Monash study may help boost peptide conception

Max Cryle, Associate Professor of Monash BDI

Peptides – short chains of amino acids – play a vital role in health and industry with a wide range of medical uses, including in antibiotics, anti-inflammatories, and anti-cancer drugs. They are also used in the cosmetics industry and to improve sports performance.

Altering the structure of natural peptides to produce improved compounds is therefore of great interest to scientists and industry. But how the mechanisms that produce these peptides work is still not clearly understood.

Associate Professor Max Cryle, a scientist at the Monash Biomedicine Discovery Institute (BDI), revealed a key aspect of peptide mechanisms in an article published in Nature communications today.

The findings will enable Associate Professor Cryle to advance his lab’s work in reengineering glycopeptide antibiotics to address the pressing global threat posed by antimicrobial resistance, and more broadly to improve the properties of peptides in general.

“Peptide synthesis machines are often largely modular assembly lines, each module being made up of different components. Changing what you make in these assembly lines – peptides with new bioactivities – is a ‘holy grail’ in redesign, ”Associate Professor Cryle said.

“One of the things we tried to figure out in this study was where the selectivity of these machines comes from – they’re very selective at making a specific peptide and understanding where that specificity comes from is a bit of a mystery,” did he declare.

“We were able to structurally characterize a part of such a machinery that generates the bonds within peptides at a stage that has not been previously determined. What we have shown is that those domains responsible for binding amino acids to peptides do not play a general role in amino acid selection during this process.

“This is good news from a reengineering point of view, because it means we don’t need to worry about changing multiple pieces of machinery to make single amino acid changes, we just need to focus. on the change of the basic element that goes. in – and that’s pretty promising.

Associate Professor Cryle led a multidisciplinary team of scientists who used various techniques to model peptide structures, including the use of the Australian synchrotron for X-ray crystallography as well as chemical and biochemical techniques. He has collaborated with groups in Canberra, Brisbane and Germany that have contributed to computational modeling and bioinformatics.

“Our ability to understand the enzymes that make natural peptides is key to our ability to produce improved ones to target issues such as antimicrobial resistance,” he said. “Now we can really start to think about ways to change the machine’s acceptance of different building blocks and in this way we can make new peptides with improved antibacterial properties,” he said.

In the future, a collaboration with the group of Dr Evi Stegmann at the University of Tübingen in Germany will help translate the results of a theoretical laboratory solution to possibly develop a commercial scale production of new and improved antibiotics. , did he declare.

Dr Thierry Izore, who has since left the Monash BDI to work at Medpace, and doctoral student Candace Ho at the University of Warwick, UK, are tied for first authors.

The work is linked to the University of Warwick. Associate Professor Cryle is a member of the ARC Center of Excellence for Innovations in Peptide and Protein Science.

Read the publication in Nature Communications, titled The structures of a non-ribosomal peptide synthetase condensation domain suggest the basis of substrate selectivity

DOI: 10.1038 / s41467-021-22623-0

About the Monash Biomedicine Discovery Institute at Monash University

Committed to making the discoveries that will ease the future burden of disease, the all-new Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally renowned research teams. Covering six discovery programs in cancer, cardiovascular disease, developmental and stem cells, infection and immunity, metabolism, diabetes and obesity, and neuroscience, Monash BDI is one of the largest Australian Biomedical Research Institutes. Our researchers are backed by world-class technology and infrastructure, and partner with industry, clinicians and researchers around the world to improve lives through discovery.

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