The ERC Starting Grant is one of Europe's most competitive and prestigious funding schemes, supporting outstanding early-career researchers pursuing ambitious, high-risk, high-gain research.

Custom-made materials that behave like biological molecules

Metal-peptide frameworks are microscopic structures formed when short peptides connect to metal ions and assemble into an ordered network. By changing the peptide building blocks or the metals used, researchers could create materials with tailored properties, from speeding up chemical reactions to conducting electricity.

While metal-peptide frameworks have shown promise as highly versatile materials, discovering new frameworks currently relies on slow and laborious chemical synthesis.

To address this, the project will harness a specially engineered bacterial strain with an expanded genetic code that allows the incorporation of non-canonical amino acids, molecular building blocks not found naturally in living organisms. By programming cells to produce diverse libraries of metal-binding peptides, the team aims to accelerate the discovery of entirely new materials that can self-assemble and be optimised through directed evolution.

The research could open up new possibilities for designing biological materials that combine the sophisticated functions of proteins with the scalability and accessibility of synthetic materials. In the longer term, these materials could be engineered to act as sustainable biocatalysts, conductive biological components or multifunctional biomaterials with applications across biotechnology and green manufacturing.

The project builds upon Martin’s previous work in synthetic genomics and genetic code expansion, an area of synthetic biology that enables researchers to introduce new chemical building blocks into living organisms. His previous research has helped expand the range of molecules that can be genetically encoded.

By combining these capabilities with materials science, the ERC-funded research aims to establish metal-peptide frameworks as an entirely new class of evolvable biomaterials. Researchers hope that understanding how these structures form and function could eventually enable the development of materials capable of coupling renewable energy sources with biological processes, contributing to future sustainable technologies and a circular bioeconomy.

Fighting antimicrobial resistance

Dr Will Smith has been awarded a University Research Fellowship to investigate how microbes deploy and evolve multiple weapons during competition with one another. His project, the evolution of multi-weapon fighting in microbes, will combine computational modelling, laboratory experiments and large-scale genomic analysis to reveal the rules governing microbial conflict.

Although antibiotics have transformed modern medicine, they represent just one example of the sophisticated weaponry that microbes use against their rivals. Bacteria can inject toxins directly into neighbouring cells using microscopic harpoons, fire toxic protein weapons, or deploy virus-derived nanomachines capable of destroying competitors from a distance.

Scientists have made major advances in understanding how many of these weapons work at the molecular level. However, a fundamental mystery remains: why do bacteria invest in multiple weapons rather than relying on just one? Will’s research aims to answer that question.

Choosing the most effective defence

Using Pseudomonas bacteria – a medically important group known for its diverse arsenal – he will investigate when different weapons are most effective, how they interact with one another, and whether carrying several weapons helps microbes adapt to changing environments and opponents. The project will also explore how rival bacteria evolve resistance, and whether combinations of weapons can make it harder for resistance to emerge.

The findings could have implications far beyond understanding microbial ecology. By uncovering the evolutionary logic behind bacterial weapon systems, the work could inform the development of new antimicrobial approaches and more resilient biocontrol technologies.

The fellowship will support an ambitious five-year programme of research examining how bacterial arsenals evolve, how different weapons perform under different environmental conditions, and which combinations are most resistant to evolutionary counter-attacks. The project will draw on expertise in evolutionary biology, microbiology, genomics and mathematical modelling to build a comprehensive picture of how microbial conflicts shape the communities that surround us. Will says of the award “I'm absolutely thrilled to receive this award, and I couldn't have done it without the amazing support Manchester has given me during my Sir Henry Wellcome Fellowship."

Ultimately, Will hopes the research will help scientists predict competitive interactions within microbial communities and develop new ways of harnessing beneficial microbes for applications in health, biotechnology and agriculture. His long-term vision is to understand how microbial weapons and defences co-evolve, opening the door to new generations of antimicrobials designed to remain effective for longer in the face of resistance.

But studying glycans has a major challenge: because many glycans are highly water-soluble, or hydrophilic, they cannot easily cross the cell membrane and must be modified with a hydrophobic moiety – a water repelling chemical group – and prepared and delivered with potentially harmful solvents.

