Parasite DNA Decoding Points Way to New Drug Development

A gene-mapping success story bodes well for developing new drugs to combat a debilitating parasitic flatworm. The parasite afflicts more than 200 million people in tropical regions across the globe. Researchers report on the complete decoding of the Schistosoma mansoni flatworm’s genome in today’s online edition of the scientific journal Nature. The flatworm, a blood fluke, causes the tropical disease known as schistosomiasis.

Conor Caffrey

Infection with the parasite can sap energy for a lifetime. Infection frequently causes severe liver disease as well as anemia. Infection also can cause reproductive problems. The growth of children can be stunted. “Schistosomiasis is a huge global health problem,” says James McKerrow, MD, PhD, director of the Sandler Center for Basic Research in Parasitic Diseases at UCSF. “Farmers can’t work in the fields. Kids can’t do well at school. It affects the social and economic structures of whole regions.” Sandler Center research scientists Conor Caffrey, PhD, Susan Mashiyama, PhD, and Mohammed Sajid, PhD, were part of the international research consortium that reported the gene mapping. The team was coordinated by the Wellcome Trust Sanger Institute in the United Kingdom. The UCSF contingent already is using the genetic information to identify potential drug targets among a class of proteins known as proteases. The targeting of proteases encoded by the genome of HIV, the AIDS virus, has been the key to survival for millions. Drug development efforts focused on proteases also may help battle tropical parasitic diseases, and the identification of suitable protease drug targets is a major focus of research at the Sandler Center. The mapping of the genome of the schistosome also increases the chance of identifying vaccine targets that are less likely to evade immune responses, and opens the way for development of a diagnostic test to determine how badly people are infected, according to McKerrow. Using the new map of the S. mansoni genome, Caffrey and colleagues identified and catalogued the parasite’s proteases. Proteases are enzymes that break down other proteins, and their activity governs important biochemical events. Caffrey and colleagues determined that the parasite has 335 different sequences of DNA that encode proteases. These proteases are grouped into 73 families, of which 60 are shared with humans. Having this map enables Caffrey and colleagues to begin to identify structural similarities and differences among proteases that are present in different types of parasites, and differences between proteases found in parasites and in humans. These structural differences often translate into differences in drug specificity. For instance, a drug might be successfully used to combat more than one parasite if the targeted protease is similar in the different species. On the other hand, it’s optimal to target protease structures that are not also found in humans. “This inventory of proteases means that we can now comprehensively examine their evolutionary relationships with other organisms, their biological interactions with and regulation by other proteins, and not least, assess the potential of individual proteases as drug targets,” Caffrey says. Drug development for schistosomiasis and other tropical parasitic diseases that are endemic in poor regions of the world has largely been neglected by major pharmaceutical companies, due to the limited potential for profit. In addition, for schistosomiasis, there already is one effective treatment, called praziquantel. “However, there is no backup drug, and considering the potential for resistance to develop against praziquantel, it’s important to identify and develop new drugs now,” Caffrey says. In a second report, appearing online this week in the journal Public Library of Science Neglected Tropical Diseases, Sandler Center researchers led by Caffrey report the development of a partially automated screening system to rapidly identify small molecules, including known drugs, that are active against schistosomes. The UCSF researchers identified promising “lead compounds,” molecules that decreased parasitic infections and disease in a mouse model of schistosomiasis. Schistosomiasis is a waterborne disease. During one stage of its life cycle, the parasite lives in certain species of freshwater snails. The larvae released from infected snails penetrate the skin of the human host, enter the bloodstream, grow into mature worms and lay eggs that are passed into water to start a new cycle of infection.

The Genome of the Blood Fluke Schistosoma Mansoni

Matthew Berriman, Brian J. Haas, Philip T. LoVerde, R. Alan Wilson, Gary P. Dillon, Gustavo C. Cerqueira, Susan T. Mashiyama, Bissan Al-Lazikani, Luiza F. Andrade, Peter D. Ashton, Martin A. Aslett, Daniella C. Bartholomeu, Gaelle Blandin, Conor R. Caffrey, Avril Coghlan, Richard Coulson, Tim A. Day, Art Delcher, Ricardo DeMarco, Appoliniare Djikeng, Tina Eyre, John A. Gamble, Elodie Ghedin, Yong Gu1, Christiane Hertz-Fowler, Hirohisha Hirai1, Yuriko Hirai1, Robin Houston, Alasdair Ivens, David A. Johnston, Daniela Lacerda, Camila D. Macedo, Paul McVeigh, Zemin Ning, Guilherme Oliveira, John P. Overington, Julian Parkhill, Mihaela Pertea, Raymond J. Pierce, Anna V. Protasio, Michael A. Quail, Marie-Adèle Rajandream, Jane Rogers, Mohammed Sajid, Steven L. Salzberg, Mario Stanke, Adrian R. Tivey, Owen White, David L. Williams, Jennifer Wortman, Wenjie Wu, Mostafa Zamanian, Adhemar Zerlotini, Claire M. Fraser-Liggett, Barclay G. Barrell and Najib M. El-Sayed

Nature
(published online July 15, 2009)

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Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening

Maha-Hamadien Abdulla, Debbie S. Ruelas, Brian Wolff, June Snedecor, Kee-Chong Lim, Fengyun Xu, Adam R. Renslo, Janice Williams, James H. McKerrow and Conor R. Caffrey

Public Library of Science Neglected Tropical Diseases
(published online July 14, 2009)

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