Novartis-led team discovers new antimalarial compounds
The IZPs target both liver and blood infections
A team of researchers led by Novartis and The Scripps Research Institute in the US has discovered a new family of antimalarial drug compounds that target both liver and blood infections and have the potential both to treat and prevent the disease.
Details of the discovery of the imidazolopiperazines (IZPs) have been published in Science Express, the online version of the US journal Science. The dual-acting compounds attack the Plasmodium parasite at both stages in its reproduction cycle. Most antimalarial drugs, including Novartis’ Coartem, only target parasites in the blood.
The scientists developed a novel assay to determine liver stage activity of candidate small molecules then used the assay and other tools to identify and optimise a chemical scaffold with activity on both blood- and liver-stage parasites in malaria mouse models. Several other compound classes, also with dual activity, are described and released by Novartis through ChEMBL – Neglected Tropical Disease at https://www.ebi.ac.uk/chemblntd.
Scientists from the Novartis Institutes for BioMedical Research (NIBR), through the Genomics Institute of the Novartis Research Foundation (GNF) and the Novartis Institute for Tropical Diseases (NITD), collaborated with the Scripps Research Institute and Swiss Tropical and Public Health Institute. The Wellcome Trust, Singapore Economic Development Board, and Medicines for Malaria Venture also supported the research.
This is the second new class of antimalarials discovered by the same group in the last two years and holds promise as a next-generation treatment for malaria.
‘Novartis is committed to the elimination of malaria. Programmes with our current anti-malarial treatment have helped save more than one million lives to date, but there remains much to be done,’ said Mark Fishman, NIBR president.
‘Concerns of potential future resistance to current medicines, and the need to treat liver forms of malaria, propel our scientists to devise new medicines. The chemical data from this successful study, and the methods of chemical analysis, have all been released to the public domain. Hopefully, such sharing will facilitate broad-based discovery efforts across the globe towards elimination of this disease.’
Researchers believe that future antimalarials will need to work against both blood and liver stages to bring us closer to the goal of eliminating malaria globally. The malaria parasite first infects the liver before moving to red blood cells and causing symptoms. However, after clearance in the blood, reservoirs of parasites can linger in the liver causing relapse and hampering efforts toward complete elimination of the disease.
They say it is important to develop new classes of treatment that are one step ahead of the parasite should parasite resistance to current therapies occur. In collaboration with research partners, NIBR is working on developing a pipeline of potential new treatment candidates for drug-resistant malaria. Last year’s development of the spiroindolone class, represented by NITD6094, is in Phase I human clinical trials, with Phase II expected to start early next year.
‘Compounds with dual activity are rare among current antimalarials,’ said Martin Seidel, GNF Institute Director. ‘The activity of the IZP compound class on liver-stage parasites, if it can be confirmed in clinical trials, gives promise to this class as a first-line therapy for the prevention and treatment of malaria.’
Broader commitment to fighting malaria: Novartis Malaria Initiative
This research is part of a broader commitment by Novartis to eliminate malaria. The Novartis Malaria Initiative is one of the industry’s largest access-to-medicines programmes, focused on treatment, access, capacity-building and r&d.