Molecular Characterization Of Dengue Virus Fusion And Antiviral Inhibitors.
Funder
National Health and Medical Research Council
Funding Amount
$573,557.00
Summary
Dengue viruses are transmitted by mosquitoes and cause major epidemics in more than 100 countries around the world, including Australia. Infection with dengue viruses cause severe and sometimes fatal disease. This proposal focuses on the way dengue virus enters cells and the development of drugs that will prevent virus entry. We have already identified compounds that inhibit the entry process of dengue into cells and this project will significantly build on these early findings.
Nuclear Functions Of Dengue NS5 Protein: Role In Disease
Funder
National Health and Medical Research Council
Funding Amount
$736,953.00
Summary
Our work indicates that the NS5 protein from Dengue virus (DV) has distinct sequences that enable it to traffic into and out of the host cell nucleus to exert pathogenic effects on transcription and thereby impair the host cell anti-viral and immune responses. We aim to characterise these properties in detail, and demonstrate their importance to DV pathogenicity using a novel animal model of the disease.
Dengue viruses are transmitted by mosquitoes and cause major epidemics in more than 100 countries in tropical and subtropical regions. Infection with Dengue viruses cause Dengue fever or its more severe and sometimes fatal form, Dengue hemmorrhagic fever-Dengue shock syndrome (DHF-DSS). Up to 100 million people are infected annually making Dengue virus one of the most important and frequent mosquito-borne viral diseases worldwide. Over the past two decades, the incidence of Dengue virus infectio ....Dengue viruses are transmitted by mosquitoes and cause major epidemics in more than 100 countries in tropical and subtropical regions. Infection with Dengue viruses cause Dengue fever or its more severe and sometimes fatal form, Dengue hemmorrhagic fever-Dengue shock syndrome (DHF-DSS). Up to 100 million people are infected annually making Dengue virus one of the most important and frequent mosquito-borne viral diseases worldwide. Over the past two decades, the incidence of Dengue virus infection has increased steadily. More than 40% of the world's population is at risk of infection and this number is expected to increase as more people travel. This proposal focuses on the way dengue virus enters cells, specifically the mechanism used by viral proteins to mediate fusion of the viral membrane with that of the host cell. A clearer understanding of the molecular basis of this process should provide potential targets for new drugs that can bind and block this process. In addition, we will also use this information in the design and generation of new vaccine candidates.Read moreRead less
INHIBITORS OF DENGUE VIRUS NONSTRUCTURAL PROTEIN 5 NUCLEAR TRAFFICKING AS PROBES OF DENGUE BIOLOGY
Funder
National Health and Medical Research Council
Funding Amount
$741,136.00
Summary
Viral disease is one of the most significant health problems world-wide, making the identification of new therapeutics of critical importance. We aim to characterise in detail novel compounds which inhibit the interaction of the host cell with Dengue virus, and test them in a series of relevant infectious models for Dengue.
Dengue is a viral infection that is transmitted by mosquitoes in tropical regions of the world, including in northern Australia. For doctors who treat dengue patients, a major unmet need is the ability to predict which patients will develop severe complications and need highly specialized supportive care. This proposal will seek to address this unmet need by examining whether markers of human genetic variation can be used to predict those patients at risk of severe dengue.
Dengue is the leading mosquito-borne virus causing morbidity and mortality in the tropics. North Queens land has a history of dengue outbreaks, with 5 outbreaks in the last 3 years. Queensland Health has developed a Dengue Fever Management Plan for north Queensland that has had considerable success in preventing small outbreaks of dengue from developing into large epidemics. The cornerstone of this plan is the application of residual insecticide inside premises near dengue cases to kill the mosq ....Dengue is the leading mosquito-borne virus causing morbidity and mortality in the tropics. North Queens land has a history of dengue outbreaks, with 5 outbreaks in the last 3 years. Queensland Health has developed a Dengue Fever Management Plan for north Queensland that has had considerable success in preventing small outbreaks of dengue from developing into large epidemics. The cornerstone of this plan is the application of residual insecticide inside premises near dengue cases to kill the mosquito vector, Aedes aegypti, before it can spread the virus. While this method is effective, it is labor intensive, requires the cooperation of homeowners who may find it intrusive and exposes nontarget insects and animals to insecticide. We propose to develop a lure and kill strategy to improve the efficacy of vector control while minimising the exposure of nontarget animals. Several chemicals have been identified as highly attractive to dengue mosquitoes. Among these are extracts from water infusions of grass that are highly attractive to egg-laying mosquitoes and emanations from human skin that attract host-seeking mosquitoes. We will develop traps incorporating a. mosquito attractants and b. a killing agent to selectively control Ae. aegypti mosquitoes. These will be collectively called lethal traps. This project will employ the following approach towards the development of a lure and kill strtaegy for dengue control a. determine which compounds are most attractive to north Queensland Ae. aegypti in a laboratory wind tunnel; b. confirm the attraction of these compounds using sticky traps in the field; c. conduct field trials of candidate lethal traps to determine the spacing and density of traps needed to control mosquitoes d. conduct a large field trial to examine the efficacy of the optimised lure and kill strategy. We will also conduct ecological studies on aging and the flight range of Ae. aegypti to enhance the development of the strategy.Read moreRead less
Design And Development Of Inhibitors Of The Dengue Virus Protease As Antiviral Drugs
Funder
National Health and Medical Research Council
Funding Amount
$362,513.00
Summary
Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This proposal focuses on a virus specific enzyme. This enzyme (called a protease) is es ....Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This proposal focuses on a virus specific enzyme. This enzyme (called a protease) is essential for the virus to multiply and so it is a potential target for new drugs that can bind to it and block its function. We have produced and purified this viral enzyme in the laboratory and now propose to design, synthesize, and develop the first drugs for the treatment of humans infected with dengue virus. We plan to do this by examining the action of the enzyme, determining its three dimensional structure, and using computers and chemical methods to obtain very powerful blockers of enzyme action. These drug candidates will be tested against the enzyme, against cells infected with virus, and in rats to find out if they can be administered by mouth or by injection and if they have any toxic side effects. This project will provide valuable information about how to develop drugs to stop dengue fever and its associated illnesses.Read moreRead less
Understanding Novel Viral Host Interactions That Modulate Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$764,246.00
Summary
Lethal viruses such as coronaviruses (MERS, SARS-CoV-1, SARS-CoV-2), Dengue, Zika, Hendra, and Nipah have developed effective mechanisms of replication by dampening the host immune system. Here we will examine how viruses carry out these immune evasion functions, and test antiviral drugs that can prevent these effects in a highly specific manner. If this idea can be proved, it will provide great promise for the development of new antivirals whilst minimising the toxic effects to the cell.