ArticlePLoS pathogens2016
Pentamidine Is Not a Permeant but a Nanomolar Inhibitor of the Trypanosoma brucei Aquaglyceroporin-2.
Article in PLoS pathogens, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 61 citations in OpenAlex.
- Article
- NewRSC medicinal chemistry · 2025Article
- Structural insights into drug transport by an aquaglyceroporin.Nature communications · 2024Article
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Evolution, function and roles in drug sensitivity of trypanosome aquaglyceroporins.Parasitology · 2021Article
- Human Aquaporins: Functional Diversity and Potential Roles in Infectious and Non-infectious Diseases.Frontiers in genetics · 2021Review
- Article
- Article
- Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance in Trypanosoma brucei.PLoS neglected tropical diseases · 2020Article
- Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria.Marine drugs · 2020Review
- The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History.Tropical medicine and infectious disease · 2020Review
- Sustainable Elimination (Zero Cases) of Sleeping Sickness: How Far Are We from Achieving This Goal?Pathogens (Basel, Switzerland) · 2019Review
- Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei.Antimicrobial agents and chemotherapy · 2019Article
- Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones.Medicina (Kaunas, Lithuania) · 2019Article
- The arginine sensing and transport binding sites are distinct in the human pathogen Leishmania.PLoS neglected tropical diseases · 2019Article
- Formate-nitrite transporters carrying nonprotonatable amide amino acids instead of a central histidine maintain pH-dependent transport.The Journal of biological chemistry · 2019Article
- Protean permeases: Diverse roles for membrane transport proteins in kinetoplastid protozoa.Molecular and biochemical parasitology · 2019Review
- Insights into antitrypanosomal drug mode-of-action from cytology-based profiling.PLoS neglected tropical diseases · 2018Article
- Inducible high-efficiency CRISPR-Cas9-targeted gene editing and precision base editing in African trypanosomes.Scientific reports · 2018Article
- Targeting Channels and Transporters in Protozoan Parasite Infections.Frontiers in chemistry · 2018Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
The chemotherapeutic arsenal against human African trypanosomiasis, sleeping sickness, is limited and can cause severe, often fatal, side effects. One of the classic and most widely used drugs is pentamidine, an aromatic diamidine compound introduced in the 1940s. Recently, a genome-wide loss-of-function screen and a subsequently generated trypanosome knockout strain revealed a specific aquaglyceroporin, TbAQP2, to be required for high-affinity uptake of pentamidine. Yet, the underlying mechanism remained unclear. Here, we show that TbAQP2 is not a direct transporter for the di-basic, positively charged pentamidine. Even though one of the two common cation filters of aquaglyceroporins, i.e. the aromatic/arginine selectivity filter, is unconventional in TbAQP2, positively charged compounds are still excluded from passing the channel. We found, instead, that the unique selectivity filter layout renders pentamidine a nanomolar inhibitor of TbAQP2 glycerol permeability. Full, non-covalent inhibition of an aqua(glycero)porin in the nanomolar range has not been achieved before. The remarkable affinity derives from an electrostatic interaction with Asp265 and shielding from water as shown by structure-function evaluation and point mutation of Asp265. Exchange of the preceding Leu264 to arginine abolished pentamidine-binding and parasites expressing this mutant were pentamidine-resistant. Our results indicate that TbAQP2 is a high-affinity receptor for pentamidine. Taken together with localization of TbAQP2 in the flagellar pocket of bloodstream trypanosomes, we propose that pentamidine uptake is by endocytosis.
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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.