Drug discovery and design

Natural products for drug discovery

The objective of this programme is to isolate new secondary metabolites with potential pharmaceutical activity from New Zealand organisms in sufficient quantities for screening in a diverse array of bioassays. The programme is based on an isolation scheme developed at Victoria University that selects for compounds with drug-like properties followed by screening by spectroscopy for new chemical entities. Using this approach, we have already isolated a number of new compounds with a wide variety of structures and biological activities.

Peloruside A, an anti-mitotic compound isolated from a marine sponge, is an example of a lead compound that is being developed by Victoria for use as an anti-cancer agent. Other new compounds are being investigated in our various biology and chemistry laboratories for details on their biological activity, structure-activity relationships, and potential as therapeutics.

Traditional bioassay-directed fractionation is also applied to discover new bioactive molecules. For areas of specific expertise not directly available at Victoria, a strong team of international collaborators has been established to help with the characterisation and promote the development of novel compounds and their natural and synthetic analogues.

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Design and synthesis of natural product analogues

This programme involves exploration of synthetic routes to many diverse biologically active natural products and the rational design of novel analogues. This latter aspect complements, and is driven by, the isolation of new secondary metabolites within the Centre for Biodiscovery. Results from the screening of both the natural products and the designed analogues will allow structure-activity analysis and, it is anticipated, improved second-generation analogues.

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Transition state analogues for drug discovery

Transition state analysis, of an enzyme catalysed reaction, based on kinetic isotope effects and computational chemistry provide electrostatic potential maps to serve as blueprints for the design and chemical synthesis of transition state analogue inhibitors. The utility of these molecules is exemplified by potential clinical applications toward leukemia, autoimmune disorders, gout, solid tumors, bacterial quorum sensing and bacterial antibiotics. In some cases, transition state analogues have chemical features that have allowed them to be repurposed for new indications, including potential antiviral use. Three compounds from this family have entered clinical trials. The transition state analogues bind to their target proteins with high affinity and specificity. The physical and structural properties of binding teach valuable and often surprising lessons about the nature of tight-binding inhibitors.

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Cell biology and mode of action of new natural products and their analogues

After an initial screening for bioactivity is carried out on newly isolated natural products, the probable mode of action of the compounds is deduced from preliminary information provided by proteomic analysis, protein/nucleic acid microarrays, and chemical genetics. More detailed characterization of the action of the compounds on their primary and secondary targets is then carried out to determine such properties as binding affinities, selectivities, and potencies. Structurally modified analogues of the lead compounds are also examined to evaluate structure-activity relationships for later pharmacophore modeling.

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Many natural products that alter common cellular processes such as proliferation or migration can also have significant effects on the functioning of the immune system. These effects are being explored and include such processes as immune activation, altered immune signaling, or suppression of inflammation. Using experimental models of immune-mediated diseases such as multiple sclerosis, the potential of these natural products as therapeutic agents can be investigated.

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Select compounds targeting specific neurotransmitter pathways can be tested at the cellular and behavioural levels to determine their ability to modulate addiction, depression, nocioception and inflammation. Cellular mechanisms of action responsible for these effects are investigated to further aid the design of pharmacotherapies with reduced preclinical side-effect profiles.

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In the area of infectious disease research, the interactions between Neisseria meningitidis and host epithelial and immune cells are being characterised in detail. Bacterial proteins are assessed for their ability to disrupt host cell signalling pathways, including those required for cell migration or immune cell function. The goal of this research is the identification of novel vaccine target candidates.

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