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UCT researcher leads discovery of new anti-malaria drug candidate

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A new paper describes the discovery and biological profiling of an exciting new anti-malarial clinical drug candidate, MMV390048, effective against resistant strains of the malaria parasite, and across the entire parasite lifecycle, with the potential to cure and protect in a single dose. Business Day reports that the research was conducted by the University of Cape Town (UCT)’s Drug Discovery and Development Centre, H3D, and Medicines for Malaria Venture (MMV), in collaboration with a team of international researchers.

The paper is the first full disclosure of data demonstrating the antimalarial promise of MMV390048 (also known as MMV048), a compound discovered by an international team led by Professor Kelly Chibale at UCT and MMV.

“The ability of MMV048 to block all life cycle stages of the malaria parasite, offer protection against infection as well as potentially block transmission of the parasite from person to person suggests that this compound could contribute to the eradication of malaria, a disease that claims the lives of several hundred thousand people every year,” said Chibale, founder and director of H3D, founding director of the South African Medical Research Council (SAMRC) Drug Discovery Research Unit at UCT, and senior author of the paper in the report.

In 2014, MMV048 became the first new antimalarial medicine to enter phase I human studies in Africa. Today, preparations are being made to begin phase IIa human trials on this promising compound as a single-dose cure.

“This compound has enormous potential,” said Dr David Reddy, MMV’s CEO. “In addition to the exciting characteristics noted, it has the potential to be administered as a single dose, which could revolutionize the treatment of malaria. At MMV, we look forward to continuing our work in partnership with Professor Chibale and colleagues at UCT to pursue the development of this and future next-generation antimalarials.”

The report says the project has benefited from sustained funding from MMV, the South African Technology Innovation Agency (TIA) and Strategic Health Innovation Partnerships (SHIP) unit of the SAMRC. MMV’s support has also been critical in helping H3D build and reinforce their scientific networks of drug discoverers and understand the compound’s role in blocking the transmission of the malaria parasite.

Despite the positive impact of medication, indoor spraying with insecticides and the use of insecticide bed-nets, around 429,000 people died from malaria in 2015, mostly in Africa, according to the World Health Organisation’s World Malaria Report.

The paper said resistance to treatment regimens still posed a threat and highlighted the importance of developing treatments containing new chemical classes with different modes of action.

Ethiopia has been chosen for the phase-2 trial because it has a high malaria burden and there are different strains of the disease in circulation, the report says.

MMV048 is one of several drugs in the MMV pipeline, which includes a second antimalaria drug candidate identified by Chibale’s unit called UCT943. UCT943 appeared more potent than MMV048 and was more soluble, which meant it would be easier to formulate, Chibale said in the report.

Abstract
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.

Authors
Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yassir Younis, Philipp P Henrich, Tara S Abraham, Marcus CS Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María José Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew M Blagborough, Sara E. Zakutansky, Anne-Marie Zeeman, Karen L White, David M Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura María Sanz, Francisco Javier Gamo, Janette Reader, Mariette Botha, Koen J Dechering, Robert W Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Shik Lim, Jeremy Burrows, Michael J Witty, Kennan C Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh M Solapure, María Belén Jiménez-Díaz, Sergio Wittlin, Susan A Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten K Hanson, Gerard Drewes, Clemens HM Kocken, Michael J Delves, Didier Leroy, David A. Fidock, David Waterson, Leslie J Street, Kelly Chibale

Business Day report
Science Translational Medicine abstract


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