Highlights

Markus Muttenthaler received his BSc in technical chemistry (2001) and his MSc in organic chemistry and technology (2004) from the Vienna University of Technology. In 2005 he obtained a PhD scholarship to join Paul Alewood’s laboratory at The University of Queensland. He then received training in peptide chemistry and was involved in the discovery, design and development of therapeutics based on bioactive venom peptides. He earned the best PhD thesis award from the Royal Australian Chemical Institute, and the Dean’s award for outstanding higher degree thesis.

As a postdoc, Dr Muttenthaler continued to expand his chemical skills repertoire and developed an interest in oxytocin and vasopressin research. Two Marie Curie Fellowships enabled him to join the Dawson lab at the Scripps Research Institute in California, distinguished for the invention of native chemical ligation, a technique that revolutionised chemical synthesis of proteins, and the Albericio lab at the Institute for Research in Biomedicine Barcelona, renowned for its innovative advancements in combinatorial and peptide chemistry.

In 2015, he was recruited back to IMB as an ARC DECRA fellow to establish his neuropeptide research program. His recent achievements earned him the IMB Industry Fellow Award as well as the prestigious Miklos Bodanszky Award for peptide-based drug research.

Research overview

Dr Muttenthaler’s interdisciplinary background has proven highly valuable to research efforts to understand fundamental human physiology and pathology. His current focus is on developing molecular probes, diagnostics and therapeutics to help in the treatment of disorders such as neuropathic pain, cancer, autism, gastrointestinal disorders and neurodegenerative diseases.

“Most of our leads come from nature,” said Dr Muttenthaler. “Venoms form a rich source of bioactive compounds, as they comprise highly complex cocktails of potent peptides that can paralyse prey or defend against predators. The similarities of prey/predator receptors to human receptors make these venom peptides excellent leads for the development of neurological tools and therapeutics.”

A recent addition to his research program is the discovery of novel gastrointestinal wound healing modulators.

“Humans continuously produce specific peptides that have a critical role in protecting and restoring our gut epithelium – the single layer of cells that protects us from pathogens.”

Dr Muttenthaler said that when the production of these gut peptides is not working properly, we become more susceptible to pathogens. This can lead to gastrointestinal inflammation that further resolves into chronic disorders such as Irritable Bowel Syndrome and Inflammatory Bowel Disease (around 15 per cent of the population are affected by these disorders).

“For someone suffering from gastrointestinal disorders, or who is undergoing chemotherapy that is harsh on the gut, the idea would be to supply an agent to protect or even restore that important epithelial layer.

“We’re interested in not just treating the symptoms, but the underlying root of the problem,” he said.

Research projects

Peptides are key mediators in many biological functions and understanding of their interaction with target proteins is fundamental to unravel the underlying mechanism of diseases. Over the years, an increasing number of bioactive peptides from animals, plants, and bacteria have been characterised, with the overwhelming realisation that these molecules often show better therapeutic performance than their human counterparts, particularly in terms of in vivo stability.

Our main research efforts situated in the field of Neuropeptide Research focus on the exploration and translation of these vast and untapped natural libraries towards the development of useful research tools and therapeutics. Solid-phase peptide synthesis, the main tool to access these compounds, is a powerful technology for the assembly and chemical modification of these highly chiral and structurally complex peptides.

Venoms to Drugs

Typical 3D NMR structures of disulfide-rich venom peptides

Venoms comprise a highly complex cocktail of bioactive peptides evolved to paralyze prey and defend against predators. Homology of prey/predator receptors to human receptors render these venom peptides also active on human receptors and they have become a rich source for neurological tools and therapeutics. Our group is involved in the discovery, synthesis and structure-activity relationship studies of these venom peptides with the goal to develop novel probes for neuroscientists as well as therapeutic drug leads.

Oxytocin and Vasopressin Research

The oxytocin and vasopressin signalling system regulates many fundamental physiological processes such as reproduction, water balance, cardiovascular responses and complex social behaviour. It is also a high-profile target for autism, schizophrenia, stress, depression, anxiety, cancer and pain. Our group is particularly interested in creating a complete molecular toolbox to study this signalling system as well as in discovering novel therapeutic leads for autism, pain, gastrointestinal disorders and breast cancer.

Neuropeptides and long-term Memory Formation

Memory is probably the single most important brain process that defines our personality and gives us the sense of individuality. Emotional events often cause the generation of strong memories that exist for many years, yet the underlying mechanisms are still poorly understood. Neuropeptides are key players in regulating emotions and have been associated with long-term memory formation. Our group is involved in the development of advanced molecular probes to understand how neuropeptides can influence long-term memory formation.

Gastrointestinal Disorders

The gastrointestinal epithelium is a major physical barrier that protects us from diverse, and potentially immunogenic or toxic content. A damaged epithelium results in increased permeability to such content, thus leading to inflammation, uncontrolled immune response, and diseases, such as irritable bowel syndrome and inflammatory bowel disease that affect 10-15% of the population. Our group is involved in the identification and validation of novel drug targets and therapeutic strategies that can protect or repair this important barrier in order to prevent or treat such disorders.

Engagement and impact

Dr Muttenthaler is internationally recognised for his expertise in venom peptide drug discovery, neuropeptide research and his pioneering methods in peptide chemistry. His work focuses on developing tools that facilitate basic fundamental research as well as drug discovery. He recently received the prestigious Miklós Bodanszky Award for his outstanding contributions for peptide-based drug research.

Peptides are key mediators in many biological functions and understanding of their interaction with target proteins is fundamental to unravel the underlying mechanism of diseases. Over the years, an increasing number of bioactive peptides from animals, plants, and bacteria have been characterised, with the overwhelming realisation that these molecules often show better therapeutic performance than their human counterparts, particularly in terms of in vivo stability.

Our main research efforts situated in this field of Chemical Biology focus on the exploration and translation of these vast and untapped natural libraries towards the development of useful research tools and therapeutics. Solid-phase peptide synthesis, the main tool to access these compounds, is a powerful technology for the assembly and chemical modification of these highly chiral and structurally complex peptides. This complexity is also responsible for their remarkable selectivity and potency as well as for their low side effect profile observed in the clinic.

Researcher biography

Dr Markus Muttenthaler is a medicinal chemist working at the interface of chemistry and biology with a strong passion for translational research. His research focus is on neuropeptides and the exploration of nature's diversity (i.e. venom peptides) to develop molecular tools, diagnostics and therapeutics. His background in drug discovery, design and development, as well as his interdisciplinary training in the fields of chemistry, molecular biology and pharmacology assist him in the characterisation of these highly potent and selective compounds and allow him to study their interactions with human physiology for medical innovations neuropathic pain, cancer, autism, gastrointestinal disorders and neurodegenerative diseases.