04:38pm Saturday 19 August 2017

Scientific sleuths design drugs to defeat parasitic disease

By Will Sansom

Years of work by researchers from three San Antonio institutions—the Health Science Center, The University of Texas at San Antonio and Texas Biomedical Research Institute—is resulting in modified drugs that promise to more effectively treat the world’s second-most-common parasitic disease.

Schistosomiasis, also called snail fever, is an infection of the larval worms of freshwater snails. Schistosome worms infect 261 million people in 78 countries, according to the World Health Organization. Infections result from contact with infested water during activities such as fishing, swimming and washing clothes. Complications such as immune reactions and damage to the bladder and other organs may occur, and contribute to an estimated 200,000 deaths annually. While two-thirds of the cases are in Africa, preventive treatment is required in many areas, including South America, the Caribbean, the Philippines, China and Indonesia.

The most frequently prescribed medication, praziquantel, is plentiful and inexpensive, but as its use increases, the parasite’s resistance is increasing, said Philip LoVerde, Ph.D., professor of biochemistry at the Health Science Center and co-principal investigator on a $3 million grant awarded by the National Institute of Allergy & Infectious Diseases (NIAID). The San Antonio group is modifying another medication, oxamniquine, with the goal of providing effective and inexpensive alternatives to praziquantel.

“Several funders are donating 250 million pills of praziquantel per year for each of the next five years to prevent the infection in sub-Saharan Africa,” Dr. LoVerde said. “The issue becomes, if the parasite develops drug resistance, we won’t have a backup. We need a second-line drug that can be used in combination with praziquantel, and that would be derivatives of oxamniquine.”

Dr. LoVerde is a sleuth hunting out the genetic and biochemical causes of parasitic infection, and has devoted much of his career to studying infections in the field worldwide. With his fellow sleuth, geneticist Tim Anderson, Ph.D., of Texas Biomedical Research Institute, he published the sequence of the schistosome parasite genome in Nature in 2009. They, together with P. John Hart, Ph.D., professor of biochemistry and director of the X-ray Crystallography Core Laboratory at the Health Science Center, followed this with a paper in Science in 2013 in which they identified the gene that enables the worms to resist oxamniquine therapy.

This research also determined the crystal structure of the protein encoded by the gene in the presence of oxamniquine. “These studies showed the details of how the drug bound to the protein and its mode of action,” said Dr. Hart, who is co-principal investigator on the NIAID grant.

Drs. LoVerde and Hart are working with medicinal chemist Stanton McHardy, Ph.D., of UTSA, whose team includes students. Dr. McHardy and team are taking the crystal information and synthesizing new derivatives of oxamniquine. This is an example of the work performed in the Center for Innovative Drug Discovery, which is a joint initiative of the Health Science Center and UTSA.

“We now have 12 derivatives of oxamniquine that kill schistosome species,” Dr LoVerde said. “Some kill species that previously were untreatable with this drug. It’s a huge advance.”

Oxamniquine works with a completely different mode of action than praziquantel, he said, which is critical for battling resistance. “We believe combination therapy is the only way to go,” he said.

A pilot grant of $55,000 from the Health Science Center’s President’s Collaborative Research Fund enabled the team to do experiments necessary to successfully compete for the NIAID grant of $3 million.

 UT Health Science Center


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