Peptides are recently attracting more attention as a therapeutic class, offering a path to engage protein–protein interactions, GPCRs, and other challenging targets long considered out of reach for small molecules.

However, to realize their full potential, peptide programs require a different kind of chemistry approach, one that embraces complexity and enables meaningful molecular innovation, particularly through the integration of non-canonical amino acids (ncAAs) and backbone modifications and how these modifications subsequently affect conformation and tertiary structure.

This is where many discovery programs falter. And where the right chemistry partner becomes a strategic asset.

Peptide Therapeutics Are Here to Stay

Since the approval of insulin over a century ago, peptide drugs have steadily expanded their footprint in medicine. More than 80 peptide therapeutics have been approved for clinical use as of 2022, with global sales surpassing $70 billion in 2019, more than double that of over a decade ago (Wang et al., 2022).

The appeal is obvious:

• High selectivity and receptor affinity, reducing off-target effects
• Favorable safety profile, as peptides degrade into natural amino acids
• Versatility, capable of binding shallow or extended interaction surfaces
• Compatibility with conjugation technologies, such as ADCs and peptide-drug conjugates

Yet these strengths are only accessible when paired with chemistry capable of keeping pace with molecular complexity.

Why Peptides Still Struggle in Development

Despite widespread interest, peptide therapeutics face persistent development hurdles:

• Low oral bioavailability and short half-life due to proteolysis
• Limited permeability, often requiring parenteral administration
• Synthetic complexity, especially for heavily modified, constrained or sequences prone to aggregation
• Challenges in introducing chemical diversity, due to reliance on the 20 canonical amino acids, limited availability of substituted canonical amino acid derivatives, and/or functional groups incompatible with solid-phase synthesis protocols

Addressing these issues demands more than access to classical solid-phase synthesis, it calls for next-generation chemistry and a broader set of building blocks.

Non-Canonical Amino Acids: Expanding What’s Possible

To overcome these limitations, drug developers are increasingly turning to non-canonical amino acids (ncAAs). These include N-alkylated residues, β-amino acids, D-amino acids, and peptoid-like structures, which offer a path to:

• Improve proteolytic stability and half-life
• Enhance permeability and conformational constraint
• Explore novel chemical space and expand IP potential
• Enable orally bioavailable peptide therapeutics

As noted by Hickey et al. in ACS Medicinal Chemistry Letters (2023), pushing beyond the standard amino acid set is “essential to advance peptide drug discovery into the next decade” (Hickey et al., 2023).

Delivering Complexity with Purpose-Built Chemistry

At Sygnature Discovery, we have built a peptide chemistry platform that enables real progress—whether you’re engineering macrocycles, incorporating ncAAs, or looking for solutions where others have failed.

Our approach combines:

• Solid- and solution-phase peptide synthesis
• Custom synthesis of canonical and non-canonical amino acids
• Side chain and backbone derivatization
• Access to a large internal library of modified building blocks
• Cross-functional support from bioscience (GPCR), DMPK, and CADD experts

To scale this capability and increase throughput, we now operate a state-of-the-art automated peptide synthesizer (CEM Multipep 2), allowing rapid parallel synthesis while maintaining flexibility for non-automated, expert-driven chemistry where needed. Peptides can be prepared as single entities or in 96-well plate format allowing quick identification of a lead compound.

However, there are some things robots cannot do, especially when it comes to sterically hindered residues, novel linkers, or purification of complex sequences. That’s where our scientists step in.

Betsylated Amino Acids: A New Tool for Advanced Peptide Design

A recent innovation from our team involves improved access to and applications of betsylated amino acids (Bts-AAs), versatile tools for:

• N-alkylation and backbone modification
• Macrocyclization strategies via Mitsunobu chemistry
• Enhanced conformational constraint for SAR studies

Originally developed by Vedejs (University of Wisconsin-Madison) and used by Tranzyme Pharma and Panagene for macrocyclic peptide and PNA development, Bts-AAs had been limited by hazardous reagents for preparation and corresponding storage challenges [(Vedejs, 1996); USP 5,900,427].

We’ve developed a safer, in situ generation method using aqueous buffered sodium hypochlorite, removing the need for elemental chlorine and allowing simplified purification without chromatography in most cases.

This approach enables fast access to SPPS-ready ncAAs with high chemical purity and without epimerization. More importantly, Bts-AAs can be readily incorporated into Fmoc- and Boc-SPPS workflows.

From Custom Building Blocks to Drug-Like Peptides

What does this mean for your project?

It means:

• Faster access to constrained or alkylated peptide analogs
• Scalable synthesis of modified libraries for SAR
• Purity-driven workflows supported by RP-HPLC and preparative SFC
• End-to-end support to evaluate permeability, solubility, and in vivo stability early, reducing surprises later

Whether you’re optimizing a known binder, exploring a new peptide modality, or looking to rescue a stalled program, our peptide chemistry team offers the flexibility and insight to move your idea forward.

Conclusion: Peptide Innovation Demands More Than Automation

The resurgence of peptides in drug discovery isn’t hype, it’s a response to real clinical need and the therapeutic possibilities peptides uniquely offer.

But peptide complexity cannot be solved by automation alone. It requires flexible, human-led chemistry, built on the right tools, the right cross-functional expertise, and a mindset that embraces challenge.

At Sygnature Discovery, we’ve designed our platform to do exactly that, from synthesis to purification, from design to data.