Discovery aids disease elimination efforts
Published on 4 September 2018
Researchers at the University of Dundee have identified a new drug target in parasites that cause major neglected tropical diseases, a discovery that contributes towards a global drive to eliminate these diseases by 2030.
African trypanosomes, transmitted by tsetse flies, cause lethal diseases in humans and livestock, known as sleeping sickness and nagana respectively. Around 70 million people in sub-Saharan Africa are thought to be at risk of contracting sleeping sickness, which kills thousands of people each year. Nagana causes vast economic harm to these countries and can exacerbate food shortages.
New drugs in development have been shown to effectively kill the parasites, but until now it has remained unclear how these drugs actually work, hindering further development of the therapies and an understanding of potential resistance mechanisms.
Taking on this challenge, a team from Dundee’s Wellcome Centre for Anti-Infectives Research examined the mode-of-action of acoziborole, a cheap, safe and effective, orally administered drug, currently progressing well in advanced clinical trials against sleeping sickness. Using cutting-edge genetic technologies, including a genome-wide gain-of-function library developed by lead author, Richard Wall, they were able to show that acoziborole targets a protein called CPSF3. Structure modelling, carried out by Iva Lukac and Fabio Zuccotto, and Cas9-based precision editing, developed by Eva Rico (published in Scientific Reports), then revealed key differences between human and parasite CPSF3, at the site where the drug binds, explaining why the drug is safe and non-toxic to humans. These findings will facilitate development of improved therapies and prediction and monitoring of drug resistance.
David Horn, Professor of Parasite Molecular Biology at the University, said, “Our starting point here was a group of potentially excellent drugs but with parasite killing mechanisms that remained a mystery. To investigate how they acted against trypanosomes, we developed and optimised a new advanced high-throughput genetic screening approach and used it to pinpoint the target of acoziborole."
"It is possible to use drugs against disease without knowing exactly how they work, but a problem arises when resistance develops because you don’t know how to tackle it and can’t set up surveillance for resistant parasites because you don’t know which genetic mutations are involved. Knowing the mode of action helps you to adapt, update and improve drugs, reduce toxicity, increase efficacy and put rational combinations together as well as understand resistance. This study is a great example of how new high-throughput and precision genetic technologies can rapidly fill that knowledge-gap. In this case, even pinpointing a key interaction with a specific site in a single enzyme. CPSF3 is now among the most comprehensively validated drug-targets in this important group of parasites”.
CPSF3 is also the target of a related compound (AN11736) in veterinary trials against nagana. Notably, CPSF3 may also be targeted by similar drugs that are effective in killing related parasites that cause other major neglected tropical diseases such as Chagas’ disease and leishmaniasis.
Acoziborole and AN11736 form part of a broader class of boron-containing compounds with many potential applications. The antitrypanosomal compounds have been progressed through pre-clinical and clinical development by Anacor, Scynexis and the Drugs for Neglected Diseases initiative (DNDi).
The new study is the result of a push to identify the targets of this increasingly important class of antitrypanosomal drugs, which offer hope of achieving a World Health Organisation target of disease control by 2030. There is currently no effective vaccine against African trypanosomes and the drugs used to treat sleeping sickness are limited in their use and efficacy due to toxicity, resistance or complexity of administration.
The paper is published today in the journal PNAS USA and the research was funded by the Wellcome Trust and the UK Medical Research Council.