preserving activity Start with limited D-substitution + matched L/D controls Iterative optimization may be required
Maximum protease resistance Full D-peptide (mirror-image peptide) Binding geometry may differ from native L-peptide
Stability-focused mimic design Retro-inverso analog (sequence reversal + D-residues) Functional similarity must be experimentally validated

D-amino acid peptide services we provide

Site-specific D-substitution

Single-point variants, hotspot protection, stereochemical controls (L vs D) and small panels.

Full D-peptides

Entire sequences in D-configuration for maximal protease resistance (application-dependent).

Retro-inverso peptides

Sequence reversal + D-substitution options for stability-enhanced mimetics (case-dependent).

Capabilities at a glance

Peptide format
  • Site-specific D-amino acid substitution peptides
  • Full D-peptides (mirror-image peptides)
  • Retro-inverso peptide synthesis (RI peptides)
Scale & purity (examples)
  • Scale: mg–g (custom scales available)
  • Purity tiers: crude, ≥95%, ≥98% (as specified)
  • Delivery: lyophilized powder (typical)

Replace the scale/purity examples with your published specs.

QC & documentation
  • Analytical HPLC/UPLC purity report
  • MS/LC-MS identity confirmation (when feasible)
  • COA + method notes

D-amino acids available

All listed items are supported at N-terminus, internal, and C-terminus positions (project-dependent).

Special AAs Code / Notation Positions Availability
D-2-Indanyl-Glycine - D-Igl [D-Igl] N-term, Internal, C-term ●●●●...●●●●
D-4-Hydroxyphenylglycine - D-Hpg [D-Hpg] N-term, Internal, C-term ●●●●...●●●●
D-Alanine *A N-term, Internal, C-term ●●●●...●●●●
D-Amino Acid [D-aa] N-term, Internal, C-term ●●●●...●●●●
D-Arginine *R N-term, Internal, C-term ●●●●...●●●●
D-Asparagine *N N-term, Internal, C-term ●●●●...●●●●
D-Aspartic acid *D N-term, Internal, C-term ●●●●...●●●●
D-Cysteine *C N-term, Internal, C-term ●●●●...●●●●
D-Glutamic acid *E N-term, Internal, C-term ●●●●...●●●●
D-Glutamine *Q N-term, Internal, C-term ●●●●...●●●●
D-Histidine *H N-term, Internal, C-term ●●●●...●●●●
D-Homocysteine [D-Homocys] N-term, Internal, C-term ●●●●...●●●●
D-Homoserine [D-Homoser] N-term, Internal, C-term ●●●●...●●●●
Diaminotrioxatridecan suc. ac. - TTDS [TTDS] N-term, Internal, C-term ●●●●...●●●●
D-Isoleucine *I N-term, Internal, C-term ●●●●...●●●●
D-Leucine *L N-term, Internal, C-term ●●●●...●●●●
D-Lysine *K N-term, Internal, C-term ●●●●...●●●●
D-Methionine *M N-term, Internal, C-term ●●●●...●●●●
D-Ornithine [D-Orn] N-term, Internal, C-term ●●●●...●●●●
D-Phenylalanine *F N-term, Internal, C-term ●●●●...●●●●
D-Proline *P N-term, Internal, C-term ●●●●...●●●●
D-Serine *S N-term, Internal, C-term ●●●●...●●●●
D-Threonine *T N-term, Internal, C-term ●●●●...●●●●
D-Tryptophan *W N-term, Internal, C-term ●●●●...●●●●
D-Tyrosine *Y N-term, Internal, C-term ●●●●...●●●●
D-Valine *V N-term, Internal, C-term ●●●●...●●●●
Additional D-residues (available upon request)

If your project uses D-variants not listed above, send the target residue(s) and position(s). Common requests include:

D-Nle (norleucine) D-Nva (norvaline) D-Cit (citrulline) D-Cha (cyclohexylalanine) D-Abu (2-aminobutyric acid) D-Pen (penicillamine) D-hPhe / D-Phg (aromatic analogs)

Availability depends on protecting groups and sequence context. We confirm feasibility during quote review.