Professor Matthew Gibson and his team have now demonstrated a new approach using a small super chaotropic nanostructure made of boron to transport these molecules directly into mammalian cells, crucially removing the need for cytotoxic organic solvents such as dimethyl sulfoxide (DMSO).

Delivering the sugars to programme cell surfaces

One widely used technique for studying glycans is metabolic oligosaccharide engineering, where modified sugars carrying a chemical ‘handle’ are introduced into cells. These sugars, specifically designed to be tracked and followed through the cell, allow researchers to investigate their biological functions. But, as these sugars are hydrophilic (water-loving), the hydrophobic cell membrane prevents them from passing through.

To combat this, the research team used the new boron delivery method, to introduce the unnatural sugars into the cell where they were metabolised and used to ‘edit’ the surface of the cell. The ‘handle’ from the modified glycan, now on the cell surface, can be used to potentially reprogramme or add new cell functions.

The researchers also used the technique to investigate recently discovered glycoRNA – RNA molecules associated with glycans which have only recently been discovered.

A cleaner delivery service for glycans

By removing some of the practical barriers associated with intracellular glycan delivery, the researchers believe the approach could provide new opportunities across glycobiology and cell-surface engineering, as well as related areas including autophagy, cryobiology and infection research.

Future research will focus on increasing the amount of glycan that can be transported into cells, with the aim of matching the delivery performance of existing acetylation-based methods.

Published in Nature Catalysis, the research addresses a long-standing challenge in chemistry: developing biological catalysts that can selectively construct complex molecular architectures. Carbon-carbon and carbon-nitrogen bonds are fundamental building blocks in many chemicals, pharmaceuticals and advanced materials.

To expand upon the reaction pathways found in natural enzymes, the researchers engineered proteins containing a non-natural catalytic amino acid. This facilitated the development of a new enzyme class, termed allylic transferases, which form highly reactive imidazolium intermediates that could then be intercepted by a variety of carbon- and nitrogen-containing molecules, selectively producing a diverse range of products.

The team used directed evolution to improve enzyme performance. One evolved variant, known as ASB1.3, achieved more than 99% conversion in several reactions while delivering products with high stereochemical purity. In a preparative-scale reaction, the enzyme produced the target compound with 98% conversion.

A second enzyme variant, ASA1.5, enabled the formation of molecules containing all-carbon quaternary stereocentres, structures that can be challenging to synthesise selectively. In preparative-scale experiments, the enzyme achieved 98% conversion.

The researchers demonstrated that the engineered enzymes could work with a broad range of reaction partners, including substituted furans, indoles, pyrroles, cyanoesters, diketones, ketoesters, anilines and isatins. Across the reactions examined, the enzymes generated a single major product with no observable by-products other than the released leaving group used for monitoring the reaction.

Expanding the biocatalysis toolbox

Structural analysis also provided new insights into how the enzymes achieve their selectivity. The team found evidence that a para-nitrophenol group released during the reaction remains in the enzyme active site and helps orient incoming reactants, contributing to stereoselective bond formation.

While further development will be needed before these enzymes can be applied more widely, the study expands the range of chemical transformations available through biocatalysis. The study highlights how engineered protein catalysts can provide new ways to access molecular structures that are difficult to produce using established small-molecule catalysts.

First author Zachary Birch-Price said:

Scientists have long tried to replicate this behaviour using synthetic materials, but most designs have focused on how molecules interact with ice at their surface.

In a study published in Chemical Science, the team – led by Professor Matthew Gibson –  have shown for the first time that the internal structure of polymer nanoparticles, rather than their outer surface, plays a key role in controlling ice growth. This was a collaboration with Professor Steve Armes FRS at Sheffield Univeristy.

Looking inside the particle

The team created a library of polymer nanoparticles using a scalable technique known as polymerisation‑induced self‑assembly. These particles consist of a water‑exposed outer layer and a hidden inner core.

Surprisingly, the researchers found that changing the chemistry of the inner core dramatically altered how effectively the particles inhibited ice recrystallisation – the process by which ice crystals grow larger over time.

