An Anopheles gambiae mosquito, one of the world’s leading malaria vectors, in the process of obtaining its blood meal. (CDC/ James D. Gathany)
A Portland State University-led research team has developed a novel chemical compound that shows promise for the treatment and prevention of malaria, one of the world's deadliest diseases.
Malaria, a mosquito-borne infectious disease caused by Plasmodium parasites, results in approximately a quarter billion clinical cases and over a half million deaths annually.
Jane X. Kelly, the project lead and a research professor of chemistry at PSU and the VA Portland Health Care System, has spent 30 years researching antimalarial drugs, including foundational work on the acridone chemical class that she began in 2009 under the mentorship of Michael Riscoe at the VA. For more than a decade, she has worked alongside Papireddy Kancharla, an associate research professor of chemistry at PSU, and PSU research chemist Rozalia Dodean to identify novel chemical entities targeting different stages of malaria.
The discovery of their leading drug candidate, named T111, has been 15 years in the making and has the potential to become a single-encounter malaria drug that would simplify treatment, prevent relapses that drive ongoing transmission and contribute meaningfully to malaria elimination efforts.
In a study published in the journal Nature Communications, Kelly's team details how T111 effectively targets all three major life-cycle stages of the malaria parasite with a single compound.
"That activity profile makes T111 a strong candidate to become a first-in-class Single Encounter Radical Cure (SERC), the kind of drug that could meaningfully change the trajectory of malaria elimination worldwide," Kelly said.
The three life-cycle stages of the malaria parasite include a liver stage, blood stage and sexual stage. When a female Anopheles mosquito carrying the parasite bites a person and takes a blood meal, it injects the parasite into them. Once inside, the parasite travels to the liver where it multiplies. Those parasites later emerge in the bloodstream to infect red blood cells.
"The number of parasites in the bloodstream is astronomical compared to what's in the liver stage," Kelly said. "This is when the patient gets sick with chills and fever."
Eventually a few of those parasites give rise to offspring, known as gametocytes, that can be taken up by a mosquito and survive. When that mosquito bites another person, the cycle begins again. Kelly says there are two species of the parasite that become dormant in the liver stage, causing relapses months, or even years later.
"With T111, a single treatment encounter could clear the parasite from all three life-cycle stages, including the dormant liver forms that cause relapse," Kelly said. "No antimalarial currently in clinical use combines all of these properties in a single drug. Existing radical-cure agents such as tafenoquine and primaquine address dormant liver-stage parasites but have significant limitations and don't cover the full life-cycle profile T111 does."
Kelly says T111 is the product of a sustained, multi-institutional effort going back to 2009. A provisional patent application for T111 has already been filed with PSU and the team is evaluating a form of T111 in non-human primates in collaboration with the Walter Reed Army Institute of Research and the Armed Forces Research Institute of Medical Sciences, as discussed in the Nature Communications article.
The next steps involve investigational new drug (IND)-enabling studies, followed by partnerships with pharmaceutical companies for clinical development.
Kancharla, the study's first author and a key partner, says the team has been working to improve how T111 is manufactured.
"Our goal has been to make the production process shorter, safer and less expensive, which is important for developing affordable new anti-malarial medicines," he said. "So far, we've made tremendous progress on this project and want to see our drug molecule in the market in coming years."
The study was selected by the editors of Nature Communications for the journal's curated highlights of the most significant recent research in microbiology and infectious diseases. Co-authors include researchers from the VA Portland Health Care System; Dominican University of California; Walter Reed Army Institute of Research; Morsani College of Medicine, University of South Florida; the Eck Institute for Global Health at the University of Notre Dame; National Institute of Allergy and Infectious Diseases; University of California San Francisco; SRI International; The University of Melbourne; Harvard T.H. Chan School of Public Health; Oregon Health & Science University; and Howard Hughes Medical Institute.