Peptides, Automation and Algorithms

INTRODUCTION

Dear Community,

If you’re a regular reader of Synthesis, you know that Matt Bio usually sets the stage with his expert perspective. This month, with Matt featured front and center in both THE LEAD REACTION and THE SIDEBAR, I’m delighted to step in and pen the introduction for Issue 5, a deep dive on tides.

The energy around peptide science is truly palpable, as seen in the energy and discussions emerging from TIDES 2026 in Boston earlier this month. What’s most inspiring is how recent breakthroughs are expanding the boundaries of medicine, offering new hope for conditions that once seemed out of reach. As researchers continue to push the science forward, I see the potential to transform patient outcomes and bring novel therapies to those who need them most.

Thanks so much for being part of our community. I hope you find something helpful or inspiring in this newsletter, and that it helps you connect with others who share your passion for science. I invite you to dive into Matt’s insights and the wealth of expertise in this edition.

Best wishes,
Thomas Loewald

THE LEAD REACTION

Making Waves in Peptide Synthesis

Synthesis sits down with Matt Bio, Chief Scientific Officer, Cambrex & President, Snapdragon Chemistry.

Earlier this month at TIDES 2026 in Boston, there was a workshop entitled: “The Next Wave of Innovation in Peptide Manufacturing.” What does this next wave look like to you?

I’d say we’re very much in the middle of the current wave of transitioning from solid-phase peptide synthesis (SPPS) to liquid-phase peptide synthesis (LPPS). It’s going to be an ongoing process that will take 5–10 years, I believe.

Beyond that, peptide crystallization is becoming very important (see THE CATALYST for my thoughts on a recent paper from Eli Lilly). Thinking more specifically in terms of synthesis, if I look further out and consider what’s happening in academia, cell-free omniligase enzymatic approaches for putting together peptides are rapidly emerging. There are also innovations on the synthetic side; Merck published a fascinating paper on unprotected amino acid couplings (again, check out THE CATALYST).

What I like about both of these approaches is that they rely on traditional equipment, so you’re not locked into a specialty facility. I believe that both of these areas will continue to evolve and, hopefully, spin up into viable manufacturing…

To find out Matt’s thoughts on microbial recombinant production, macrocyclic peptides, analytical algorithms, regulatory starting materials and more, read the full interview here.

THE METHOD

Automation and algorithms

TIDES (oligonucleotides and [poly]peptides) are an exciting and growing sector of the pharmaceutical industry. But complex synthetics are not without challenges. Higher production costs (driven up by waste and scalability issues), greater difficulties in process development and less than straightforward analytical characterization can all hamper forward momentum.

Fortunately, automation coupled with algorithmic optimization (whether Bayesian or SNOBFIT) is on hand to enhance efficiency in key areas, says Adrian Amador, Director of Chemistry at Snapdragon Chemistry, in a recent webinar.

In terms of algorithm-driven auto-optimization of reaction conditions, Adrian details several advances that have culminated in the development of a fully automated liquid phase peptide synthesizer. Developed to eliminate the bottleneck of LPPS process development, the automated platform has already been used to identify problematic reaction steps, assess materials for testing fragment assembly, determine solubility of peptide fragments and generate material to screen for isolation points, crystallizations and more.

The utility of the “LPPS Peptimizer™” is showcased using the example of tirzepatide fragment 5, with in-process control HPLC, tracking successful synthesis from the dimer through to the final 14mer. Impressively, synthesis at the 35 gram scale resulted in only 20 liters of waste (of which over 75 percent was water) – orders of magnitude less waste than the equivalent solid phase peptide synthesis process.

In the final part of the webinar, Adrian explores algorithm-driven auto-optimization of another time-consuming and costly task: HPLC method development. Adrian’s team uses a two-pronged attack: i) automated column and mobile phase screening, followed by ii) algorithmic optimization of the best performer in screening. The approach can also be coupled with automated impurity synthesis, which reliably generates process-relevant markers (such as deletions, double additions and epimers).

In the accompanying case study, the approach fully resolves two critical pairs in 40 experimental iterations despite a theoretical design space of over 1700 combinations. Put another way, work that would have taken four weeks using traditional means was completed in just two days.

Adrian concludes by stating that when it comes to development of complex therapeutics, the combination of algorithm prediction tools, algorithmic optimization and automation is invaluable.

Watch the full webinar.

THE CATALYST

What Matt Bio is reading…

Alongside academic partners at Imperial College London, Eli Lilly colleagues just published a paper (DOI: 10.1107/S2053230X26001937) outlining a systematic approach to identifying peptide crystals and intermediates, which offers an opportunity to move away from purification of peptides using environmentally challenging chromatography. Specifically, the research team obtained what they believe to be the first crystal structure of a GLP-1 and GIP analogue lipopeptide using a “microseed matrix-screening protocol.”

Though peptide synthesis using unprotected amino acid coupling was explored many, many years ago, it was somewhat set aside because of inherent challenges and limitations. But now, thanks to better (bio)catalysts, more advanced tools and improved understanding of such couplings, Merck & Co researchers (over 100 of them!) clearly believe the approach is worth revisiting. The authors report the convergent assembly of a complex macrocyclic peptide (enlicitide), using engineered enzymes to catalyze selective fragment formation, coupling and macrocyclization – all without the need for protecting groups. Linking back to the Eli Lilly research above, the team also demonstrated efficient crystallization to remove chromatography from the equation. Certainly, if we can build up peptides in an aqueous or partially aqueous medium with no protecting groups at all, it would be a huge innovation in the field of peptide synthesis.

THE SIDEBAR

Accelerating peptides through smarter synthesis

There's a whole wave of promising peptide drugs coming in behind semaglutide that don't have a home because manufacturing capacity is limited by solid phase synthesis. By leveraging liquid phase peptide synthesis, we can help get those really valuable molecules to market fast.