Particles with “soft” cores showed significantly higher activity, strongly suppressing ice growth, while those with more rigid cores were less effective.

Even more strikingly, chemically locking the core structure removed this activity entirely.

A new design principle

The findings challenge the conventional view that only the surface of a material interacts with ice. Instead, they show that internal mobility and structure within nanoparticles can influence how ice crystals behave.

The study suggests that individual polymer chains within the particles may play a role in interacting with ice as conditions change during freezing and thawing.

Applications from medicine to materials

Materials that control ice growth are important in a wide range of applications, from preserving cells and tissues to improving the texture of frozen foods and developing anti‑icing coatings.

By providing a new way to design these materials, the research opens up opportunities to develop more effective, scalable and cost‑efficient alternatives to natural antifreeze proteins.

The work also establishes a broader framework for designing functional nanoparticles, showing that internal structure can be as important as surface chemistry in determining performance.

The study, published today in the Journal of the American Chemical Society (JACS), describes how the research team, led by Professors Anthony Green and Nick Turner, used directed evolution to develop a bespoke aminotransferase, a type of enzyme, to significantly accelerate the manufacturing process and reduce production costs. This new biocatalytic route has the potential to improve global access to this important medicine.

Lenacapavir, recently approved by the FDA and MHRA, is a twice‑yearly injectable drug that has shown extremely high levels of protection in pre‑exposure prophylaxis (PrEP) trials. Royalty‑free licence agreements are already in place to enable generic manufacturers to supply Lenacapavir to 120 lower‑income countries, yet the high cost of producing its active pharmaceutical ingredient remains a major barrier to widespread availability.

A sustainable route to a complex molecule

Made up of four distinct building blocks, Lenacapavir’s highly functionalised central core is a very challenging building block to synthesise. This core is constructed from a chiral amine that can exist in two mirror-image forms (like a left and a right hand). The handedness – or chirality – is important in pharmaceuticals as only one form of the molecule will work as intended.

Currently, Lenacapavir is made via traditional multi-step chemical synthesis, but due to the central core’s chirality and challenging molecular structure it is a costly and time-consuming process. Biocatalysis offers significant potential for faster and cheaper production.

To achieve this, the MIB team focused on using directed evolution – a method that speeds up nature’s trial-and-error evolution process – to develop an enzyme that could catalyse the target reaction to produce the chiral amine core. Using an approach known as substrate walking, the researchers began with an aminotransferase that showed no detectable activity on the desired substrate. Over eight rounds of directed evolution, involving screening more than 12,000 enzyme variants, they installed ten mutations that progressively unlocked activity, improved stability and reshaped the active site of the enzyme so that it could accept the central amine core’s bulky ketone precursor.

The final enzyme performed exceptionally well, converting 98% of the starting substrate, producing a yield of more than 90% with a purity of over 99% enantiomeric excess (e.e.) meaning that the correct chiral form was produced. The researchers also tested the enzyme under industrially relevant conditions showing its potential to work at scale.

The team also used X-ray crystallography to create a detailed 3D picture of the improved enzyme showing how the molecular changes arising from evolution allowed the enzyme to accept the substrate and transform it into the target product. Understanding the enzyme’s structure helps scientists unpick its mechanism of action which allows them to improve future enzyme design campaigns.

Towards large‑scale implementation

The team is now collaborating with industrial partners to translate the methodology from laboratory scale to industrial biomanufacturing. The details of this new manufacturing route are also freely available for companies to use. Any company interested in producing Lenacapavir via this new process can contact Prozomix to request free samples of the enzyme. If implemented at scale, the process could enable a shorter, cleaner and more economical production route for Lenacapavir, supporting ambitions to make long‑acting HIV prevention accessible worldwide.

Sulfonamides are a cornerstone of modern medicinal chemistry, forming part of many antibacterial, anticancer and antiviral medicines. Yet despite their widespread use, producing sulfonamides synthetically can be difficult, often requiring harsh reagents and generating environmentally damaging by‑products. Natural examples of sulfonamide‑containing molecules are extremely rare, and until now very little was known about how biological systems make them.

