Abstract
Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.
Original language | English (US) |
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Pages (from-to) | 258-268.e12 |
Journal | Cell |
Volume | 183 |
Issue number | 1 |
DOIs | |
State | Published - Oct 1 2020 |
All Science Journal Classification (ASJC) codes
- General Biochemistry, Genetics and Molecular Biology
Keywords
- PfHT1
- Plasmodium falciparum
- antimalarial
- crystal structure
- glucose transporter
- hexose transporter
- inhibitor-binding-induced pocket
- malaria parasite
- orthosteric and allosteric dual inhibition
- structure-facilitated drug discovery