ARCCFBD

Huge success at the 2023 Ramaciotti Biomedical Research Award

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Congratulations to CFBD CI Professor Sally-Ann Poulsen, ECR Dr Louise Sternicki and the team at GRIDD for being the recipient of the prestigious 2023 Ramaciotti Biomedical Research Award.

This $1 million grant from the Ramaciotti Foundations is awarded every two years to a group or individual undertaking biomedical research. The award will fund the purchase and use of a first-in-Australia, cutting-edge new technology – native Charge Detection Mass Spectrometry ‘nCDMS’ that will enable characterisation of complex and large biomolecules and biomolecular interactions that cannot be analysed with existing infrastructure in Australia. The Ramaciotti Australian Native Mass Spectrometry Platform for Health Discoveries will be nationally accessible through the NCRIS Therapeutic Innovation Australia (TIA) platform. CFBD CI Professor Sally-Ann Poulsen was the lead investigator with the GRIDD team together with Professor Kathy Andrews, Frank Sainsbury, CFBD member Dr Louise Sternicki and Miaomiao Liu.

More information can be found here.

Multiple prizes for CFBD members at the 18th Annual Graduate Research Symposium

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The Parkville Postgraduate Association (PPA) at Monash University held its 18th Annual Graduate Research Symposium yesterday. The main focus of the Symposium is to give graduate research students a platform to showcase their current research whilst improving their public speaking and presentation skills in the form of oral and poster presentations. The annual event provides an excellent opportunity to learn more about the diverse research carried out at the Monash Parkville Campus.

This year, CFBD members were particularly successful at the event: PhD Candidate Jeyan Osman won the People’s Choice Oral Presentation Award worth $150, PhD Candidate Jason Pun received the Oral Presentation Encouragement Award ($100) and PhD Candidate Imesha Hettige Most Outstanding Poster Presentation Award worth $300. Congratulations to all winners at the event!

How the Caribbean sea anemone can tackle autoimmune and neuroinflammatory diseases

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PhD candidate Karol Sanches recently published a paper in Proteins: Structure, Function, and Bioinformatics about the heterologous expression of the intrinsic membrane protein of the Caribbean sea anome.

The venoms of sea anemones are rich mixtures of biologically active compounds, some of which have the potential to be developed into novel therapeutics or bioinsecticides. ShK is a 35-residue peptide first isolated from the Caribbean sea anemone Stichodactyla helianthus as a potent blocker of voltage-gated potassium channels. The upregulation of one of these channels, KV1.3, occurs in many autoimmune and neuroinflammatory diseases, and inhibitors are therefore valuable molecular tools and potential therapeutic leads. The heterologous expression of this intrinsic membrane protein is one of the projects being pursued within the CFBD.

     Since its discovery in a sea anemone, the ShKT domain has been found in numerous other species, including plants, algae, protozoa, other cnidarians (such as hydra and jellyfish), sea urchins, molluscs, sea squirts, fish, nematodes, parasitic worms, snakes, amphibians, birds, and mammals. However, only a small fraction of these ShKT domains has been characterized functionally. Although some peptides display the same ShK-like fold and contain the dyad Lys-Tyr important for KV1.3 blockade, their function may not be related to potassium channel inhibition. As ShKT domains are highly abundant in nature and their functions are important to define, we investigated whether a combination of structure determination and/or prediction with molecular dynamics (MD) simulations could be useful for predicting activity against voltage-gated potassium channels. We show that weak or absent activity against KV1.x channels correlated with either a buried or only partially exposed dyad during MD simulations. We anticipate that structure determination in combination with MD simulations may allow the function of new sequences in the ShKT family to be predicted, at least for potassium channel blockers.

Full house at inaugural Hit ID Symposium

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The Centre had the pleasure of supporting the inaugural Hit ID Symposium 2023 on 27 October. The sold-out event took place at the Woodward Conference Centre in Melbourne and consisted of scientific sessions, interactive events and networking opportunities focussed on introducing delegates to the topic of hit identification within a small molecule drug discovery setting. 