International collaboration cracks the code

The international research team – including computational chemist Dr Sam de Visser and PhD student Henrik Wong from the MIB – has uncovered how the enzyme SbzM enables bacteria to form sulfonamides as part of the biosynthesis of the natural product altemicidin. Their work shows that SbzM uses nickel, rather than the more common iron cofactor found in related enzymes, to convert the amino acid L‑cysteine into a reactive sulfonamide intermediate.

Using a combination of structural biology, biochemical assays and advanced quantum‑mechanical computational modelling, the researchers showed that SbzM performs chemistry never before observed in nature. The study reveals:

• SbzM is strictly nickel‑dependent, requiring Ni²⁺ to function and cycling between Ni²⁺ and Ni³⁺ during the reaction.
• Two separate oxygen molecules are incorporated into the final sulfonamide product, a striking contrast to iron‑based cysteine dioxygenases, which use a single oxygen molecule.
• A previously unknown reaction pathway is at work: the enzyme first triggers an oxidative decarboxylation step to form a mercaptoimine intermediate, followed by sequential oxygenation and rearrangement steps that ultimately build the sulfonamide group.
• The enzyme family is far more widespread in bacteria than previously recognised, suggesting nature may harbour many more yet‑undiscovered sulfonamide biosynthetic pathways.

Understanding how nature constructs sulfonamide motifs opens a realistic route to engineering enzymes capable of producing drug-like building blocks more sustainably. The Manchester team’s computational modelling was essential in mapping the step‑by‑step reaction mechanism and identifying why nickel, uniquely, drives this transformation, and by revealing the fundamental “instruction manual” behind sulfonamide formation, the study lays essential groundwork for creating scalable, low waste biocatalytic processes for pharmaceutical manufacturing.

The next steps will focus on expanding the range of molecules SbzM can process, enhancing its robustness, and demonstrating industrially relevant biocatalysis.

Meet the researchers

Sam de Visser Reader in Computational Chemistry at the Manchester Institute of Biotechnology, investigates inorganic mechanisms in first‑row transition‑metal enzymes using quantum chemistry and molecular dynamics, focusing on heme and nonheme iron enzyme reactivity.

• Email Dr de Visser >>
• View academic profile >>

Henrik Wong is a University of Manchester PhD student using molecular dynamics and quantum chemistry to study metal‑dependent enzymes and guide their redesign for sustainable biocatalysis, reaction discovery and improved biosynthetic applications.

• Email Mr Wong >>
• View academic profile >>

The research, published today in the journal, npj Parkinson's Disease, demonstrates that compounds or ‘volatiles’ found in sebum — the oily substance produced by our skin —hold key biomarkers for identifying Parkinson’s in its earliest stages.

Using a technique known as Thermal Desorption-Gas Chromatography-Mass Spectrometry (TD-GC-MS), scientists at The University of Manchester, in collaboration with Salford Royal NHS Trust and the Medical University of Innsbruck, analysed skin swabs from participants with Parkinson’s, healthy volunteers, and those with a sleep disorder called isolated REM Sleep Behaviour Disorder (iRBD) — a known early warning sign of Parkinson’s disease.

The results showed that people with iRBD had distinct chemical profiles in their sebum that were different from healthy individuals, but not yet as pronounced as those with established Parkinson’s disease. This supports the idea that Parkinson’s disease leaves a detectable trace on the body well before physical symptoms appear.

Joy Milne – the ‘super smeller’ who inspired the research  –  was also able to distinguish swabs from people with iRBD from the control group and Parkinson’s patients. Intriguingly, she was able to detect both diseases in two of the swabs that came from iRBD individuals, who were later diagnosed with Parkinson’s at their next clinical appointment, after sampling.

Professor Perdita Barran, Professor of Mass Spectrometry at The University of Manchester, said: “This is the first study to demonstrate a molecular diagnostic method for Parkinson’s disease at the prodromal or early stage. It brings us one step closer to a future where a simple, non-invasive skin swab could help identify people at risk before symptoms arise allowing for earlier intervention and improved outcomes.”

