May 19, 2010 An international team led by St. Jude Children's Research Hospital investigators have released data detailing the effectiveness of nearly 310,000 chemicals against a malaria parasite that remains one of the world's leading killers of young children.
The research, which appears in the May 20 edition of the scientific journal Nature, identified more than 1,100 new compounds with confirmed activity against the malaria parasite. Of those, 172 were studied in detail, leading to identification of almost two dozen families of molecules investigators consider possible candidates for drug development. St. Jude researchers already used one of the molecules to stop the parasite's growth in mice.
The six-year malaria project was launched by R. Kiplin Guy, Ph.D., St. Jude Department of Chemical Biology and Therapeutics chair, in an effort to revive malaria drug development. Guy is senior author of the study. W. Armand Guiguemde, Ph.D., a postdoctoral fellow in Guy's laboratory, is the first author.
"Malaria causes roughly 8 percent of childhood deaths worldwide and remains among the greatest threats to children in the developing world," Guy said. "At St. Jude, we focus on diseases that kill children, but lack good treatments. That is what drove us to start this work."
"These are the same tools and techniques that we are now using to find new targets and drugs to treat childhood cancer. This work illustrates their enormous power for drug discovery," said Dr. William Evans, St. Jude director and chief executive officer.
The effort has grown into a consortium that includes investigators at nine institutions and foundations in the U.S., Australia and Europe. Collaborators are taking cooperation a step further and launching a public database to share the results of their research and the underlying data.
"We've provided a toolbox to the global community and given them a lot of the early results from working with the tools so they won't have to repeat the work," Guy said. "This new information doubles the number of chemical structures available for anti-malarial drug development."
The database includes the chemical structure and activity profile of each of the 309,474 molecules in the St. Jude library of drugs, natural compounds and other chemicals. There is additional information about the 172 compounds that were more comprehensively evaluated. The compounds are all commercially available. Researchers interested in accessing the database can visit www.stjuderesearch.org/guy/data/malaria.
In recent years, malaria drug development has focused on creating medications against specific targets or on improving existing medications. The approach focused on a handful of chemical targets, and results have been disappointing.
For this study, investigators used a different strategy and surveyed the hospital's library of compounds looking for those effective against the entire malaria parasite. Scientists tested the chemicals against the Plasmodium falciparum, the deadliest of the malaria parasites. The work led St. Jude researchers to three families of molecules, including two believed to act against new targets. Investigators hope to have a new drug in the clinic within a decade.
Collaborating scientists on this project include Anang Shelat, David Smithson, Michele Connelly, Julie Clark, Fangyi Zhu, all of St. Jude; David Bouck, formerly of St. Jude; Sandra Duffy and Vicky Avery, both of Griffith University, Brisbane, Australia; Gregory Crowther, Wesley Van Voorhis, Joseph Fowble and Pradipsinh Rathod, all of the University of Washington, Seattle; Paul Davis and David Roos, both of the University of Pennsylvania, Philadelphia; María Jiménez-Díaz, María Martinez, Iñigo Angulo-Barturen and Santiago Ferrer, all of GlaxoSmithKline, Tres Cantos; Joseph DeRisi, Emily Wilson, Jiri Gut and Philip Rosenthal, all of the University of California, San Francisco; Abhai Tripathi and David Sullivan Jr., both of Johns Hopkins Bloomberg School of Public Health, Baltimore; Elizabeth Sharlow and John Lazo, both of the University of Pittsburgh; Ian Bathurst, Medicines for Malaria Venture, Geneva, Switzerland; Farah El Mazouni and Margaret Phillips, both of the University of Texas Southwestern Medical Center at Dallas; and Isaac Forquer and Michael Riscoe, Portland Veterans Administration Medical Center, Portland, Oregon.
The research was supported in part by St. Jude, the Medicines for Malaria Venture, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the Welch Foundation, the Doris Duke Charitable Foundation, the Ellison Medical Foundation and ALSAC.
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- W. Armand Guiguemde, Anang A. Shelat, David Bouck, Sandra Duffy, Gregory J. Crowther, Paul H. Davis, David C. Smithson, Michele Connelly, Julie Clark, Fangyi Zhu, María B. Jiménez-Díaz, María S. Martinez, Emily B. Wilson, Abhai K. Tripathi, Jiri Gut, Elizabeth R. Sharlow, Ian Bathurst, Farah El Mazouni, Joseph W. Fowble, Isaac Forquer, Paula L. McGinley, Steve Castro, Iñigo Angulo-Barturen, Santiago Ferrer, Philip J. Rosenthal, Joseph L. DeRisi, David J. Sullivan, John S. Lazo, David S. Roos, Michael K. Riscoe, Margaret A. Phillips, Pradipsinh K. Rathod, Wesley C. Van Voorhis, Vicky M. Avery, R. Kiplin Guy. Chemical genetics of Plasmodium falciparum. Nature, 2010; 465 (7296): 311 DOI: 10.1038/nature09099
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