It was the first small molecule drug discovery symposium showcasing the hit identification infrastructure and success stories to come out of Melbourne’s Parkville precinct. The event provided a unique opportunity to support a wide-reaching symposium that focused on hit-finding screening campaigns in drug discovery, delivered by experts actively working in the field from both within academia and industry.

The symposium introduced researchers and clinicians to the topic of small molecule drug discovery and the support that is available to engage in such a program, starting with the identification of a hit. Attendees were guided through how to do drug discovery, how to fund it and how to protect it.

The event was supported by:

Funding Success for CFBD Director

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CFBD Director Prof Martin Scanlon received funding through CSIRO’s CUREator – a national biotechnology incubator run by Brandon BioCatalyst to support the development of Australian biomedical research and innovations.

The project is led by Prof Bernie Flynn (Monash), Prof Colin Pouton (Monash) and CFBD Director Prof Martin Scanlon. The funding will support their aim to respond to the risk of viral and bacterial replication through the development of a platform capability in polynucleotide fragment based drug design (pFBDD) that is better able to discover small-molecules for targeting RNA and DNA.

CUREator is delivered through an initial $40m in funding from the Federal Government’s Medical Research Future Fund (MRFF) and $3m from Australia’s national science agency, CSIRO. CUREator was established by Brandon Capital in 2021 as a new approach for bridging the gap between where research grant funding ends and commercial investment begins.

How the venom of sea anemones can tackle Alzheimer’s and Parkinson’s

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PhD student Karol Sanches (Monash node) recently published a paper titled “Interaction of the Inhibitory Peptides ShK and HmK with the Voltage-Gated Potassium Channel KV1.3: Role of Conformational Dynamics” in J. Chem. Inf. Model.

In her paper, she describes the effects of KV1.3 on diseases like Alzheimer’s and Parkinson’s. KV1.3 is a voltage-gated potassium channel found in the membrane of the cells. The upregulation of KV1.3 in T lymphocytes is related to many autoimmune diseases and, in microglia, in the brains of patients with Alzheimer’s and Parkinson’s diseases and ischemic stroke. The blockage of KV1.3 is an attractive mechanism for treating autoimmune and neuroinflammatory diseases. Indeed, several peptides found in the venom of sea anemones have proven to be potent blockers of KV1.3, including the ShK from Stichodactyla helianthus, and HmK from Heteractis magnifica, both inhibitors of the KV1.3 channel.

Mutagenesis analysis have shown that both peptides block KV1.3 through the Lys-Tyr dyad. Although ShK and HmK share 60% sequence identity by BLAST, ShK is nearly 300-fold more potent against KV1.3 than HmK. We used a combination of docking and molecular dynamics (MD) simulations to investigate the conformational dynamics in ShK and HmK and the implications of this flexibility for channel recognition. Besides sharing high sequence and structure identity, the dynamics of ShK and HmK differ. While HmK is highly rigid, ShK is dynamic, sampling three major configurations. Both peptides bind to KV1.3 with Lys22 occupying the channel’s pore; intriguingly, the more flexible peptide, ShK, binds with significantly higher affinity than HmK.

Find the full paper here.

Loving the industry life – Yildiz’s placement experience

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Post written by Yildiz Tasdan, PhD Candidate at the CFBD Monash node

About four years ago, I was interviewed for the ITTC PhD Program on the day I submitted my Master’s thesis in Singapore. Now, I am in England doing my industry placement at Vernalis as part of my PhD at MIPS in Australia, and I have just returned from the US for a conference. I would not think a career in science would give me so many travelling opportunities. All these became possible thanks to the support from ARC CFBD.