The study involved more than 80 participants, including 46 people with Parkinson’s, 28 healthy controls, and nine with iRBD.  They found 55 significant features in the sebum that varied between the groups. Those with iRBD often showed levels that sat between the healthy controls and the Parkinson’s group, reinforcing the possibility of detecting the disease in its early phase.

Dr Drupad Trivedi, a researcher from The University of Manchester, built a model that examined the markers in a longitudinal sampling study. He collected samples from Parkinson’s patients over a three-year period and found patterns that suggest this method can also be used to map the progression of the disease, which could have use in refining treatment options and improve patient outcomes.

Sebum is also easy to collect using gauze swabs from the face or upper back, making it ideal for non-invasive routine screening and regular monitoring. Previous research by the team has also shown it does not need to be stored in the same cold conditions as other biofluids, such as blood, reducing associated costs.

The research is inspired by the observations of Joy Milne, who detected a unique scent in individuals with Parkinson's disease, prompting researchers at The University of Manchester to explore sebum as a source of diagnostic biomarkers.

By using mass spectrometry, a technique that measures the weight of molecules, they have found that there are distinctive Parkinson’s markers in sebum, which has led them to develop this non-invasive swab test.

These findings have recently been validated in another paper, published today in the Journal of Parkinson’s Disease, where trained dogs were able to detect Parkinson’s in the patients recruited by Prof Barren and Dr Trivedi with remarkable accuracy by smelling skin swabs.

Now, the researchers are continuing to develop and improve the sebum-based testing to eventually use as a practical tool in real-world clinical settings.

Dr Drupad Trivedi, Lecturer in Analytical Measurement Sciences at The University of Manchester, said: "Our goal is to develop a reliable, non-invasive test that helps doctors detect Parkinson’s earlier, track its progression, and ultimately improve patient outcomes.

“We’re also keen to hear from other hyperosmic individuals, potential ‘super smellers’ like Joy, whose remarkable sense of smell could help extend our work to detect other diseases with potential odour signatures."

***

This research was published in the journal npj Parkinson's Disease

Full title: Classification of Parkinson’s Disease and idopathic REM Sleep Behaviour Disorder: Delineating Progression Markers from the Sebum Volatilome

DOI: 10.1038/s41531-025-01026-8

Link: https://www.nature.com/articles/s41531-025-01026-8

***

Biotechnology is enabling us to find new and more sustainable ways to produce chemicals, materials, and everyday products, by understanding and harnessing nature’s own processes and applying them at industrial scales. Supported by the Manchester Institute of Biotechnology, our 400+ experts are innovating solutions in environmental sustainability, health and sustainable manufacturing. Find out more about our biotechnology research.  

Enzymes are proteins that catalyse chemical reactions, turning one substance into another. In labs, scientists engineer these enzymes to perform specific tasks like the sustainable creation of medicines, and materials. These biocatalysts have many environmental benefits as they often produce higher product quality, lower manufacturing cost, and less waste and reduced energy consumption. But to find ‘the one’, scientists must test hundreds of variants for their effectiveness, which is a slow, expensive, and resource-intensive process.

Research conducted by The University of Manchester in collaboration with AstraZeneca is changing this. The team developed a method for a technique that can test enzyme activity up to 1,000 times faster than traditional methods. The new method, developed over the last eight years and detailed today in the journal Nature Protocols  is called DiBT-MS (Direct Analysis of Biotransformations with Mass Spectrometry).

It builds on an existing technology called DESI-MS (Desorption Electrospray Ionization Mass Spectrometry), a powerful tool that allows scientists to analyse complex biological samples without the need for extensive sample preparation. 

By making small adaptations to the technology, the scientists designed a protocol to directly analyse enzyme-triggered chemical reactions, known as biotransformations, in just minutes. The new method can process 96 samples in just two hours—tasks that would previously take days using older techniques.

It has also been optimised to allow the researchers to reuse sample slides multiple times improving testing efficiency and decreasing the use of solvents and plasticware.

The team has already successfully applied this technique to a range of enzyme-driven reactions, including those enzymes particularly valuable in the development of therapeutics.

