Book chapter
Naphthoquinones: Atovaquone, and Other Antimalarials Targeting Mitochondrial Functions
Treatment and Prevention of Malaria, pp 127-139
01 Nov 2011
Abstract
Mitochondria in malaria parasites are highly divergent from their counterparts in mammalian hosts. This degree of divergence underlies the validity of mitochondrial functions as targets for antimalarial drugs. The mitochondrial electron transport chain (mtETC) at the cytochrome bc1 complex is selectively inhibited in malaria parasites by atovaquone. Proguanil, the synergistic partner of atovaquone, appears to target an alternative pathway that generates electropotential across the inner membrane of parasite mitochondria. However, the rapid emergence of atovaquone-resistance mutations effectively negates the synergistic effect of proguanil. New antimalarials targeting the mtETC with reduced propensity for resistance development could overcome this challenge. A critical function of the mtETC is to serve mitochondrially located dihydroorotate dehydrogensae (DHODH), an enzyme of the pyrimidine biosynthesis pathway. Compounds with selective activity against parasite DHODH are under development as potential new antimalarials. Recent studies on unusual tricarboxylic acid metabolism and ATP synthase structure point to additional opportunities for investigations aimed to identify other selective inhibitors.
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3 citations in Scopus
Details
- Title
- Naphthoquinones: Atovaquone, and Other Antimalarials Targeting Mitochondrial Functions
- Creators
- Akhil B. Vaidya - Department of Microbiology and Immunology Drexel University College of MedicineAshok B Vaidya - Microbiology and Immunology
- Publication Details
- Treatment and Prevention of Malaria, pp 127-139
- Series
- Milestones in Drug Therapy
- Publisher
- Springer Basel; Basel
- Resource Type
- Book chapter
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Scopus ID
- 2-s2.0-84866975784
- Other Identifier
- 991019174009004721