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Dissecting catalysis and inhibition of a unique endo-acting mannose-processing glycosidase. Defects in the attachment of carbohydrates to proteins are a hallmark of diseases such as cancer and viral infection. This project will dissect the molecular details of the bond-making and breaking steps that occur during the synthesis of glycoproteins assisting in the development of innovative new drugs.
Chemical probes for the study of a unique enzyme from Mycobacterium tuberculosis. The design and chemical synthesis of molecules that selectively inhibit pathogen-specific enzymes is a validated approach toward new therapeutic agents. Mycobacterium tuberculosis contains a unique cytochrome P450 enzyme that catalyses an unusual chemical transformation to generate the product mycocyclosin. This research project will synthesise chemical probes to study the mechanism of this enzyme and the biologica ....Chemical probes for the study of a unique enzyme from Mycobacterium tuberculosis. The design and chemical synthesis of molecules that selectively inhibit pathogen-specific enzymes is a validated approach toward new therapeutic agents. Mycobacterium tuberculosis contains a unique cytochrome P450 enzyme that catalyses an unusual chemical transformation to generate the product mycocyclosin. This research project will synthesise chemical probes to study the mechanism of this enzyme and the biological role of mycocyclosin. Selective inhibitors of the enzyme will be developed, which will provide a foundation for the exploitation of these molecules in cellular research and medicine.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE130101673
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Access to biomimetic carbohydrate receptors using dynamic combinatorial chemistry. This project aims to utilise novel synthetic technology for the development of cyclic peptide libraries as novel drug leads for the treatment of Dengue virus, HIV and cancer.
Discovery Early Career Researcher Award - Grant ID: DE120101653
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Selective fluorination chemistry: a tool for creating bioactive, shape-controlled peptides. Fluorine atoms are desirable substituents in drug candidates because they can increase metabolic stability and hydrophobicity, and because they can be used to constrain molecules into optimal bioactive conformations. These concepts are being exploited to create shape-controlled peptides with applications in anti-cancer and anti-microbial therapy.
Novel peptide mimics for the disruption of chemical communication in bacteria. It is now well established that bacteria communicate with each other via small diffusible signalling molecules and coordinate their activities such as biofilm formation, swarming and expression of virulence factors in a coordinated manner. This project will investigate the synthesis of novel organic molecules that have the capacity to disrupt chemical communication in bacteria. This could allow control of the unwante ....Novel peptide mimics for the disruption of chemical communication in bacteria. It is now well established that bacteria communicate with each other via small diffusible signalling molecules and coordinate their activities such as biofilm formation, swarming and expression of virulence factors in a coordinated manner. This project will investigate the synthesis of novel organic molecules that have the capacity to disrupt chemical communication in bacteria. This could allow control of the unwanted microbial activity without the use of growth inhibitory agents such as antibiotics, preservatives and disinfectants that select for the resistant organisms. This elegant approach to eradicating the virulence behaviour of microbes represents a novel strategy to combat antimicrobial resistance.Read moreRead less
New scaffolds for antimicrobial discovery. This project aims to investigate the synthesis of novel glyoxylamide antimicrobial peptide mimics that have the capacity to disrupt bacterial membranes. The innovative interdisciplinary approach expects to generate new, small molecular antimicrobial mimics that possess a low propensity for developing resistance. This could allow control of the unwanted microbial activity without the use of antibiotics that select for the resistant organisms. It will pro ....New scaffolds for antimicrobial discovery. This project aims to investigate the synthesis of novel glyoxylamide antimicrobial peptide mimics that have the capacity to disrupt bacterial membranes. The innovative interdisciplinary approach expects to generate new, small molecular antimicrobial mimics that possess a low propensity for developing resistance. This could allow control of the unwanted microbial activity without the use of antibiotics that select for the resistant organisms. It will provide excellent training for young researchers and lead to high quality research publications in international journals.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE160100482
Funder
Australian Research Council
Funding Amount
$364,536.00
Summary
Indoleamides as Molecular Interventions for Tuberculosis. This project aims to develop chemical probes capable of inhibiting the transport of essential mycolic acid across the cell wall of Mycobacterium tuberculosis. The emergence of resistant strains of Mycobacterium tuberculosis necessitates the identification of new, validated biological target(s) in the current control of tuberculosis. Preliminary data in this proposal demonstrate the discovery of indoleamides as a novel chemical entity. Dev ....Indoleamides as Molecular Interventions for Tuberculosis. This project aims to develop chemical probes capable of inhibiting the transport of essential mycolic acid across the cell wall of Mycobacterium tuberculosis. The emergence of resistant strains of Mycobacterium tuberculosis necessitates the identification of new, validated biological target(s) in the current control of tuberculosis. Preliminary data in this proposal demonstrate the discovery of indoleamides as a novel chemical entity. Development of these indoleamides may provide insights into a novel mechanism of action that could be targeted in combination with existing antitubercular agents.Read moreRead less
An Open Source Approach to Understanding an Important Parasite Ion Pump. This project plans to synthesise new compounds that bind the protein ATP4, an essential ion pump in the malaria parasite. It plans to generate a three-dimensional map to understand how these compounds stop ATP4 from working. Several promising new medicines for malaria target ATP4, yet we do not understand properly how they do so. The project’s intended aims will be achieved using new methods in synthetic chemistry and membr ....An Open Source Approach to Understanding an Important Parasite Ion Pump. This project plans to synthesise new compounds that bind the protein ATP4, an essential ion pump in the malaria parasite. It plans to generate a three-dimensional map to understand how these compounds stop ATP4 from working. Several promising new medicines for malaria target ATP4, yet we do not understand properly how they do so. The project’s intended aims will be achieved using new methods in synthetic chemistry and membrane biology, and by leveraging global scientific inputs through online research methods allowing anyone to participate.Read moreRead less
Chemical proteomics: proteomics with no detection limit. Half of all drugs are derived from natural products, yet little is known about how most achieve their therapeutic action. This project aims to develop a methodology to rapidly uncover drug-protein interactions and pave the way for faster drug development and a better understanding of drug action.
Interrogating diarylquinoline toxicity with targeted organic synthesis. Bedaquiline is the only new first-line treatment with a new mechanism of action to treat TB in the last 40 years, approved by the FDA on 31 December 2012. Alarmingly, this compound, has significant toxicities. The hypothesis tested in this project is that decreasing lipophilicity and basicity in this class of compounds while retaining target affinity will decrease toxicity but retain anti-TB activity. The project aims to: sy ....Interrogating diarylquinoline toxicity with targeted organic synthesis. Bedaquiline is the only new first-line treatment with a new mechanism of action to treat TB in the last 40 years, approved by the FDA on 31 December 2012. Alarmingly, this compound, has significant toxicities. The hypothesis tested in this project is that decreasing lipophilicity and basicity in this class of compounds while retaining target affinity will decrease toxicity but retain anti-TB activity. The project aims to: synthesise novel heteroarylalkylamines distinct from bedaquiline and designed to be more polar, less basic, and metabolically more stable; and, test all successfully synthesised target compounds for mechanism-based anti-tuberculosis activity, hERG-mediated cardiotoxicity, metabolic instability, and phospholipidosis.Read moreRead less