"Bacteria are brilliant chemists"

Peptides make powerful drugs, but they are difficult to synthesize. The pharmaceutical company Johnson & Johnson teams up with VIB experts to explore how to harness the biosynthetic creativity of microbes to make peptide mass manufacturing more cost-effective and sustainable. ​

Peptides are taking the therapeutic space by storm. We have all heard of the obesity wonder drugs Ozempic and Wegowy, originally developed to help diabetes patients; but other peptide-based drugs like Copaxone (to treat relapsing MS) or Lupron (for endometriosis) have also reached ‘blockbuster’ status, generating more than a billion euro in annual revenue.

From cancer to heart disease, metabolic disorders, or immune disease, drug developers are increasingly looking at peptides as the go-to therapeutic modality. Successful peptide drugs typically act as agonists, replacing naturally missing or low-abundant hormones or other regulators. They combine the advantages of small molecules—high specificity, efficacy, and safety—with those of biologics—low immunogenicity and membrane permeability.

Finetuning therapeutic peptides with non-natural amino acids

Therapeutic peptides often incorporate non-natural amino acid building blocks to further expand the possibilities offered by combining the twenty naturally occurring amino acids. These modified amino acids can be used to introduce new chemical functionalities that improve the peptide’s stability or efficacy, or its resistance to enzymatic degradation.

Non-natural amino acids allow, for example, to create peptides that remain active in the bloodstream for longer, or that bind with more specificity to their targets. New computational approaches greatly facilitate the search for increasingly stable peptide designs, however creating them quickly becomes tricky.

Contrary to peptide drugs like insulin or Semaglutide (the active compound of Ozempic and Wegowy), which consist entirely of natural amino acids and can be produced through recombinant biotechnology, therapeutic peptides that contain a mix of natural and non-natural amino acids require synthetic approaches, such as solid or liquid-phase peptide synthesis. It’s already clear that neither of these approaches will be able to cover the huge projected rise in demand.

Mass manufacturing synthetic peptides

Nico Vervoort is Director of High Throughput Experimentation at J&J Innovative Medicine. He knows like no other that bringing a new drug to market involves much more than just finding the right molecule. “We need to figure out how to synthesize new drug candidates in a scalable, sustainable, and cost-effective way. We need to ensure the process can be transferred across production plants and so on.”

This part of drug development typically takes pharma players years to complete. Major regulatory challenges need to be met in the process, and the competition is fierce.

For peptides specifically, more efficient production routes will be needed to make these drugs affordable at scale.

“Current methods have limitations in terms of cost and sustainability. They are very resource-intensive, generate a lot of waste, and have a high process mass intensity. The latter is a measure of all materials used within a pharmaceutical process, including reactants, reagents, solvents (used in the reaction and purification), and catalysts. The many cycles of protection and deprotection steps, along with chromatographic purification steps, make it all very expensive.”

That is why, as Scientific Director of High-Throughput Experimentation, Vervoort and his team are looking into biocatalysis as a way to leverage the high specificity of enzymes to create a diverse spectrum of peptides and proteins.

“The biocatalysis group at J&J explores how to make different peptides enzymatically. It's a very complex problem, and we turned to experts at VIB to help us discover new, alternative enzymes that could enable us to synthesize specific types of peptides.”

More specifically, the company reached out to Joleen Masschelein, group leader at the VIB-KU Leuven Center for Microbiology.

Biocatalysis: more cost-effective and sustainable

“Bacteria are brilliant chemists,” says Masschelein, whose team is focused on the many potentially useful biocatalytic processes that have yet to be discovered in different bacterial species.

“Bacteria can make the most impressive, complex compounds with remarkable ease. We study how they create secondary metabolites and characterize the enzymes they employ. Often, these enzymes are relatively promiscuous and can couple even unnatural substrate analogs.”

Masschelein and Vervoort have teamed up to develop more efficient biotransformation approaches that could give the Belgian pharmaceutical industry a competitive edge.

While developing and integrating biocatalytic processes in commercial manufacturing will be vital for a knowledge-based bioeconomy like Flanders, Vervoort stresses that cost-effectiveness is only part of the story. “First and foremost, we need to find more sustainable synthetic approaches.”

Conventional chemical processes rely on metal catalysts and strong acids, and they use energy-intensive processes that require high temperatures and pressures.

Biocatalysis is based on renewable resources, like sugars, and employs biodegradable enzymes produced through sustainable fermentation. These enzymes catalyze reactions under mild conditions—ambient temperature, neutral pH, and aqueous solvents—minimizing energy and hazardous reagent use. Their high selectivity reduces side reactions and purification steps, making biocatalysis a greener, more efficient alternative for peptide synthesis.

