Mimicking Protein Surfaces With Cyclic Peptides: W-conotoxin GVIA Mimics As Novel Analgesic And Neuroprotective Agents
Funder
National Health and Medical Research Council
Funding Amount
$216,412.00
Summary
The omega-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, omega-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered to the CNS via an intrathecal catheter, MVIIA and GVIA are analgesic in acute, chronic and neuropathic pain models, and protective following ischaemia-induced neuronal injury, such as occurs following stroke. They do not suffer from the development ....The omega-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, omega-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered to the CNS via an intrathecal catheter, MVIIA and GVIA are analgesic in acute, chronic and neuropathic pain models, and protective following ischaemia-induced neuronal injury, such as occurs following stroke. They do not suffer from the development of tolerance, in contrast with the opioids, such as morphine, which lose their analgesic potency over time and have undesirable side effects. We have determined the three-dimensional structure of GVIA and mapped onto that structure its calcium channel binding surface. This information is a starting point for the structure-based design of truncated and stabilised peptidic analogues of GVIA, which should have several advantages over the native polypeptides as candidates for the treatment of chronic pain and ischaemia-induced neuronal damage. In the course of this work we shall also generate a range of libraries of experimentally determined and predicted structures based on small, cyclic peptides. These libraries will be valuable tools for mimicking key functional regions of protein surfaces in small molecules that are easily (and cheaply) synthesised and have potentially favourable bioavailability. Thus, this project will also increase our understanding of the attributes of small cyclic peptides as mimics of functionally important protein surfaces and provide valuable tools for the design and evaluation of such peptides.Read moreRead less
Pre-clinical Development Of A Chemically Synthetic Anti-toxic Vaccine Against Malaria
Funder
National Health and Medical Research Council
Funding Amount
$165,000.00
Summary
Plasmodium falciparum malaria infects 5-10% of the global population (400 million clinical cases) and kills two million people annually1. As such it ranks along with HIV and TB as the most serious infectious disease of humanity. It is widely accepted that an efficacious vaccine is required to afford protection against malarial fatalities. The induction of broad-ranging sterilizing immunity is not considered a likely objective for anti-malarial vaccines. Instead, reduction in morbidity and mortal ....Plasmodium falciparum malaria infects 5-10% of the global population (400 million clinical cases) and kills two million people annually1. As such it ranks along with HIV and TB as the most serious infectious disease of humanity. It is widely accepted that an efficacious vaccine is required to afford protection against malarial fatalities. The induction of broad-ranging sterilizing immunity is not considered a likely objective for anti-malarial vaccines. Instead, reduction in morbidity and mortality is the realistic aim of malaria vaccine strategies. Traditional approaches seek to provide this clinical protection indirectly, by killing the parasite or by reducing parasite multiplication. To this end, current anti-malarial vaccines candidates seek to confer on the host parasiticidal immune mechanisms, which have as their target antigenic proteins expressed on the surface of the different stages of the parasite. No malaria vaccine is yet on the market. There exist several potentially competitive leads in late-stage pre-clinical-early stage clinical development, particularly recombinant proteins. The US Navy MUSTDO-25 DNA vaccines are not living up to their promise. Most leading “vaccine candidates” are polymorphic alleles. There are significant prospects for vaccine-induced selection of breakthrough variants. Multiple alleles may also prove cost-prohibitive for vaccine development. The novelty and uniqueness of this approach have contributed to the acceptance of this study for publication by Nature. The aims of this proposal are four-fold: i) to further rationalize the target through chemical synthesis of intermediates and partial structures; (ii) to examine antigenicity and immunogenicity in large experimental mammals, and undertake epitope mapping of human anti-GPI IgG responses; (iii) to obtain preliminary safety data in these animals; and (iv) to undertake a vaccine trial in a simian malaria model. We envisage objectives (i)-(iii) will take 12 months. Objective (iv) will proceed in the six months thereafter.Read moreRead less
Factors Affecting The Toxicity Of The Dinoflagellate, Gambierdiscus Toxicus, And The Development Of Ciguatera Outbreaks
Funder
Fisheries Research and Development Corporation
Funding Amount
$22,600.00
Summary
Objectives: 1. Define factors influencing ciguatoxin production by cultures of Gambierdiscus toxicus. 2. Examine reef disturbance effects & significance of genetic heterogeneity in G. toxicus in toxin production. 3. Establish requirements for growth & bloom formation by G. toxicus & other dinoflagellates
Production Of Antibodies Against Toxins Involved In Ciguatera Fish Poisoning
Funder
Fisheries Research and Development Corporation
Funding Amount
$87,050.00
Summary
Objectives: 1. Develop method of detection of ciguatoxin (CTX) to extract & purify sufficient CTX to service requirements of program. 2. Develop an en enzyme imunassay for measuring anti-CTX production. 3. Develop method of schedule immunisation to allow production of monoclonal antibodies
Tactical Research Fund: Revision Of The Australian Shellfish Quality Assurance Program Manual - In Light Of The FRDC Funded PST Review Report
Funder
Fisheries Research and Development Corporation
Funding Amount
$39,000.00
Summary
The updating of the ASQAP manual is urgently needed to ensure that guidance on shellfish management is up to date, sufficient to allow consistency in interpretation and risk assessment and is in line with best practice. The ASQAAC committee represents the Australian bivalve shellfish producers, the program managers from the relevant food safety jurisdictions and the national legislative agencies (Department of Agriculture and FSANZ). It is the key consultative group with regards to bivalve shell ....The updating of the ASQAP manual is urgently needed to ensure that guidance on shellfish management is up to date, sufficient to allow consistency in interpretation and risk assessment and is in line with best practice. The ASQAAC committee represents the Australian bivalve shellfish producers, the program managers from the relevant food safety jurisdictions and the national legislative agencies (Department of Agriculture and FSANZ). It is the key consultative group with regards to bivalve shellfish safety in Australia.
The PST event that occurred in Eastern Tasmania and Bass Strait over the last 24 months, and the FRDC funded review report into the PST incident has highlighted the need to get this national guidance manual updated. It is expected that an updated manual will be outcome focused and provide clear guidance that is internationally robust and meets best practice approaches. The updated ASQAP manual will provide the framework to the relevant state agencies in running their state shellfish safety programs.
The current ASQAP manual is outdated and it was clear from the FRDC PST review report that it urgently needs revision. This position has been accepted by ASQAAC.
Objectives: 1. An updated ASQAP manual will be produced in consultation with all members of ASQAAC 2. The updated manual will be internationally peer reviewed 3. The updated manual will be endorsed by the ASQAAC for agreement by ISC Read moreRead less