Structural analysis of the Plasmodium V-ATPase bound to antimalarial lead compounds.

Malaria, a disease caused by infection of red blood cells by single-celled Plasmodium parasites, imposes a significant health burden around the world. Over half the world’s population is exposed to malaria, resulting in 247 million cases and 619,000 deaths in 2021 alone. These malaria infections are increasingly drug resistant, and with climate change, the number of people exposed to malaria is increasing every year. Discovery of new malaria treatments is urgently needed. Plasmodium parasites possess an important molecule called the V-ATPase. The V-ATPase is responsible for controlling acid/base balance in different parts of the Plasmodium cell and helps the parasite acidify the red blood cells that they infect. The parasite does this to digest the hemoglobin of the red blood cells, allowing it to grow and replicate. Recent experiments identified the Plasmodium V-ATPase as a target for candidate antimalarial drugs because blocking the parasite’s V-ATPase with drugs causes Plasmodium cells to die. The investigator will look at the Plasmodium V-ATPase bound to new antimalarial drugs. The team will use a technique called electron cryomicroscopy to reveal the structure of the drug-bound V-ATPase at extremely high resolution. This technique is particularly well-suited to look at the interactions of drugs and large, dynamic molecules like the V-ATPase and determine the positions of all the atoms in the V-ATPase and the drug candidates. This atomic-resolution information will tell us how these new drugs work to slow down or stop the V-ATPase. Determining the high-resolution structures of the Plasmodium V-ATPase bound to candidate antimalarial drugs will guide the development of safer, more effective antimalarial drugs, helping to reduce the global health burden of malaria.

Project details

Basic Science
Drug-based Strategies
Enabling Technologies & Assays

Sep 2024 — Aug 2027

$84,214

Canada