A joint project with complementary expertise

To make their ambitious plans a reality, Vervoort and Masschelein have applied for funding through the VLAIO program of the Flemish government, designed to expand or enhance the R&D capacity of companies in Flanders through an academic collaboration [decision pending at the time of writing]. In a typical VLAIO mandate, both partners contribute something—knowledge, prior expertise, funding—and the government provides additional funding. The academic partner brings knowledge and resources, and the output is shared so that all parties benefit, allowing the results to be applied to other fields.

Masschelein has extensive knowledge of bacterial metabolic pathways and enzymes, as well as methods to find them in the genome, and characterize and engineer them. Vervoort and the team at J&J bring deep expertise in applying these enzymes in a productional setting and moving them forward into industrial processes.

“VLAIO makes it more feasible for us to invest in high-risk research and to establish connections with academic partners,” says Vervoort. Apart from the opportunity to connect with academic research, such collaborations also serve as a way to engage in talent development. “In projects like these, we can share our challenges with the academic world, and they can help us to address them. Ideally, we don’t just work with people or teams for two years, but hope to retain partnerships in some shape or form in the long term.”

Masschelein stresses the importance of funding channels such as VLAIO to get collaborations like this one off the ground. “I am very glad that programs like the Baekeland mandate for PhDs and VLAIO for postdocs exist to enable industrial collaborations. Without VLAIO, the collaboration with J&J in its current form would not have been possible."

On successful matchmaking

The initial contact that led to the collaboration was sparked via a shared connection in the VIB Innovation and Business team and evolved pretty organically from there, recalls Masschelein.

“The team at J&J was interested in our capabilities and immediately came up with several projects and questions. It made me realize that as academics, we sometimes don’t even realize the possible application routes for our work and the variety of problems we could assist with." Masschelein is grateful for the help she got from VIB Innovation & Business. “Especially for a relatively new lab like ours, still building a name for itself, their involvement has made a real difference."

Vervoort: “The advantage of working with VIB and KU Leuven is, of course, their close geographic proximity, which allows for more frequent interactions through VLAIO and similar initiatives. Conferences like those organized by VIB can also be helpful for getting in touch with research we might otherwise not come across. In the end, a strong personal network remains very beneficial,” he says.

Masschelein concurs. “Sometimes people ask me directly, ‘Do you know anyone at that company I could talk to?’ I advise anyone seeking to set up industrial research collaboration to just ask around in their network.”

In the absence of direct connections, she recommends getting in touch with institutional valorization officers like the Business Development team at VIB or the Leuven Research & Development Office. “They have the network. Make sure you highlight the unique aspects of your lab and where you think you can add value. It's important to present yourself well—industrial partners value efficiency and solution-oriented approaches; they want things to be practical and applied.”

J&J also creates space for its different teams to explore new academic partnerships, through the organization of its annual R&D Symposium, for example, or at knowledge-exchange and match-making events at the different Flemish universities. If there is a good scientific match, academic researchers are usually open to collaboration, says Vervoort: “Academic partners recognize the scientific challenge in the problems we present them. If there is a good match in expertise, that usually gets the ball rolling.”

Tapping into cutting-edge expertise

Vervoort: “For a company like ours, having a strong connection within the local academic network is crucial. At our site in Beerse, there are around 5,000 employees, many of whom have PhD degrees. We’re constantly on the lookout for people with the right expertise, from data scientists to people with expert knowledge on complex modalities such as cell and gene therapy.” ​

Knowledge evolves rapidly, and that also counts for developments in the biocatalysis space, he adds: “We have many chemists and engineers in our process development and supply teams. In the past, there wasn’t much demand for molecular biologists or enzymologists, but with biocatalysis becoming increasingly important, we need to recruit the relevant profiles. Naturally, it is much easier to recruit good talent in Flanders than internationally.”

It also means there is more and more overlap in scientific interest between the activities of J&J and VIB, says Vervoort: “While historically, there has been a lot of focus on small molecules and antibodies, we’re now seeing that modalities are becoming much more complex—oligo’s combined with peptides, antibodies with peptides—we’re increasingly moving towards life sciences.”

For Masschelein, industrial collaborations make for a rewarding addition to the research performed in her lab. “I find it fascinating to hear industry perspectives on developments in our field. Being able to work on projects that are much closer to clinical applications, like drug development, is a true enrichment to our work. It is great to see how our expertise can contribute directly to solving some of the practical challenges pharmaceutical developers face.”

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