Workflow

Typical workflow
  • Sequence + D-position review (or “recommend”)
  • SPPS route planning for D-residue incorporation
  • Cleavage + purification strategy aligned to hydrophobicity/charge shifts
  • Analytical verification (HPLC/UPLC + LC-MS when feasible)
Best info to include in requests
  • Sequence + terminal state (free/capped)
  • D-substitution positions (or cleavage-site goal)
  • Intended use (stability, binding, control peptide, etc.)
  • Quantity + target purity

Quality control & deliverables

Standard QC
  • Analytical HPLC/UPLC purity profile
  • LC-MS intact mass confirmation (when feasible)
  • COA + method notes
Comparative sets
  • L vs D matched controls
  • Single-point D-scan panels
  • Multi-point designs (project-defined)
Optional add-ons
  • Amino acid analysis (as needed)
  • Stability study planning support (design-level)
  • Custom handling/packaging

FAQ

Is D-amino acid incorporation a backbone modification?

It is typically categorized as a stereochemical amino acid substitution (chirality inversion at Cα) with unchanged peptide bond connectivity [2].

Can D-substitutions reduce activity?

Yes—especially if placed within a critical binding motif. Many programs start with cleavage-site protection and matched controls [1].

What is a retro-inverso peptide?

A retro-inverso analog typically reverses sequence direction and uses D-residues to approximate side-chain topography of the parent peptide (context-dependent) [3].

Why do D-peptides resist proteolysis?

Many proteases evolved to recognize L-configured substrates; D-configured residues frequently reduce recognition and cleavage [1].

More FAQ'sAll FAQ's

Contact & quote request

For the fastest quote, send your sequence(s), the D-substitution position(s) (or “recommend”), desired termini state (free/capped), target quantity, purity, and intended use (stability, binding, SAR panel, stereochemical control, etc.).

Fast quote checklist
  • Peptide sequence(s) (single-letter code) + any known cleavage sites
  • D-residue positions (e.g., “D-Pro at position 6”), or “recommend”
  • Termini state: free vs Acetylated N-terminus / Amidated C-terminus
  • Desired format: single-point variant, D-scan panel, multi-point design, or full D-peptide
  • Quantity (mg/g) + number of variants
  • Purity target (e.g., ≥95% / ≥98%) and salt form preference (if any)
  • Intended use: stability, binding, cell assay, diagnostic, control peptide, etc.
  • Special requests: solubility constraints, cysteine/disulfide needs, cyclization, labeling
If you have limited info

Send just the sequence + your goal (e.g., “increase protease resistance”). We can propose: (1) a minimal set of D-substitutions to test, (2) a matched L vs D control strategy, and (3) an efficient QC plan.

Commercial & project inquiries
Request a Quote Contact Us View D-AA list Decision guide
D-substitution planning L vs D matched controls Full D-peptides Retro-inverso options QC documentation

Not sure where to put the D-residue? Tell us the goal (e.g., “improve serum stability” or “protect this cleavage site”) and we’ll suggest practical substitution positions and a synthesis/QC plan.

Related peptide synthesis capabilities

Peptide Cyclization

Head-to-tail, side-chain, and disulfide strategies.

Unnatural Amino Acids

Expanded residue chemistries for SAR optimization.

Isotope-Labeled Peptides

13C/15N incorporation for quantitative analysis.

Recommended Reading

These peer-reviewed articles provide background on D-amino acid incorporation, stereochemical substitution, retro-inverso peptide design, and stability enhancement strategies.

Why Choose Bio-Synthesis

Trusted by biotech leaders worldwide for over 40+ years of delivering high quality, fast and scalable synthetic biology solutions.

Greetings Researchers,

Please be advised that any information, guidelines, writeups, and oral/video/graphic content on our website are intended solely as general guidelines.
It is the researcher's sole responsibility to conduct thorough research on the designs of the products intended for their experiments before submitting
their designs to Biosynthesis for review of production feasibility.
Thank you for your understanding.

Quick Links