| This research proposal describes the rational design, synthesis and biological testing of a new type of small molecule influenza therapeutics. Influenza viruses cause the common flu, but also the lethal Asian bird flu. Current antivirals such as Tamiflu attack the virus by inhibiting an essential viral enzyme. This enzyme, called sialidase, cleaves N-acetylneuraminic acid sugars from human cells. However, certain strains have already developed resistance against these antivirals by mutation of the sialidase. With this proposal innovative mechanism-based sialidase inhibitors will be developed. These inhibitors closely resemble the sialidase's natural target and also undergo the same chemical reaction as N-acetylneuraminic acid in the enzyme. Resistance development against this new type of inhibitor is unlikely because if the virus would 'successfully' mutate its sialidase it would also not be able to react with its natural target and consequently not be viable. The proposed influenza sialidase inhibitors will also be tested for inhibition of a trans-sialidase enzyme from the human parasite, Trypanosoma Cruzi. Infection with this parasite leads to Chagas disease, a serious health risk in South America. The enzyme trans-sialidase transfers N-acetylneuraminic acids from human cells to the parasite and is essential for its survival making it an interesting therapeutic target. |
