ArticlePLoS genetics2012
Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- Clioquinol inactivates thiamine pyrophosphate by increasing cellular oxidative stress.Redox biology · 2026Article
- New antifungal strategies and drug development against WHO critical priority fungal pathogens.Frontiers in cellular and infection microbiology · 2025Review
- Heterologous (Over) Expression of Human SoLute Carrier (SLC) in Yeast: A Well-Recognized Tool for Human Transporter Function/Structure Studies.Life (Basel, Switzerland) · 2022Review
- Existing Drugs Considered as Promising in COVID-19 Therapy.International journal of molecular sciences · 2021Review
- Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Chloroquine and hydroxychloroquine for COVID-19: Perspectives on their failure in repurposing.Journal of clinical pharmacy and therapeutics · 2021Review
- Fibrillar α-synuclein toxicity depends on functional lysosomes.The Journal of biological chemistry · 2020Article
- Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders.Fluids and barriers of the CNS · 2020Review
- Yeast α-arrestin Art2 is the key regulator of ubiquitylation-dependent endocytosis of plasma membrane vitamin B1 transporters.PLoS biology · 2019Article
- iSeq: A New Double-Barcode Method for Detecting Dynamic Genetic Interactions in Yeast.G3 (Bethesda, Md.) · 2017Article
- Prolonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine.Drug safety - case reports · 2016Article
- Partial Decay of Thiamine Signal Transduction Pathway Alters Growth Properties of Candida glabrata.PloS one · 2016Article
- Autophagy in cancer.F1000prime reports · 2015Review
- Signaling of chloroquine-induced stress in the yeast Saccharomyces cerevisiae requires the Hog1 and Slt2 mitogen-activated protein kinase pathways.Antimicrobial agents and chemotherapy · 2014Article
- Identification of yeast and human 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAr) transporters.The Journal of biological chemistry · 2014Article
- Reply to "chloroquine, an antifungal but also a fertility drug".Antimicrobial agents and chemotherapy · 2013Article
- Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine.Antimicrobial agents and chemotherapy · 2013Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 2 countries.
Funding
Abstract
Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combination of genome-wide drug-gene synthetic lethality (DGSL), gene-gene synthetic lethality (GGSL), and dosage suppression (DS) screens in the model organism Saccharomyces cerevisiae and is thus termed SL/DS for simplicity, we found that CQ inhibits the thiamine transporters Thi7, Nrt1, and Thi72 in yeast. We first discovered a thi3Δ mutant as hypersensitive to CQ using a genome-wide DGSL analysis. Using genome-wide GGSL and DS screens, we then found that a thi7Δ mutation confers severe growth defect in the thi3Δ mutant and that THI7 overexpression suppresses CQ-hypersensitivity of this mutant. We subsequently showed that CQ inhibits the functions of Thi7 and its homologues Nrt1 and Thi72. In particular, the transporter activity of wild-type Thi7 but not a CQ-resistant mutant (Thi7(T287N)) was completely inhibited by the drug. Similar effects were also observed with other quinoline-containing antimalarials. In addition, CQ completely inhibited a human thiamine transporter (SLC19A3) expressed in yeast and significantly inhibited thiamine uptake in cultured human cell lines. Therefore, inhibition of thiamine uptake is a conserved mechanism of action of CQ. This study also demonstrated SL/DS as a uniquely effective methodology for discovering drug targets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.