Therapeutic Development

Our immune system maintains a careful balance between health and disease.  Dysregulation can lead to a myriad of diseases, including increased susceptibility to infection and cancer, as well as inflammatory and autoimmune diseases, such as rheumatoid arthritis, diabetes and asthma.  Therefore, understanding how our body regulates immune responses is critically important and drives the development of new therapeutic strategies and treatments to many diseases.

ILRUN

In 2018, our team assigned function to a previously undefined gene, C6orf106 (a placeholder reflecting its location in the human genome), as a new immune regulator.  We found that C6orf106 acts as an inhibitor of the production of signalling molecules (called cytokines) that drive inflammatory and antiviral immune responses, through a unique mechanism.  C6orf106 targets the ‘master transcription regulators’ CBP and p300 for degradation, preventing formation of the transcription complexes necessary for cytokine production.

Based on this discovery, our team was involved in assigning an official name to C6orf106, ILRUN (inflammation and lipid-regulator with UBA-like and NBR1-like domains).  Subsequent studies by other groups have additionally implicated ILRUN in other biological roles, including cancer and obesity, suggesting ILRUN to be multifunctional.  Thus, ILRUN is an attractive therapeutic target for the treatment of numerous diseases, both infectious and non-infectious, of significant human health concern.  Furthermore, ILRUN is well conserved within the animal kingdom, extending its relevance to the agricultural and conservation sectors.

Our team is currently investigating the molecular mechanisms underlying the functions of ILRUN in disease and pursuing the discovery of small molecules to modify its function for the development of therapeutic candidates.

Fibrillarin

Antivirals are an important arsenal against dangerous pathogens for which vaccination is not efficacious or not yet in sufficient supply, such as when a virus is newly emerged. In order to stockpile an effective drug in preparation for future pandemics we need it to be broad spectrum, i.e. able to target any virus. Drugs targeting the virus directly fall short of this requirement. An alternative approach is to target host proteins that are required for virus replication but not the host, with an acceptable therapeutic index.

Our lab performed a genome-wide siRNA screen of host factors required for the highly pathogenic paramyxoviruses Hendra and Nipah in order to identify antiviral targets for further development into small molecule inhibitors. The most potent host antiviral target was a protein called Fibrillarin. Fibrillarin is a ribonucleoprotein that performs sequence-specific methylation of RNA, mostly ribosomal RNA, which in turn directs translation of a subset of mRNAs containing an IRES. This capacity to allow translation of IRES containing mRNA makes it an ideal therapeutic target for cancers that depend on MYC. For antiviral development we are characterising the mechanism through which Fibrillarin allows viral replication, uncovering important aspects of viral subversion of host translation.

Relevant Publications

• Tribolet L, Alexander MR, Brice AM, Jansen van Vuren P, Rootes CL, Mara K, McDonald M, Bruce KL, Gough TJ, Shi S, Cowled C, Bean AGD, Stewart CR. (2021) ILRUN Downregulates ACE2 Expression and Blocks Infection of Human Cells by SARS-CoV-2. Journal of Virology. Jul 12;95(15):e0032721. PubMed
  
• Ambrose RL, Brice AM, Caputo AT, Alexander MR, Tribolet L, Liu YC, Adams TE, Bean AGD, Stewart CR. (2020). olecular characterisation of ILRUN, a novel inhibitor of proinflammatory and antimicrobial cytokines. Heliyon, 6. Science Direct
• Deffrasnes C, Marsh GA, Foo CH, Rootes CL, Gould CM, et al. (2016) Genome-wide siRNA Screening at Biosafety Level 4 Reveals a Crucial Role for Fibrillarin in Henipavirus Infection. PLOS Pathogens 12(3): e1005478. PLoS One