Looking ahead, The University of Manchester will continue to explore ways to boost partnerships between laboratories and tackle other challenges that often hinder collaboration, such as geographical barriers and limited funding.

This research was partly funded by a UKRI Prosperity Partnership grant in collaboration with AstraZeneca.

Journal: Nature Protocols

Full title: Direct analysis of biotransformations with mass spectrometry—DiBT-MS

DOI: 10.1038/s41596-025-01161-9

Link: https://www.nature.com/articles/s41596-025-01161-9

Biocatalysis is a process that uses enzymes as natural catalysts to carry out chemical reactions. Scientists at The University of Manchester and AstraZeneca have developed a new biocatalytic pathway that uses enzymes to produce nucleoside analogues, which are vital components in many pharmaceuticals used to treat conditions like cancer and viral infections.

Typically, producing these analogues is complicated, time consuming and generates significant waste. However, in a new breakthrough, published in the journal Nature Synthesis, the researchers have demonstrated how a "biocatalytic cascade" — a sequence of enzyme-driven reactions — can simplify the process, potentially cutting down production time and reducing environmental impact.

The researchers engineered an enzyme called deoxyribose-5-phosphate aldolase, enhancing its range of functions to efficiently produce different sugar-based compounds, which serve as building blocks for nucleoside-based medicines, such as oligonucleotide therapeutics. These building blocks were combined using additional enzymes to develop a condensed protocol for the synthesis of nucleoside analogues which simplifies the traditional multi-step process to just two or three stages, significantly improving efficiency.

With further refinement, this method could help streamline the production of a wide range of medicines, while significantly reducing their environmental footprint. The team are now continuing this work with the MRC funded Nucleic Acid Therapeutic Accelerator (NATA) manufacturing challenge, which looks to develop sustainable biocatalytic routes towards functionalised nucleosides, nucleotides and oligonucleotides.

These findings have the potential to accelerate the discovery of novel, more efficient cryoprotectants - and may also allow for the repurposing of molecules already known to slow or stop ice growth.

Professor Matthew Gibson, from Manchester Institute of Biotechnology at The University of Manchester, added: “My team has spent more than a decade studying how ice-binding proteins, found in polar fish, can interact with ice crystals, and we’ve been developing new molecules and materials that mimic their activity. This has been a slow process, but collaborating with Professor Sosso has revolutionized our approach. The results of the computer model were astonishing, identifying active molecules I never would have chosen, even with my years of expertise. This truly demonstrates the power of machine learning.”

The full paper can be read here.

Sugars play a crucial role in human health and disease, far beyond being just an energy source. Complex sugars called glycans coat all our cells and are essential for healthy function. However, these sugars are often hijacked by pathogens such as influenza, Covid-19, and cholera to infect us.

One big problem in treating and diagnosing diseases and infections is that the same glycan can bind to many different proteins, making it hard to understand exactly what’s happening in the body and has made it difficult to develop precise medical tests and treatments.

In a breakthrough, published in the journal Nature Communications, a collaboration of academic and industry experts in Europe, including from The University of Manchester and the University of Leeds, have found a way to create unnatural sugars that could block the pathogens.

The finding offers a promising avenue to new drugs and could also open doors in diagnostics by ‘capturing’ the pathogens or their toxins.

Professor Matthew Gibson, a researcher from Manchester Institute of Biotechnology at The University of Manchester, said “During the Covid-19 pandemic, our team introduced the first lateral flow tests which used sugars instead of antibodies as the ‘recognition unit’. But the limit is always how specific and selective these are due to the promiscuity of natural sugars. We can now integrate these fluoro-sugars into our biosensing platforms with the aim of having cheap, rapid, and thermally stable diagnostics suitable for low resource environments.”

Professor Bruce Turnbull, a lead author of the paper from the School of Chemistry and Astbury Centre for Structural Molecular Biology at The University of Leeds, said “Glycans that are really important for our immune systems, and other biological processes that keep us healthy, are also exploited by viruses and toxins to get into our cells. Our work is allowing us to understand how proteins from humans and pathogens have different ways of interacting with the same glycan. This will help us make diagnostics and drugs that can distinguish between human and pathogen proteins.”

