The spread of drug resistance through malaria parasite populations calls for the development of new therapeutic strategies. However, the seemingly promising genomics-driven target identification paradigm is hampered by the weak annotation coverage. To identify potentially important yet uncharacterized proteins, we apply support vector machines using profile kernels, a supervised discriminative machine learning technique for remote homology detection, as a complement to the traditional alignment based algorithms. In this study, we focus on the prediction of proteases, which have long been considered attractive drug targets because of their indispensable roles in parasite development and infection. Our analysis demonstrates that an abundant and complex repertoire is conserved in five Plasmodium parasite species. Several putative proteases may be important components in networks that mediate cellular processes, including hemoglobin digestion, invasion, trafficking, cell cycle fate, and signal transduction. This catalog of proteases provides a short list of targets for functional characterization and rational inhibitor design.
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Acknowledgments We thank the anonymous reviewers for their constructive comments. We thank PlasmoDB for providing an all-inone portal for malaria genomic data. The project described is supported by grants 1SC1GM081068, 8SC1AI080579, and R21AI067543 from the National Institute of General Medical Sciences and National Institute of Allergy and Infectious Diseases to Y. Wang. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases or the National Institutes of Health. YW is also supported by NIH grant G12RR013646, and San Antonio Area Foundation Biomedical Research Funds. RK is supported by Grant-in-Aid of Research, Artistry and Scholarship at University of Minnesota, and the Biomedical Informatics and Computational Biology Seed Grant for UM-Mayo-IBM Collaboration. JG is supported by PSC-CUNY 37 Research Award and Summer Research Award for faculty at College of Staten Island/CUNY.