Toronto, ON – Researchers at the Toronto General Research Institute and Ontario Cancer Institute have discovered a synthetic compound that targets and kills malaria parasites, including a drug-resistant strain.
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.”