Combating Influenza Using a Novel Drug Strategy
During the last century three Influenza pandemics occurred and the threat of a new Influenza pandemic has become imminent. A new pandemic would indicate that the Influenza virus would have undergone major changes such as antigenic reassortment. Current treatments are unlikely to be effective and new vaccines and antiviral agents will be essential to combat such an outbreak.
The FluDrugStrategy approach is to develop a new class of antiviral drug candidates. The target protein is highly conserved among human strains of the virus as well as strains infecting other species, including birds. This would indicate that its rate of mutation is considerably lower than those of the surface proteins (i.e., hemagglutinin, neuraminidase and the M2 ion channel) upon which the currently available antiviral drugs act. Another feature of the target that makes it highly interesting and very promising in this context is its involvement in a variety of important viral and cellular processes. The FluDrugStrategy project will design and synthesize molecules that either inhibit or, conversely, stabilize protein-protein interactions, so that either the formation of virus particles is prevented or release of the viral genetic material does not occur.
The project combines knowledge-based design and synthesis of compounds with unique patented image analysis and mathematical algorithm software to find and develop these new types of potential antiviral molecules. The methodology allows for rapid discovery of lead molecules. Key molecules with optimal binding kinetics to the target protein will be designed and synthesized then analysed and tested in two separate experimental systems for their effect upon the virus structure and maturation process.[+] Read More
At present, vaccination is the main clinical approach to protecting against Influenza infection. However, the epitopes on the surface of the Influenza virus change rapidly, which means that a new vaccine must be developed each year. Thus, we are always one year behind, employing the vaccines raised against the previous season's prevalent viral strains and hoping that this year's prevalent strains are not too different. This approach means that the efficacy of current vaccines fluctuates greatly. For example, in 1997 this efficacy was only 50%, whereas in 1998 it was 86%. There are also two classes of antiviral medication that can be effective in the prophylaxis and treatment of Influenza. These are inhibitors of neuraminidase and of M2 ion channels. However, the Influenza virus can develop resistance to these standard antiviral drugs, and during the 2005-06 influenza season the USA CDC recommended against treatment with M2 ion channel inhibitors.
This project instead focuses on antivirals which inhibit virus maturation. This is a novel class of antivirals and is of interest for three important reasons; 1. The targets for this class of antivirals are mainly protein-protein contacts between the virus structural proteins, contacts that are crucial for correct assembly of the virus into infectious virions. 2. The target protein is highly conserved among different viruses within the same family which could result in broad range antivirals. 3. Development of drug resistance to this type of antiviral is less likely since this would affect protein-protein interactions that are critical for the overall virus particle integrity and survival.
The FluDrugStrategy project aims to produce a novel class of maturation inhibiting antiviral drug candidates against the Influenza A virus. We have chosen a systematic approach that is rapid and efficient and offers unique opportunities to define lead compounds against novel targets for antiviral therapy. The project will bring together experts from highly diverse fields starting from identification of small organic compounds that interact with virus proteins; to the design and synthesis of these compounds and derivatives thereof; to the observation and analysis of the effects of these compounds on particle formation; to testing of their efficacy in combating the influenza virus, employing unique patented technology; and, finally, to the production of novel antiviral drug candidates.
This project is expected to deliver maturation inhibiting lead compounds against the Influenza A virus. This will include the identification of substances that inhibit maturation and/or alter the structure of the influenza virus, as well as description of the mechanisms of action of these compounds.
The work will develop methods to screen fragments directed against the target protein of the Influenza A virus, molecular models for the protein target and in silico screening and determine the pharmacologically relevant properties of the lead compounds.
The work will also optimize the algorithm for detection and characterization of influenza virions in electron micrographs.
The FluDrugStrategy consortium proposes a novel class of antivirals against Influenza virus. Upon successful completion of the project we hope to have a broad range antiviral lead compound that is insensitive to virus mutation. Such an antiviral would have great value considering the evolution of the Influenza virus and the threat it poses for initiating a human pandemic.