The Importance of Noncanonical Amino Acids in Peptide Therapeutics

Overview

Peptide therapeutics are transforming the drug development landscape by offering favorable pharmacokinetic profiles, high specificity, and access to previously undruggable targets. However, their full potential hinges on the ability to explore molecular space that simply isn’t accessible with canonical amino acids alone.

Noncanonical amino acids (ncAAs) dramatically expand the toolkit for developing peptide- and peptidomimetic-based therapeutics. By introducing chemical functionalities not found in the standard 20 amino acids, ncAAs enable precise control over a peptide’s structure, stability, and biological activity. They also provide chemical handles for bioconjugation, introduce structural constraints that lock in bioactive conformations, and help improve cell permeability or oral bioavailability, particularly when combined with formulation strategies.

This isn’t a new idea; ncAAs have long played a role in both synthetic and natural peptide drugs.  Examples span decades: from octreotide (approved 1998, three ncAAs) to modern GLP-1 analogs like semaglutide (approved 2017, one ncAA) and tirzepatide (approved 2022, two ncAAs). What has changed is the scale and sophistication of ncAA use. Today, more than half of approved and clinical-stage peptide-based drugs contain at least one ncAA, and in some cases, ncAAs make up the majority of residues. Once seen as an advanced feature, ncAAs are now a foundational element of modern peptide drug design.

The Use of ncAAs in Drug Discovery

Noncanonical amino acids are a powerful tool in modern peptide drug discovery. The ability to access new chemical space allows discovery teams to generate higher-quality hits, access new therapeutic targets, and overcome common limitations in peptide therapeutics such as poor stability, solubility, or selectivity.

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In Silico Design

Modern computational approaches, such as Rosetta and deep-learning models, can screen ncAA-containing libraries in silico that would be impractical to build and test experimentally. While expanded chemical space offers clear value, these predictions only become meaningful if the corresponding ncAAs can be synthesized and validated. In addition, current models are limited by sparse training data on ncAAs, both as individual residues and within longer peptide sequences. To reach their full potential, in silico methods depend on fast, flexible access to a diverse ncAA toolbox.

Display Technologies

Phage, mRNA, and synthetic display platforms now support libraries containing millions to trillions of unique peptides per round. Large libraries increasingly contain ncAAs to explore backbone-modified scaffolds, reactive side chains, and post-translational mimics, significantly broadening functional diversity. These affinity-based screens have been particularly powerful for discovering macrocyclic peptides.

Other Screening Strategies

In addition to display and in silico methods, solid-phase peptide synthesis (SPPS) enables the construction of high-diversity combinatorial libraries with full control over stereochemistry, backbone modifications, and macrocyclization. These libraries are often used in parallel with biochemical assays, biophysical screens, or structural analyses. Fragment-based design also benefits from ncAAs to introduce conformational bias, non-natural linkages, or covalent reactivity to expand what’s possible in early-stage discovery.

Lead Optimization

Once a hit is identified, ncAAs provide critical tools for tuning structure–activity relationships. They can be used to modulate selectivity, increase proteolytic stability, enhance pharmacokinetics, or introduce imaging and labeling handles for target engagement studies. These modifications often unlock drug-like properties that are difficult to achieve with canonical residues alone, accelerating the transition from hit to lead to candidate.

ncAAs in Development & Manufacturing

Translating an early-stage hit into a manufacturable therapeutic requires practical chemistry. While the synthetic challenges once associated with noncanonical amino acids were a major bottleneck, today they are increasingly manageable. 

Amino Acid Synthesis

Traditional chemical synthesis of ncAAs is well established. Common methods typically rely on chiral auxiliaries, asymmetric catalysis, or multi-step protecting group strategies. These approaches are flexible and modular, but tend to be step-intensive, solvent-heavy, and dependent on specialized reagents. Such process constraints may limit the diversity of ncAAs that are accessible through purely chemical means.

Biomanufacturing offers a compelling alternative. Enzyme-driven synthesis delivers high chemical and stereochemical purity under mild, water-based conditions, with fewer steps and less waste. These methods can reduce CO₂ emissions, energy use, and process mass intensity by up to 100×, while also cutting costs, simplifying downstream purification, and enabling on-demand production. As biocatalysis continues to evolve, it’s redefining what’s possible in the scalable production of complex building blocks like ncAAs.

Peptide Synthesis

Regardless of how they’re made, many ncAAs are now readily available in protected forms compatible with solid-phase peptide synthesis (SPPS). For more complex residues, tailored coupling strategies or orthogonal protection schemes can be applied without major disruption. 

On the biological side, genetic code expansion and engineered tRNA/aaRS systems have enabled site-specific incorporation of ncAAs into recombinant proteins. While still emerging, these technologies are steadily becoming more viable at scale.

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Challenges with ncAAs in Peptide Therapeutics

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While the benefits of noncanonical amino acids are well established, they also introduce practical challenges across discovery, development, and manufacturing. The table below outlines some of the most common issues that teams encounter when working with ncAAs in peptide therapeutics.

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Aralez Bio: Your Noncanonical Partner

The benefits of noncanonical amino acids are clear, but so are the challenges. At Aralez Bio, we focus on making the right ncAAs accessible, scalable, and sustainable for real-world use. With our unique enzyme platform, we can support peptide innovation at all stages of development.

Access to hard-to-find building blocks

Over 70% of our portfolio is made up of ncAAs that aren’t commercially available anywhere else. If you’re working with rare or custom residues, we can apply our flexible enzyme platform to deliver it without derailing your development timeline.

Scale without surprises

Many ncAAs are available only in milligram quantities during early-stage research. Our platform is designed for continuity: the same processes we use for discovery-scale production also support clinical and commercial supply, helping you avoid costly redesigns.

High quality products

We specialize exclusively in amino acid chemistry. Our materials come with clear specifications, impurity profiles, and documentation designed to eliminate sourcing guesswork.

Sustainable by design

Our biocatalytic processes dramatically reduce CO₂ emissions, energy use, and process-mass intensity (PMI) compared to traditional chemical routes—helping you build a cleaner, more resilient pipeline.

Resilient, domestic manufacturing

As the only US-based manufacturer focused on ncAAs for therapeutics, we offer a secure, transparent supply chain that supports speed, control, and long-term planning.

Whether you're optimizing a lead or preparing for scale-up, we help you move faster by delivering the building blocks you need.

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