What is the context of this research?
Our goal is to chemically sterilize the male Anopheles gambiae mosquito to reduce the spread of malaria in Africa. The reason to target the male is that only female mosquitoes bite people, so releasing sterilized males poses no risk of disease. Our current target is a male-specific enzyme called A. gambiae transglutaminase, or AgTG3.
Transglutaminases bond proteins together to form a cross-linked mesh or gel. The A. gambiae male uses AgTG3 to crosslink a protein called Plugin, coagulating his semen into a gooey plug that he pushes into the female. This ‘mating plug’ is required for the female to store his sperm, so chemical inhibitors of AgTG3 should be specific chemosterilants of A. gambiae mosquitoes.
We have already purified AgTG3, developed assays for its activity, and identified several chemical inhibitors. In this project we will synthesize additional inhibitors in order to:
- Perform rigorous kinetic assays to measure the potency of our inhibitors.
- Perform crystallographic studies to determine the atomic structure of the enzyme bound to our inhibitors.
- Alter the inhibitors’ chemical structures to improve their potency and/or pharmacokinetic properties.
What is the significance of this project?
Malaria is the world’s most devastating parasitic disease causing ~1 million deaths per year, mostly children under the age of five in Sub-Saharan Africa. The war against this disease is tough: there is currently no vaccine, malaria parasites are developing resistance to current antimalarial drugs, and insecticides. Therefore, we must develop new tools to continue the fight to control, and eventually to eradicate, malaria.
The Sterile Insect Technique (SIT) has been successfully used to control many insect pests including the cattle screwworm fly, the Mediterranean fruit fly, and the tsetse fly. Yet SIT has never been successfully deployed against malaria. This is largely due to logistical or regulatory barriers to previous methods of sterilization: γ-irradiation and genetic modification.
Chemosterilization was successfully tested in mosquitoes as early as the 1970s, but never implemented due to environmental concerns related to the chemicals involved. If successful, our research has the potential to provide a new class of specific and environmentally friendly chemicals to facilitate the application of SIT in the fight against malaria.
What are the goals of the project?
Your donation will be used directly to employ an experienced research
chemist at an hourly rate to synthesize and test inhibitors of AgTG3. Our funding goal will allow this researcher to scale up synthesis of our best inhibitor specifically on this project.
Your donation will be matched by additional funds to cover the required health benefits and all the material costs required for these experiments. Backers will receive regular updates on the compounds synthesized and their activity as inhibitors of AgTG3.
We are committed to the dissemination of our research to the public: our results will be published in scientific journals adhering to the Open Access model, with acknowledgement of funding from Microryza backers. Should we be successful in determining the atomic structure of AgTG3 in complex with any inhibitors, this data will be deposited in the publicly accessible Protein Databank.