My placement started at Vernalis, England four months ago, and I am absolutely loving the industry life. The first thing that surprised me here was how enthusiastic everyone is about research and training. I have been working on the synthesis of an extensive library of compounds using flow chemistry which provides excellent efficiency in the synthesis. I came here with no prior knowledge of flow chemistry. Thanks to the excellent training that my mentors provided, I am getting confident with my knowledge in the field and am willing to learn more. I am also learning about drug design and biophysics from the experts here. Everything I am learning here is in addition to the fundamental knowledge I gained in the first three years of my PhD at MIPS. The ITTC program prepared me for this placement very well, and ultimately it has been preparing me for an industry career.

CHI Drug Discovery Chemistry Conference Poster Presentation Award Ceremony (left to right; Anjani Shah, Yildiz Tasdan, An-Dinh Nguyen)

I was also fortunate to receive the CFBD travel grant to attend the CHI Drug Discovery Chemistry conference in San Diego. I had an opportunity to communicate my research with industry experts from various disciplines and expand my network. I attended two short courses and over 30 talks in 4 days, which was overall very fruitful. Through my poster presentation, I received the best poster prize as well.

I recommend every student and ECR follow the opportunities ARC CFBD offers and reach Anne to propose any training ideas and ask for additional support.

Thank you to Yildiz for writing this guest blog for CFBD and for sharing her experience with us!

2023 Inspiring Leadership Award

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Congratulations to our Partner Investigator Professor Susie Nilsson from CSIRO for receiving the 2023 Inspiring Leadership Award from the BioMelbourne Network

Image credit: https://biomelbourne.org/women-in-leadership-awards/women-in-leadership-awards-honour-roll/

Launched in 2015, BioMelbourne Network’s Women in Leadership Awards recognise and champion women who are making outstanding contributions to the health-tech industry. The 2023 Awards Ceremony honoured three remarkable leaders, at different stages of their careers, who have taken strategic risks, tenaciously pursued goals and served as role models to the younger generation.

Susie Nilsson received the award in the category “Inspiring Leadership Award – Making it Happen”. This award recognises women playing an inspiring and pivotal role in the leadership of a project, partnership or collaborative initiative, approximately within the last 5-10 years.

Fantastic Success for CI Prof Michael Kassiou (Uni Sydney)

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CFBD CI Prof Michael Kassiou, founder of Kinoxis, has secured a lucrative partnership with Boehringer Ingelheim to investigate drugs that treat aggression and social withdrawal in people with psychiatric disorders.

Michael developed small molecules that interact with oxytocin receptors which could be used to target oxytocin receptors with the aim of creating medicine to treat schizophrenia, depression and other neuropsychiatric illness. Read the full article in the Sydney Morning Herald from 4 May.

Paper alert! Rapid Elaboration of Fragments into Leads (REFiL)

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The challenge in fragment-based drug discovery (FBDD) is not finding hits, we typically find plenty, it’s what to do with them. In their recent publication, Centre members demonstrate a systematic approach for the Rapid Elaboration of Fragments into Leads (REFiL), where they take weak binding fragment hits and quickly develop them into higher affinity ligands that can be used as chemical probes or as starting points for a drug discovery program.

The paper was published in the Journal of Medicinal Chemistry by the following researchers and Centre members: Luke Adams, Lorna Wilkinson-White, Menachem Gunzburg, Stephen Headey, Biswaranjan Mohanty, Centre Director Martin Scanlon, Deputy Director Ben Capuano, Theme Leader Joel Mackay and Brad Doak.

Abstract

The development of low-affinity fragment hits into higher-affinity leads is a major hurdle in fragment-based drug design. Here, we demonstrate the Rapid Elaboration of Fragments into Leads (REFiL) by applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure–activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. After a fragment screen against bromodomain-3 extra-terminal (BRD3-ET) domain, we applied the REFiL workflow, which allowed us to develop a series of ligands that bind to BRD3-ET. With REFiL, we were able to rapidly improve binding affinity > 30-fold. REFiL can be applied readily to a broad range of proteins without the need for a structure, allowing the efficient evolution of low-affinity fragments into higher-affinity leads and chemical probes.