Paper of the Month: OHSU scientists develop new drugs against T. gondii
"This important advance made by an OHSU research team of medicinal chemists and biologists offers promise for patients suffering from an extremely debilitating, widespread parasitic disease – Toxoplasma gondii – which affects one third of the world's population."
- Mary Stenzel-Poore, Ph.D.
Senior Associate Dean for Research
This month's featured paper is from the laboratory of Dr. Michael Riscoe, and is titled, "Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis." It was published in the Proceedings of the National Academy of Sciences (PNAS). The research in this paper was conducted by investigators at the Portland Veterans Affairs Medical Center, the OHSU Department of Molecular Microbiology & Immunology, the Stanley Division of Developmental Neurovirology, The Johns Hopkins University School of Medicine; the Department of Microbiology and Immunology, University of Michigan Medical School; the Centre for Drug Candidate Optimisation, Australia; the Monash Institute of Pharmaceutical Sciences, Medicines for Malaria Venture, Switzerland; and the Centre de Génétique Moléculaire, France.
Toxoplasma gondii (T. gondii), is a protozoan parasite that was first described in 1908 by Charles Nicolle and Louis Manceaux. T. gondii undergoes sexual reproduction in the small intestine of cats, and is then spread through the environment in its cyst form.
Roughly 10 percent of the U.S. population has been infected with T. gondii compared to some areas in the developing world where rates of infection are as high as 90 percent. Overall, it is estimated that one third of the world's population is infected with T. gondii.
In humans, the initial infection is usually mild, causing flu-like symptoms and lymphadenopathy. However, if T. gondii infects a woman during pregnancy, the fetus may develop a severe or fatal infection, and if a previously infected person becomes immunocompromised, the T. gondii that has been lying dormant in the brain can grow, causing encephalitis. In immunocompetent individuals, T. gondii may cause eye disease and is one of the leading causes of blindness in South America.
"Modern treatment for T. gondii can be effective, but may be difficult for patients to tolerate," said Dr. Doggett. "Current therapy also does not fully eradicate the infection leaving patients at risk for recurrent infection."
For the last five years, he and other scientists in Michael Riscoe's Lab have worked to develop T. gondii drug candidates from the core structure of endochin, an antimalarial drug that was found to have anti-Toxoplasma activity over 60 years ago.
"We have been able to build on the core structure of endochin," said Michael Riscoe, Ph.D., a research biochemist at the Portland Veterans Affairs Medical Center and professor of molecular microbiology and immunology. "The new drugs that we have made, called endochin-like quinolones (ELQs), have improved potency and pharmacologic properties against toxoplasmosis and malaria. This was an important discovery for us, because we crossed over into the territory of a clinically applicable anti-Toxolplasma drug."
In a paper published in the Proceedings of the National Academy of
Sciences (PNAS), titled, Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis, the team described the efficacy of 2 lead ELQs against T. gondii in vitro and in vivo against acute and latent infection.
"The compounds in this study proved extremely potent against T. gondii in vitro at concentrations that inhibit parasite growth at picomolar concentrations," said Dr. Riscoe. "Importantly, they were not toxic to human host cells at concentrations over ten thousand times higher than the active concentration."
The ELQs described in their paper are strong candidates for further preclinical studies and have the potential to be used to treat human toxoplasmosis. "The results from this study suggest that these compounds may be able to eradicate latent T. gondii infection," said Dr. Doggett. "If we can produce a drug that is active against latent infection, it could revolutionize how we treat patients because the vast majority of severe toxoplasmosis is due to recurrent infection."
"The next step toward clinical evaluation is further testing of the toxicology and pharmacologic properties of the lead ELQs," said Dr. Riscoe. "We will also evaluate the lead ELQs for synergy with currently used anti-Toxoplasma drugs."
"At a more basic level, the ELQ mechanism of action is an exciting area of investigation given that it represents a mechanism that is different from currently used anti-Toxoplasma drugs," said Dr. Doggett. "The library of ELQs that we have developed will allow us to further characterize the drug target and understand how to make better drugs against Toxoplasma and malaria."
Pictured: (top from left) Drs. Riscoe and Doggett; (middle) Model of ELQ-316, one of the lead anti-Toxoplasma drugs descibed in PNAS; (bottom) Vials containing anti-Toxoplasma and anti-malarial drugs made in the Riscoe lab, ELQ-271, ELQ-316 and ELQ-400.
J. Stone Doggett, M.D.
Aaron Nilsen, Ph.D.
Isaac Forquer, Ph.D.
Keith W. Wegmann, Ph.D.
Lorraine Jones-Brando, Ph.D.
Robert H. Yolken, M.D.
Susan A. Charman, Ph.D.
Kasiram Katneni, Ph.D.
Tracey Schultz, B.S.
Jeremy N. Burrows, Ph.D.
David J. Hinrichs, Ph.D.
Brigitte Meunier, Ph.D.
Vern B. Carruthers, Ph.D.
Michael K. Riscoe, Ph.D.
ABOUT THE PAPER OF THE MONTH
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.
More Published Papers
The entire list of OHSU papers published this month is here.