The researchers used a combination of enzymes and chemical synthesis to edit the structure of 150 sugars by adding fluorine atoms. Fluorine is very small meaning that the sugars keep their same 3D shape, but the fluorines interfere with how proteins bind them.

Professor Sabine Flitsch, a researcher from Manchester Institute of Biotechnology at The University of Manchester, said “One of the key technologies used in this work is biocatalysis, which uses enzymes to produce the very complex and diverse sugars needed for the library. Biocatalysis dramatically speeds up the synthetic effort required and is a much more green and sustainable method for producing the fluorinated probes that are required.”

They found that some of the sugars they prepared could be used to detect the cholera toxin – a harmful protein produced by bacteria – meaning they could be used in simple, low-cost tests, similar to lateral flow tests, widely used for pregnancy testing and during the COVID-19 pandemic.

Dr Kristian Hollie, who led production of the fluoro-sugar library at the University of Leeds, said: “We used enzymes to rapidly assemble fluoro-sugar building blocks to make 150 different versions of a biologically important glycan. We were surprised to find how well natural enzymes work with these chemically modified sugars, which makes it a really effective strategy for discovering molecules that can bind selectively.”

The study provides evidence that the artificial “fluoro-sugars” can be used to fine-tune pathogen or biomarker recognition or even to discover new drugs. They also offer an alternative to antibodies in low-cost diagnostics, which do not require animal tests to discover and are heat stable.

The research team included researchers from eight different universities, including Manchester, Imperial College London, Leeds, Warwick, Southampton, York, Bristol, and Ghent University in Belgium.

The breakthrough, published in the journal Nature, could significantly improve accessibility of essential protein-based drugs in developing countries where cold storage infrastructure may be lacking, helping efforts to diagnose and treat more people with serious health conditions.

The researchers, from the Universities of Manchester, Glasgow and Warwick, have designed a hydrogel – a material mostly made of water – that stabilises proteins, protecting its properties and functionality at temperatures as high as 50°C.

The technology keeps proteins so stable that they can even be sent through the post with no loss of effectiveness, opening up new possibilities for more affordable, less energy-intensive methods of keeping patients and clinics supplied with vital treatments.

Protein therapeutics are used to treat a range of conditions, from cancer to diabetes and most recently to treat obesity and play a vital role in modern medicine and biotechnology. However, keeping them stable and safe for storage and transportation is a challenge. They must be kept cold to prevent any deterioration, using significant amounts of energy and limiting equitable distribution in developing countries.

The medicines also often include additives – called excipients – which must be safe for the drug and its recipients limiting material options.

The findings could have major implications for the diagnostics and pharmaceutical industries.

Dave Adams, Professor at the University of Glasgow’s School of Chemistry, is one of the paper’s corresponding authors. He said: “In the early days of the Covid vaccine rollout, there was a lot of attention given in the news media to the challenges of transporting and storing the vaccines, and how medical staff had to race to put them in people’s arms quickly after thawing.  

“The technology we’ve developed marks a significant advance in overcoming the challenges of the existing ‘cold chain’ which delivers therapeutic proteins to patients. The results of our tests have very encouraging results, going far beyond current hydrogel storage techniques’ abilities to withstand heat and vibration. That could help create much more robust delivery systems in the future, which require much less careful handling and temperature management.”

The hydrogel is built from a material called a low molecular weight gelator (LMWG), which forms a three-dimensional network of long, stiff fibres. When proteins are added to the hydrogel, they become trapped in the spaces between the fibres, where they are unable to mix and aggregate – the process which limits or prevents their effectiveness as medicines.

The unique mechanical properties of the gel’s network of fibres, which are stiff but also brittle, ensures the easy release of a pure protein. When the protein-storing gel is stored in an ordinary syringe fitted with a special filter, pushing down on the plunger provides enough pressure to break the network of fibres, releasing the protein. The protein then passes cleanly through the filter and out the tip of the syringe alongside a buffer material, leaving the gel behind.

