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.
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 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.
CFBD researchers are again invited to apply for a CFBD Travel Grant to the value of up to $3,500. This grant may be used for travel to a national or international conference, a visit to a partner organisation for research collaboration or a visit to a research laboratory to learn a new technique. The CFBD TravelGrant is an annual award.
The Royal Australian Chemical Institute (RACI) is the national professional body for chemists in industry, academia and government and is the primary voice of chemistry in Australia. Every five years the RACI holds a national Congress, with the RACI 2022 National Congress held from 3 to 8 July in Brisbane. This was a significant meeting (last held in 2017) with 1,148 people registered to attend, 615 speakers, 21 exhibitors, 12 sponsors and 325 poster presentations.
The CFBD members were heavily involved in the fabric of this significant meeting. CI Prof Sally-Ann Poulsen (Griffith Uni) was on the RACI2022 Congress Organising Committee and was Symposium Chair of the 4-day Medicinal Chemistry & Chemical Biology Symposium (the largest of all the Symposiums within the Congress). CI Prof Michael Kassiou (Uni Sydney) and Dr Louise Sternicki (Griffith Uni) were invited speakers, with Dr Luke Adams (Monash) and PhD Candidate Ashley Taylor (Monash) giving contributed talks and PhD Candidate Jamie Currie (Monash)- together showcasing the breadth of ARC CFBD research, while ARC CFBD Chief Investigators, ECRs and PhD candidates from the three universities and several of our industry partners were well represented. We were fortunate to have a catch-up dinner during the Congress – meeting face-2-face for the first time and a lot of laughs to be had. ‘The First Scientists’ artwork for the Congress is by Artist Steven Bekue.
Not one but five CFBD members from our three nodes published a paper on DsbA titled “Identification and characterization of two drug-like fragments that bind to the same cryptic binding pocket of Burkholderia pseudomallei DsbA” in Acta Crystallographica Section D.
Disulfide-bond-forming proteins (Dsbs) play a crucial role in the pathogenicity of many Gram-negative bacteria. Disulfide-bond-forming protein A (DsbA) catalyzes the formation of the disulfide bonds necessary for the activity and stability of multiple substrate proteins, including many virulence factors. Hence, DsbA is an attractive target for the development of new drugs to combat bacterial infections. Here, two fragments, bromophenoxy propanamide (1) and 4-methoxy-N-phenylbenzenesulfonamide (2), were identified that bind to DsbA from the pathogenic bacterium Burkholderia pseudomallei, the causative agent of melioidosis. The crystal structures of oxidized B. pseudomallei DsbA (termed BpsDsbA) co-crystallized with 1 or 2 show that both fragments bind to a hydrophobic pocket that is formed by a change in the side-chain orientation of Tyr110. This conformational change opens a `cryptic’ pocket that is not evident in the apoprotein structure. This binding location was supported by 2D-NMR studies, which identified a chemical shift perturbation of the Tyr110 backbone amide resonance of more than 0.05 p.p.m. upon the addition of 2 mM fragment 1 and of more than 0.04 p.p.m. upon the addition of 1 mM fragment 2. Although binding was detected by both X-ray crystallography and NMR, the binding affinity (Kd) for both fragments was low (above 2 mM), suggesting weak interactions with BpsDsbA. This conclusion is also supported by the crystal structure models, which ascribe partial occupancy to the ligands in the cryptic binding pocket. Small fragments such as 1 and 2 are not expected to have a high energetic binding affinity due to their relatively small surface area and the few functional groups that are available for intermolecular interactions. However, their simplicity makes them ideal for functionalization and optimization. The identification of the binding sites of 1 and 2 to BpsDsbA could provide a starting point for the development of more potent novel antimicrobial compounds that target DsbA and bacterial virulence.
Congratulations to CFBD CI Professor Joel Mackay from Sydney University who received an NHMRC Ideas Grant worth $829, 494.
New approaches to cancer treatment through mRNA display
This project will pioneer the development of a new class of molecules – cyclic peptides – that will block the activity of proteins that regulate gene expression and have been shown to be promising targets for a range of diseases, predominantly cancer. These molecules have the potential to be much more selective and potent than existing molecules and to also open up new directions for cancer therapy by allowing previously intractable molecular targets to be addressed.
The Centre for Fragment-Based Design officially commenced on 22 July 2019 with the execution of our Participants Agreement and the Centre was launched by The Honourable Kevin Andrews MP on 12 November 2019. The launch was held in conjunction with Australia’s national conference on Fragment-Based Drug Design, which allowed us to leverage a full week of activities including our first Scientific Advisory Board meeting and the Centre’s first training events, in partnership with key industry and international stakeholders.
The launch, conference and training workshops were very well received by attendees, with many of our academic and industry participants and other stakeholders in attendance. These initial activities have established a strong base of interest in the Centre for further collaborative opportunities that will drive our research initiatives and support growth, productivity and competitiveness in fragment-based design for the sector.
There was some great coverage of the event. Monash and Griffith both had media releases publicising the launch event, which were picked up by a Universities to Business article.
Our partners GE Healthcare (now Cytiva) had a number of representatives, including Paul Belcher all the way from Boston, who wrote a great LinkedIn article about the event.
Dan Erlanson wrote a great summary article on his Practical Fragments blog.
Our objective to establish a coherent and collaborative national network to provide access to the technology necessary to support fragment screening against a wide range of protein targets, has now been firmly grounded in the established Centre. We now have a strong platform and clear means to implement our training program activities, accelerate research translation and continue to engage with industry to meet the growing needs within the rapidly moving sector.
Feature image: Centre CIs (L-R: Professor Jonathan Baell, Professor Sally-Ann Poulsen, Professor Michael Kassiou, Professor Joel Mackay, Dr Maria Halili, Professor Martin Scanlon and Professor Ray Norton) with ARC CEO Professor Sue Thomas and Centre Manager Dr Narelle Tunstall.