UCSF researchers help crack parasite genome, identify drug leads

Two UCSF research papers this week are marking major breakthroughs in the effort to tackle schistosomiasis (bilharzia), a tropical disease that infects more than 200 million people worldwide and causes long-term debilitating illness and occasional paralysis or death.

One paper documents a multinational success, led by a team at the Wellcome Trust Sanger Institute, in England, in sequencing the genome of the Schistosoma mansoni blood fluke, which has taken nearly a decade to achieve, researchers said.

Three UCSF researchers contributed to that research by identifying and characterizing the parasite’s complement of proteolytic enzymes, known as the “degradome,” which in many other biomedical contexts has provided valuable drug targets. Findings are published in the July 16, 2009 issue of “Nature” and can be found online at www.nature.com .

The second paper, published July 14, 2009 in “PLoS Neglected Tropical Diseases” and online at www.plosntds.org , documents the UCSF development of a medium-throughput screening system for the schistosome parasite and the discovery of a range of “hit” and “lead” compounds from a collection of approved drugs that may quickly translate into therapies to combat the disease.

The work was conducted jointly by the Sandler Center for Basic Research in Parasitic Diseases and the Small Molecule Discovery Center, both of which are UCSF centers affiliated with the California Institute of Quantitative Biosciences (QB3).

Just one drug is currently widely available to treat schistosomiasis, which researchers say poses the risk of encouraging the parasite’s drug resistance as aid organizations extend the current medication to more infected populations, according to Conor R. Caffrey, PhD, a research scientist in the UCSF Department of Pathology, who co-authored both papers and was senior author on the PLoS paper on the compound discovery work. The current drug also is not ideal as it mainly targets the adult stage in the life cycle of the parasite, enabling immature parasites to escape and re-establish the infection.

“Together, these two projects offer powerful tools to combat this insidious pathogen, both in expanding our understanding of the complex biology of the blood fluke, and in helping identify new drug targets and drugs,” said Caffrey, who is associated with both the Sandler Center and with QB3 at UCSF.

“Schistosomiasis is considered by many international health experts to be second only to malaria as a critically ‘neglected tropical parasitic disease’ that adversely affects global health.”

Caffrey said the disease places an estimated 600-700 million people at risk of infection. The parasite actively infects humans via the skin, taking approximately 6 weeks to reach adulthood and reproduce. For disease transmission, those eggs must be evacuated in urine or feces into fresh water, where the next parasitic stage seeks out a snail host to continue the life cycle.

“It’s a wonderfully evolved pathogen,” Caffrey said, noting the intricate parasite biology. The Sandler Center’s mission is to chemically interrupt parasite development in humans and alleviate the significant morbidity associated with the disease.

“Research with the schistosome worm presents a number of unique challenges not found with single-celled organisms, bacteria or viruses,” he said. “Developing a screening system required a series of elements to be in place concurrently, including a reliable source of the parasite.”

The Sandler Center has a “snail farm” that generates hundreds of thousands of parasites on a weekly basis, Caffrey said. The group focused on the immature parasite, rather than the adult, as the juvenile’s greater availability and smaller size make it more amenable to the robotic systems maintained at the Small Molecule Discovery Center.

“That, combined with the extensive collections of compounds at the small-molecule center, has meant that we can now screen large compound collections at a much higher rate than with the more traditional approach of screening adult parasites, either in culture or in small animal models,” Caffrey said

For the genome research, Caffrey and two other UCSF and QB3 researchers, Susan T. Mashiyama, PhD, and Mohammed Sajid, PhD, were asked to contribute to the genome project based on the track record of the Sandler Center’s research into the biology and therapeutic potential of parasite proteolytic enzymes.

Directed by James H. McKerrow, MD, PhD, a professor in the UCSF Department of Pathology, the Sandler Center has shown that proteases make excellent drug targets in many parasites and that small-molecule protease inhibitors can limit or cure experimental infections of Chagas’ disease, Human African Trypanosomiasis and schistosomiasis. The detailed characterization of the S. mansoni degradome, therefore, may similarly lead to the identification and development of new protease-targeted chemotherapies for schistosomiasis.

The “Nature” genome paper was co-authored by 56 researchers and was led by Matthew Berriman at the Wellcome Trust Sanger Institute in Cambridge, England. The multinational effort included co-authors from 21 institutes or universities in Brazil, England, France, Germany, Ireland, Japan and the United States. A full list of authors can be found online at www.nature.com .

Maha-Hamadien Abdulla and Debbie S. Ruelas were jointly the lead authors on the drug discovery paper in “PLoS Neglected Tropical Diseases.” Both are affiliated with the UCSF Sandler Center, along with co-authors Kee-Chong Lim, Fengyun Xu and James McKerrow. Additional co-authors include Brian Wolff, June Snedecor, Adam R. Renslo and Janice Williams, from the QB3 Small Molecule Discovery Center at UCSF.

UCSF research for these papers was funded by The Sandler Foundation with Susan Mashiyama receiving a PhRMA Foundation Postdoctoral Fellowship in Informatics. Researchers report no conflicts of interest in the funding of this research.

Established in 2001, the Sandler Center for Basic Research in Parasitic Diseases is a research consortium at UCSF dedicated to the discovery of affordable, safe and effective drugs to treat the “neglected tropical diseases,” including Chagas’ disease, sleeping sickness, leishmaniasis and schistosomiasis. For further information, visit www.sandler.ucsf.edu .

The UCSF Small Molecule Discovery Center aims is to assist UC researchers in the identification of small molecules that modulate biochemical or cellular processes and have the potential to alter disease states. The SMDC works with investigator labs to develop and execute high-throughput assays and identifies those targets with the greatest potential for follow-up medicinal chemistry. (smdc.ucsf.edu/index.htm)

QB3 is a cooperative effort among private industry and more than 200 laboratories at UCSF, UC Berkeley and UC Santa Cruz. Established in 2000 by the California Governor as an economic engine, the Institute harnesses the quantitative sciences to integrate and enhance scientific understanding of biological systems, enabling scientists to accelerate discovery and innovation to benefit society. (www.qb3.org)

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, visit www.ucsf.edu.