The discovery of a new class of dual-acting antimalarial compounds - the imidazolopiperazines (IZPs) - was published in the journal Science online, at the Science Express website[1]. The findings report on compounds that target both liver and blood infections, attacking the Plasmodium parasite at both stages in its reproduction cycle.
The findings describe how scientists developed a novel assay to determine liver stage activity of candidate small molecules, then used the assay and other tools to identify and optimize 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.
"For over a decade, Novartis has engaged in the front ranks of combating malaria, pioneering the not-for-profit supply of our antimalarial treatment Coartem® to the public sector of endemic countries," commented Joseph Jimenez, CEO of Novartis. "These new findings further demonstrate our innovative and sustainable research commitment in this important area which has become integral to our corporate strategy for social responsibility."
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. Research was supported by the Wellcome Trust, Singapore Economic Development Board, and Medicines for Malaria Venture. 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 if confirmed.
"Novartis is committed to the elimination of malaria. Programs with our current anti-malarial treatment have helped save more than one million lives[2] 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. Each year there are about 250 million cases of malaria and nearly one million deaths - mostly among children living in Africa[3].
It is important to develop new classes of treatment that are one step ahead of the parasite should parasite resistance to current therapies occur, according to researchers. 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 NITD609[4], is now in Phase I human clinical trials, with Phase II expected to commence in early 2012.
"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."
According to Elizabeth Winzeler, GNF Department Head and lead investigator, "Little was known about malaria liver stages when we started this work and as a consequence, we didn't have a good idea about how to approach the problem. Eventually we decided to develop an automated microscopy method to look for compounds that would alter the appearance of the developing liver stages. We are excited that by publishing the full set of compounds active in both blood and liver stages, new targets might be identified."
Broader commitment to fighting malaria: Novartis Malaria Initiative
This research is part of a broader commitment by Novartis in the fight against malaria. The Novartis Malaria Initiative is one of the pharmaceutical industry's largest access-to-medicines programs, focused on treatment, access, capacity-building and research & development. Over the last decade, the initiative has delivered over 400 million treatments without profit to the public sector, in more than 60 countries, and has helped save more than one million lives[2]. Novartis believes that increasing access to medicines in developing countries is not just a matter of buying medicines and distributing them, it also requires bringing together good clinical practice, logistics management and other expertise to ensure a long-term sustainable approach to improving health.
About Novartis
Novartis Institutes for BioMedical Research (NIBR) is the global pharmaceutical research organization for Novartis. NIBR's research network is comprised of more than 6,000 scientists, physicians and business professionals working together across more than ten locations to discover innovative medicines to treat diseases with high unmet medical need. GNF is located in San Diego, CA; NITD is in Singapore.
Headquartered in Cambridge, MA, NIBR is an affiliate of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2010, the Group's continuing operations achieved net sales of USD 50.6 billion, while approximately USD 9.1 billion (USD 8.1 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 121,000 full-time-equivalent associates and operate in more than 140 countries around the world.
1. Imaging of Plasmodium liver stages to drive next generation antimalarial drug discovery. Science Express, Nov. 17, 2011. Copies of paper available to reporters through
2. Estimate based on the ratio between annual malaria cases and deaths published in the WHO World Malaria Report, a distribution analysis of the cumulatively supplied artemether-lumefantrine treatments over time and the efficacy rate of artemether-lumefantrine as per published clinical trial data.
3. World Health Organization, World Malaria Report 2010. P 60.
4. http://www.sciencemag.org/content/329/5996/1175.abstract