Theme 2: Drug DevelopmentTheme 2 has the expertise and capabilities to take on targets discovered by Theme 1 and carry out lead finding and optimization programs. It conducts high-throughput screening, medicinal chemistry and pharmacology for lead finding, optimization and preclinical development to deliver new TB drug candidates for clinical development. The theme also develops imaging biomarkers that can provide an early indication of activity of drugs or combination regimens against dormant TB bacilli, as well as works on animal models of TB and to conduct the subsequent pre-clinical development studies to support investigational product use in humans. |
Theme 2 Lead: Prof. Alex Matter
Experimental Therapeutics Centre (ETC), Agency for Science, Technology and Research (A*STAR), Singapore |
ProjectsNovel inhibitor of mycobacterial transporter MmpL3
Project lead: Annanya Shetty A high-throughput screen of ~72,000 compounds identified 16 hits that inhibited growth of Mycobacterium bovis BCG. Of these hits, a novel acetamide E11 was prioritized based on i) its ability to induce the cell envelope stress responsive promotor piniBAC; ii) its potent cidal activity against growing and non-growing M. tuberculosis; iii) low cytotoxic and hemolytic activity and iv) a dynamic structure activity relationship. Resistant mutant selection and whole genome sequencing revealed the mycolic acid transporter (Mycobacterial Membrane Protein Large) MmpL3 as a candidate target of the hit. Biochemical analyses using mycobacterial spheroplasts suggest that E11 indeed inhibits translocation of trehalose monomycolate (TMM) and subsequent synthesis of trehalose dimycolate (TDM). With the therapeutic potential of MmpL3 extensively reviewed, our novel scaffold represents an anti-mycobacterial lead with attractive potency and selectivity for optimization. Select publication: Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption. Front Microbiol. 2018 Dec 4;9:2960. Novel PET Tracers for mABs: TB Imaging
Project lead: Dr. Claire Naftalin The project aims to develop new PET tracers for application in imaging pulmonary TB based on labelled monoclonal antibodies (initially, monoclonal antibodies against tumour necrosis factor-α). TNF-α is a critical cytokine in both the immune response to TB and also to the inflammatory response and clinical symptomatology of the disease. The immuno-PET approach involves giving tracer doses of labeled anti-TNF-α that will enable to quantify and localize the site of TNF-α secretion. This approach will be later extended to label other monoclonal antibodies for use in TB imaging. TB Animal Model Platform
Project Lead: Dr. Rupangi Verma This project aims to develop a better approach to TB animal models to help prioritize regimens for use in clinical trials. It tests a number of mouse TB relapse models (established and several potential new models) and further adjusts and refines them to produce relapse rates equivalent to those seen in TB clinical trials. It also incorporates PET-based imaging of mice so that they can be followed for relapse over time, again resembling the approach of clinical trials more closely than the usual method of sacrificing animals randomly to check for TB relapse. |
Theme 2 CollaboratorsInstitute of Molecular & Cell Biology, A*STAR, Singapore
Singapore Bioimaging Consortium, A*STAR, Singapore
Comparative Medicine, National University of Singapore, Singapore
Public Health Research Institute, New Jersey, USA
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Essential to Theme 2, Experimental Therapeutics Centre (A*STAR) has industry standard drug discovery facilities and expertise for lead finding and optimization to deliver TB drug candidates for clinical development. Theme 2 research further benefits from National University of Singapore's BSL-3 animal facility and A*STAR-NUS Clinical Imaging Research Centre (CIRC) with state-of-the-art tools, such as PET/MRI, which allows for fundamental advancements in TB imaging.
