Scientists Discover New Compound That Kills Drug-Resistant Malaria

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Scientists at the Centre for Molecular Design and Preformulations, at Toronto General Hospital created a chemical compound in their laboratory that can bind itself to the malaria enzyme and prevent it from replicating.


Their research paper entitled, A Potent, Covalent Inhibitor of ODCase with Antimalarial Activity , was published today in the Journal of Medicinal Chemistry. However, clinical trials on humans are three to five years away.

“Our work paves the way for a new class of drugs that could help combat this debilitating disease. We have the extensive expertise and sophisticated technology to design compounds which specifically target this parasitic enzyme and kill it,” said lead author of the study Dr. Lakshmi Kotra, Co-Director at the Centre for Molecular Design and Preformulations, Scientist , Division of Cellular & Molecular Biology, Toronto General Research Institute and Assistant Professor of Chemistry and Pharmacy at the University of Toronto . “We are able to take basic biological findings and translate them into potential therapies by designing unique and highly selective small molecule drugs.”

Professor Dr. Emil Pai, Ontario Cancer Institute, Princess Margaret Hospital, Department of Biochemistry, University of Toronto, Dr. Kevin Kain, Director, McLaughlin-Rotman Centre for Global Health and other researchers at University Health Network and the University of Toronto contributed to this work.

The synthetic compound, KP-15, was tested against several strains of human malaria, including multidrug resistant strains of Plasmodium falciparum, that causes the world’s deadliest type of malaria. The compound works by binding to and inhibiting a key enzyme required for the parasite to reproduce and survive. This is significant for potential drug treatment because this is the first time that a malaria parasite has been effected by this new class of compounds.

The compound was designed using a multidisciplinary approach using x-ray crystallography, computer modeling and medicinal chemistry, at the Centre for Molecular Design and Preformulations. X-ray crystallography is a technology in which the pattern produced by passing x-rays through the atoms in a crystal is recorded and then analyzed, in this case to reveal the three-dimensional structure of KP-15 bound to the target enzyme. The Centre then uses the knowledge of the three-dimensional structures and computer modeling tools to design new drugs.

“This is an exciting breakthrough, because this is the first step in the creation of a new anti-malarial drug,” said Dr. Kevin Kain, Director, McLaughlin-Rotman Centre for Global Health and Professor of Medicine, University of Toronto. “This discovery is an excellent example of scientists from multiple disciplines coming together to develop innovative solutions for some of the world’s most challenging global health threats. Malaria is a massive public health problem that exacts a huge toll of illness and suffering on 2 billion people. We urgently need better tools to detect and monitor emerging infectious disease threats.”

“This discovery represents an amazing new approach to finding therapeutic solutions. Evaluating the structure of abnormal proteins and genes in order to devise new drugs is an approach we will continue to pursue to cure other chronic diseases. This potential new therapy for malaria represents the first of many new treatments we hope to provide from our institution,” said Dr. Richard Weisel, Director of the Toronto General Research Institute and Professor and Chairman of the Division of Cardiac Surgery at the University of Toronto.

Malaria can be found in 105 countries and is responsible for 500 million clinical infections and more than a million deaths each year. Malaria is not an isolated problem of the developing world. Major increases in international travel and migration now place 50-80 million international travelers at risk of drug-resistant malaria each year. Each year at least 30,000 North American and European travelers contract malaria. According to Health Canada from 1990 to 2002, between 364 to 1,029 cases of malaria were reported per year, giving Canada a per capita rate three to 10 times that of the US and one of the highest rates of imported malaria in the developed world.

The global burden of malaria has increased over the last 2 decades and may continue to rise in the face of increases in drug resistance, escalating international travel and migration, ecological and climate change.
This research was partially supported by funds from a Canadian Institutes of Health Research, Johnson & Johnson-UHN Development Acceleration Award and the McLaughlin-Rotman Centre for Global Health.

About the Toronto General Research Institute
The Toronto General Research Institute (TGRI) is the research arm of the Toronto General Hospital. TGRI’s research program encompasses research in cardiology, transplantation, immunology and autoimmunity, infectious diseases, tissue injury and diabetes. Building upon this work, scientists are able to develop improved methods of treatment and cure. Organ transplants, cardiac pacemakers, novel therapies for endocrine and autoimmune disorders—all are based upon research carried out in TGRI laboratories and clinics.

About the Ontario Cancer Institute
Princess Margaret Hospital and its research arm, Ontario Cancer Institute, have achieved an international reputation as global leaders in the fight against cancer. Princess Margaret Hospital is a member of University Health Network, which also includes Toronto General Hospital and Toronto Western Hospital. All three are teaching hospitals affiliated with the University of Toronto. Source : University Health Network, February 12, 2007

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