eLife Assessment: Insights from aquaporin structures into drug-resistant sleeping sickness

In this important study, the authors set out to determine the molecular interactions between the AQP2 from Trypanosoma brucei (TbAQP2) and the trypanocidal drugs pentamidine and melarsoprol to understand how TbAQP2 mutations lead to drug resistance.Using cryo-EM, molecular dynamics simulations, and lysis assays the authors present convincing evidence that mutations in TbAQP2 make permeation of trypanocidal drugs energetically less favourable, and that this impacts the ability of drugs to achieve a therapeutic dose.Overall, this data will be of interest for those working on aquaporins, and development of trypanosomiasis drugs as well as drugs targeting aquaporins in general.Abstract Trypanosoma brucei is the causal agent of African trypanosomiasis in humans and animals, the latter resulting in significant negative economic impacts in afflicted areas of the world.Resistance has arisen to the trypanocidal drugs pentamidine and melarsoprol through mutations in the aquaglyceroporin TbAQP2 that prevent their uptake.Here, we use cryogenic