title: Proposal for a new therapy for drug-resistant malaria using Plasmodium synthetic lethality inference.
abstract: Many antimalarial drugs kill malaria parasites, but antimalarial drug resistance (ADR) and toxicity to normal cells limit their usefulness. To solve this problem, we suggest a new therapy for drug-resistant malaria. The approach consists of data integration and inference through homology analysis of yeast-human-Plasmodium. If one gene of a Plasmodium synthetic lethal (SL) gene pair has a mutation that causes ADR, a drug targeting the other gene of the SL pair might be used as an effective treatment for drug-resistant strains of malaria. A simple computational tool to analyze the inferred SL genes of Plasmodium species (malaria parasites Plasmodium falciparum and Plasmodium vivax for human malarial therapy, and rodent parasite Plasmodium berghei for in vivo studies of human malarias) was established to identify SL genes that can be used as drug targets. Information on SL gene pairs with ADR genes and their first neighbors was inferred from yeast SL genes to search for pertinent antimalarial drug targets. We not only suggest drug target gene candidates for further experimental validation, but also provide information on new usage for already-described drugs. The proposed specific antimalarial drug candidates can be inferred by searching drugs that cause a fitness defect in yeast SL genes.
authors.affiliation: Center for Biofluid and Biomimic Research, Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), San 31, Hyoja Dong, Namgu, Pohang 790-784, Republic of Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Center for Biofluid and Biomimic Research, Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), San 31, Hyoja Dong, Namgu, Pohang 790-784, Republic of Korea.
authors.forename: Eunseok
authors.initials: E
authors.lastname: Seo
authors.affiliation: Samsumg SDS, Trade Center ASEM Tower, Samseong 1-dong, Gangnam-gu, Seoul 135-798, Republic of Korea.
authors.forename: Yonghyun
authors.initials: Y
authors.lastname: Cho
keywords: ADR, antimalarial drug resistance; Antimalarial therapy; Drug targeting; Drug-resistant malaria; GO, gene ontology; GOA, gene ontology annotation; P., Plasmodium; PDB, Protein Data Bank; SL, synthetic lethal; SW, Smith–Waterman; Synthetic lethality