Structure-function studies of the malaria drug target, mitochondrial respiratory complex III

The parasite that causes malaria infects hundreds of millions of people and causes hundreds of thousands of deaths every year, primarily in children under the age of five in Africa. Global malaria control is heavily dependent on antimalarial drugs, but resistance to the current frontline antimalarial, artemisinin, has emerged globally, threatening current control efforts. New drugs and new drug targets are urgently needed. Almost all complex cells, including the cells in our body and the single-celled parasites that cause malaria, require an energy-converting compartment called the mitochondrion to survive. Inside this mitochondrion there is a chain of protein complexes or “micro-machines” that drive the conversion of energy. These micro-machines are essential for the malaria parasite’s ability to grow inside human red blood cells, which causes the symptoms of malaria, and for their ability to spread from person to person via mosquitoes. Due to these critical roles, inhibitors that disrupt the activity of these parasite micro-machines, without affecting their human counterparts, can make effective anti-parasitic drugs. There is already one antimalarial drug, atovaquone, along with a series of inhibitors in different stages of drug development, which target complex III (CIII), the third micro-machine in the chain, but the exact details of how this complex works is currently not known. Likewise, it cannot be explained why these inhibitors interacts so well with parasite CIII, and not the human counterpart. The answers to both questions, which our project aims to provide, will likely help make better drugs.

Human CIII is made of eleven parts, eight of which supports its stability and its interactions with the other micro-machines in the chain. It was found that parasite CIII is lacking some of these eight parts, and instead contains parts not found in the human complex. These differences in malaria and human CIII composition are intriguing as they represent divergence in a fundamental cell biology process and a unique feature of this deadly infectious organism which could potentially be targeted by new drugs. It is not currently known how this divergent composition affects CIII structure and function. While atovaquone is highly potent, the malaria parasite can become resistant to it rapidly, so other inhibitors that target the parasite CIII and are active against atovaquone resistant parasites need to be developed. CIII has two pockets where drugs could bind: atovaquone binds one pocket, while some of the newly developed inhibitors bind to the other. We will use advanced structural approaches to precisely map the binding interaction of at least two inhibitors, which each bind a different pocket. This will provide critical information to support the future development of new antimalarial drugs. In summary, this project will uncover the composition, function, and mechanism of the malaria CIII focusing on the features that are divergent from the human complex. It will therefore expand the understanding of a fundamental cell biology process in divergent organisms, while also providing detailed insight into how drugs are able to inhibit malaria CIII and informing antimalarial drug development.

UKRI project details

Basic Science

Jan 2025 — Dec 2027

$1.23M

United Kingdom