Anticancer and Antimicrobial peptide treatments
Scientists based at the Translational Research Institute (TRI) are developing new, peptide-based therapies for cancers and antimicrobial treatments.
Queensland University of Technology (QUT) Group Leader, Dr Sónia Henriques (pictured right), is leading the development of more selective and potent anticancer peptide-based treatments for melanoma, triple negative breast cancer, leukaemia and metastatic circulating cells as well as more selective and potent anticancer bacterial diseases such as the tropical disease, Melioidosis.
Her team is also involved in identifying potential new treatments for cancers and bacteria from peptides produced by Australian flora and fauna.
The Portuguese-born scientist says she loves research for the challenge and excitement of discovering new things.
“It’s a great way to learn and discover new things,” says Dr Henriques.
Peptide-based therapeutics for cancer
In the cancer space, Dr Henriques and her group are harnessing peptides to create therapies, which can enter cancer cells and hit an intracellular target of interest.
The cell membrane controls entry to cells, and according to Dr Henriques, the ability of peptides to cross this barrier and deliver biological macromolecules, such as biomarkers and therapeutics, inside cells has endless opportunities to change a cell’s activity.
“Our focus is trying to understand how peptides can cross cell membranes and how we can use this to make them specific for a cancer target,” she says.
“So, we are working towards making peptides that can cross the cell membrane. My team is looking at specifically inhibiting cancer pathways involved in breast cancer, leukaemia and melanoma.”
With the peptide inside the cancer cell, they hope to ‘deactivate’ cancer cells and stop the cancer from growing and spreading. If it works, healthy cells will remain unaffected by the treatment. The group is also looking at how they can modify peptides to enter cancer cells selectively, particularly in melanoma.
Melanoma
Dr Henriques has discovered peptides, which can selectively target drug-resistant melanoma cells in laboratory-based experiments. Her group has found that melanoma cancer cells have special properties on their cellular surface, which make them more susceptible to some peptides.
Working in collaboration with The University of Queensland Academic Dermatologist, Dr Helmut Schaider, who also has a laboratory at TRI, they hope to develop a new melanoma therapeutic.
Dr Henriques says the project is very exciting.
“In laboratory models we’ve seen some cell-lines, which are no longer responsive to chemotherapy drugs, are killed by our peptides, meaning they could be used to kill drug-resistant melanoma. We want to develop a peptide treatment which has a double targeting approach: the drug can only enter melanoma cells and then, once in the cell it hits an intracellular target of interest within this cell to destroy it.”
Breast cancer
In many cancers, including breast cancer, the cancer cells are able to produce additional energy through the over-production of an enzyme known as Lactate dehydrogenase A (LDHA). Dr Henriques’ PhD Student, Ferran Nadal‐Bufí, is developing a peptide-based therapy to inhibit LDHA.
They hope the peptide will cut the cancer cells’ energy supply and make them more sensitive to current treatments.
“We are concentrating for now on triple negative breast cancer as it’s very hard to treat. If successful, we think this treatment could be used as an alternative therapy in combination with chemotherapy,” says Dr Henriques
New antimicrobial treatments
All organisms produce peptides naturally to fight pathogens such as bacteria, which means there are many potential antimicrobial peptides available to researchers. Dr Henriques says the abundance of antimicrobial peptides has inspired an international research effort into their use as a natural alternative to antibiotics.
“Knowing that there is so much multi-drug resistance these days it’s always good to have alternatives and therapies that work in a different way,” she says.
“Peptides bring a new, alternative mode of action for fighting bacteria and because it depends on the lipid membrane layer properties, bacteria will find it more difficult to develop resistance.”
Most antimicrobial peptides work by targeting the cell surface of the pathogens to disrupt their cell membranes, which are more negatively charged than the host cells. Dr Henriques is specifically looking at host defence peptides and ways to improve their properties so that they can better target pathogens and increase their toxicity towards these cells.
One of the projects they are working on, in collaboration with Dr Nicole Lawrence at the University of Queensland and her PhD student Anna Amiss, is a peptide treatment to target the bacterium, Burkholderia pseudomallei, which is responsible for Melioidosis or Whitmore's disease. This is an infectious tropical disease, which can infect both humans and animals.
“The problem with this bacterium is that it grows within the host’s cells, which makes it naturally resistant to many antibiotics. We’ve been trying to combine the antimicrobial properties of peptides with cell penetrating properties so that we can use peptides that can cross the cell membrane and kill the bacteria from inside its cell.“
Australia’s native treasure trove
Dr Henriques is one of 14 Chief Investigators with the ARC Centre of Excellence for Innovations in Peptides and Protein Science (CRIPPS). Launched in late 2020, the Centre focuses on discovering new proteins and peptides, decoding their biological functions, and developing new proteins and peptides to address challenges in health, agriculture and industry.
“This is one of the big projects I’m involved in. We investing in Australian flora and fauna because peptides are expressed in multicellular organism as part of host defence (e.g. blood cells) or attack system (e.g. venom). I’m trying to see how they can be used as new cancer or bacteria treatments.”
Why use peptides as drugs?
Every living organism produces peptides. Shorter than proteins, peptides are made up of short chains of two to 50 amino acids. They play key roles in regulating the activities of other molecules and cellular activity.
Dr Henriques says peptides have many advantages as therapeutics.
“Peptides can have high specificity for the target, be safer, cells are less likely to develop resistance to them, and some [not all] of them can cross the cell membrane. In our own body, host-defence peptides are expressed by our immune system in response to fungal and bacterial infections and some have been shown to be able to kill tumour cells.”