In the paper, the researchers show how the hydrogel works to store two valuable proteins: insulin, used to treat diabetes, and beta-galactosidase, an enzyme with numerous applications in biotechnology and life sciences.

Ordinarily, insulin must be kept cold and still, as heating or shaking can prevent it from being an effective treatment. The team tested the effectiveness of their hydrogel suspension for insulin by warming samples to 25°C and rotating them at 600 revolutions per minute, a strain test far beyond any real-world scenario. Once the tests were complete, the team were able to recover the entire volume of insulin from the hydrogel, showing that it had been protected from its rough treatment.

The team then tested samples of beta-galactosidase in the hydrogel, which was stored at a temperature of 50°C for seven days, a level of heat exceeding any realistic temperature for real-world transport. Once the enzyme was extracted from the hydrogel, the team found it retained 97% of its function compared against a fresh sample stored at normal temperature.

A third test saw the team put samples of proteins suspended in hydrogel into the post, where they spent two days in transit between locations. Once the sample arrived at its destination, the team’s analysis showed that the gels’ structures remained intact and the proteins had been entirely prevented from aggregating.

Matthew Gibson, Professor at The University of Manchester, is the paper’s other corresponding author. He said: “Delivering and storing proteins intact is crucial for many areas of biotechnology, diagnostics and therapies. Recently, it has emerged that hydrogels can be used to prevent protein aggregation, which allows them to be kept at room temperature, or warmer. However, separating the hydrogel components from the protein or proving that they are safe to consume is not always easy. Our breakthrough eliminates this barrier and allows us to store and distribute proteins at room temperature, free from any additives, which is a really exciting prospect.”

The team are now exploring commercial opportunities for this patent-pending technology as well as further demonstrating its applicability. 

Researchers from the University of East Anglia and Diamond Light Source Ltd also contributed to the research. The team’s paper, titled ‘Mechanical release of homogenous proteins from supramolecular gels’, is published in Nature.

The research was supported by funding from the European Union’s Horizon 2020 programme, the European Research Council, the Royal Society, the Engineering and Physical Sciences Research Council (EPSRC), the University of Glasgow and UK Research and Innovation (UKRI).

Peptides are comprised of small chains of amino acids, which are also the building blocks of proteins. Peptides play a crucial role in our bodies and are used in many medicines to fight diseases such as cancer, diabetes, and infections. They are also used as vaccines, nanomaterials and in many other applications. However, making peptides in the lab is currently a complicated process involving chemical synthesis, which produces a lot of harmful waste that is damaging to the environment.

In a new breakthrough, published in the journal Nature Chemical Biology, Manchester scientists have discovered a new family of ligase enzymes – a type of molecular glue that can help assemble short peptide sequences more simply and robustly, yielding significantly higher quantities of peptides compared to conventional methods.

The breakthrough could revolutionise the production of treatments for cancer and other serious illnesses, offering a more effective and environmentally friendly method of production.

For many years, scientists have been working on new ways to produce peptides. Most existing techniques rely on complex and heavily protected amino acid precursors, toxic chemical reagents, and harmful volatile organic solvents, generating large amounts of hazardous waste. The current methods also incur high costs, and are difficult to scale up, resulting in limited and expensive supplies of important peptide medicines.

The team in Manchester searched for new ligase enzymes involved in the biological processes that assemble natural peptides in simple bacteria. They successfully isolated and characterised these ligases and tested them in reactions with a wide range of amino acid precursors. By analysing the sequences of the bacterial ligase enzymes, the team identified many other clusters of ligases likely involved in other peptide pathways.

The study provides a blueprint for how peptides, including important medicines, can be made in the future.

Dr Guangcai Xuz, who also worked on the project said, “The ligases we discovered provide a very clean and efficient way to produce peptides. By searching through available genome sequence data, we have found many types of related ligase enzymes. We are confident that using these ligases we will be able to assemble longer peptides for a range of other therapeutic applications.”

Following the discovery, the team will now optimise the new ligase enzymes, to improve their output for larger scale peptide synthesis. They have also established collaborations with a number of the top pharmaceutical companies to help with rolling out the new ligase enzyme technologies for manufacturing future peptide therapeutics.