Title | Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Huang, J, Yuan, Y, Zhao, N, Pu, D, Tang, Q, Zhang, S, Luo, S, Yang, X, Wang, N, Xiao, Y, Zhang, T, Liu, Z, Sakata-Kato, T, Jiang, X, Kato, N, Yan, N, Yin, H |
Journal | Proc Natl Acad Sci U S A |
Volume | 118 |
Issue | 3 |
Date Published | 2021 Jan 19 |
ISSN | 1091-6490 |
Keywords | Allosteric Site, Amino Acid Sequence, Animals, Antimalarials, Crystallography, X-Ray, Glucose, Glucose Transporter Type 1, Glucose Transporter Type 3, Malaria, Falciparum, Monosaccharide Transport Proteins, Plasmodium falciparum, Protein Conformation, Protozoan Proteins, Structure-Activity Relationship |
Abstract | <p>Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a "selective starvation" strategy by inhibiting hexose transporter 1 (PfHT1), the sole hexose transporter in , over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.</p> |
DOI | 10.1073/pnas.2017749118 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 33402433 |
PubMed Central ID | PMC7826358 |