Benefits of being a researcher at TRI and in Australia
TRI attracted Dr Henriques because of its combination of researchers from different institutions and proximity to the Princess Alexandria Hospital.
“I saw working at TRI as an opportunity to connect with the clinicians and make my research more translational,” says Dr Henriques.
And, as for choosing to move her research base from Portugal to Australia after a stint here as a post-doctoral researcher, Dr Henriques says Australia has many advantages over Europe.
“For me, the projects here were exciting and there were lots of opportunities. There’s a better work-life balance in Australia and I like the work dynamics here. I think people are very welcoming. I love the multi-cultural environment. It’s still a country where there is so much going for research. There are amazing facilities and amazing researchers. All that made me want to come back to Australia and establish my team here.”
About Dr Henriques
Dr Sónia Troeira Henriques is an ARC Future Fellow at the Queensland University of Technology (QUT) within Translational Research Institute. The Peptide Therapeutics and Membrane Biology Research Group leader, and senior lecturer at QUT since 2018, Dr Henriques leads a collaborative, multidisciplinary research program with national and international linkages to academia and industry.
Dr Henriques graduated in Biochemistry and obtained a PhD degree in Biochemistry/Molecular Biophysics from University of Lisbon in Portugal. In 2008, Dr Henriques was awarded an ARC Australian Postdoctoral Fellowship and started her postdoctoral research at The University of Queensland in Professor David Craik’s group. In 2009, Dr Henriques was awarded an international outgoing Marie Curie Fellowship and was appointed as an invited lecturer at the University of Lisbon. In 2012, Dr Henriques returned to Australia after receiving a DECRA fellowship, and in 2015 she was awarded an ARC Future Fellowship.
Dr Henriques holds several leadership and mentoring roles, she chairs the ARC Centre of Excellence for Innovations in Peptides and Protein Science Equity and Diversity committee. She is the co-author of more than 80 publications on cyclic peptides, drug design and/or the mechanism of action of peptides, and has presented more than 50 oral communications in scientific conferences, including invited talks in prestigious national and international conferences.
Find out more: https://research.qut.edu.au/ptmbrg/
Research projects
- Development of peptide-based drugs to treat melanoma
- Characterization and redesign of host defense peptides to treat bacterial infections
- Understanding how peptide therapeutics interact/cross cell membranes
- Characterization of cancer cell membrane properties
- Design of peptides able to inhibit protein:protein interactions involved in cancer progression
- Use of cell-penetrating peptides as drug delivery systems
Recent journal publications on this body of research
- Philippe G.J.B., Mittermeier A., Lawrence N., Huang Y.H., Condon, N.D., Loewer A., Craik, D.J., Henriques S.T. (2021), Angler peptides: macrocyclic conjugates inhibit p53:MDM2/X interactions and activate apoptosis in cancer cells, ACS Chem Biol, 3 February 2021, doi.org/10.1021/acschembio.0c00988
- Benfield A.H., Defaus S., Lawrence N., Chaousis S., Condon N., Cheneval O., Huang Y.-H., Chan L. Y., Andreu D., Craik D.J., Henriques S.T. (2021) Cyclic gomesin, a stable redesigned spider peptide able to enter cancer cells, BBA-Biomembranes 1863, 183480.
- Ferran Nadal‐Bufí, Sónia Troeira Henriques, "How to overcome endosomal entrapment of cell‐penetrating peptides to release the therapeutic potential of peptides?", Peptide Science, 7 May 2020. https://doi.org/10.1002/pep2.24168
- Julia Skalska, Vitor M Andrade, Gabrielle L Cena , Peta J Harvey, Diana Gaspar, Érica O Mello, Sónia T Henriques, Javier Valle, Valdirene M Gomes, Katia Conceição , Miguel A R B Castanho, David Andreu, Synthesis, Structure, and Activity of the Antifungal Plant Defensin Pv D1, J Med Chem, Aug 31 2020, DOI: 10.1021/acs.jmedchem.0c00543
- Benfield A.H., Henriques S.T. (2020) Mode-of-action of antimicrobial peptides: membrane disruption vs intracellular mechanisms, Front Med Tech, 11 December 2020. DOI: 10.3389/fmedt.2020.610997
- Nicole D Barth, Ramon Subiros-Funosas, Lorena Mendive-Tapia, Rodger Duffin, Mario A Shields, Jennifer A Cartwright, Sónia Troeira Henriques, Jesus Sot, Felix M Goñi, Rodolfo Lavilla, John A Marwick, Sonja Vermeren, Adriano G Rossi, Mikala Egeblad, Ian Dransfield, Marc Vendrell, “A fluorogenic cyclic peptide for imaging and quantification of drug-induced apoptosis”, Nat Commun, 2020 Aug 12;11(1):4027. doi: 10.1038/s41467-020-17772-7
- Sónia Troeira Henriques, Hayden Peacock, Aurélie H Benfield, Conan K Wang, David J Craik, “Is the Mirror Image a True Reflection? Intrinsic Membrane Chirality Modulates Peptide Binding”, J Am Chem Soc, 2019 Dec 26;141(51):20460-20469. doi: 10.1021/jacs.9b11194. Epub 2019 Dec 10.
- Vernen F., Craik D.J., Lawrence N., Henriques S.T. (2019) Cyclic Analogues of Horseshoe crab peptide tahcyplesin I with anticancer and cell penetrating properties, ACS Chem Biol, 14, 2895-2908. DOI: /10.1021/acschembio.9b00782.
