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Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

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Abstract
Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.
Keywords
General Biochemistry, Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, General Medicine

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MLA
Alghamdi, Ali H., et al. “Positively Selected Modifications in the Pore of TbAQP2 Allow Pentamidine to Enter Trypanosoma Brucei.” BIORXIV, 2020, doi:10.1101/2020.03.08.982751.
APA
Alghamdi, A. H., Munday, J. C., Campagnaro, G. D., Gurvic, D., Svensson, F., Okpara, C. E., … De Koning, H. P. (2020). Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei. BIORXIV. https://doi.org/10.1101/2020.03.08.982751
Chicago author-date
Alghamdi, Ali H., Jane C. Munday, Gustavo D. Campagnaro, Dominik Gurvic, Fredrik Svensson, Chinyere E. Okpara, Arvind Kumar, et al. 2020. “Positively Selected Modifications in the Pore of TbAQP2 Allow Pentamidine to Enter Trypanosoma Brucei.” BIORXIV. https://doi.org/10.1101/2020.03.08.982751.
Chicago author-date (all authors)
Alghamdi, Ali H., Jane C. Munday, Gustavo D. Campagnaro, Dominik Gurvic, Fredrik Svensson, Chinyere E. Okpara, Arvind Kumar, Juan F. Quintana, Maria Esther Martin Abril, Patrik Milić, Laura Watson, Daniel Paape, Luca Settimo, Anna Dimitriou, Joanna Wielinska, Graeme Smart, Laura F. Anderson, Christopher M. Woodley, Siu Pui Ying Kelly, Hasan M. S. Ibrahim, Fabian Hulpia, Mohammed I. Al-Salabi, Anthonius A. Eze, Ibrahim A. Teka, Simon Gudin, Mark C. Field, Christophe Dardonville, Richard R. Tidwell, Mark Carrington, Paul M. O’Neill, David W. Boykin, Ulrich Zachariae, and Harry P. De Koning. 2020. “Positively Selected Modifications in the Pore of TbAQP2 Allow Pentamidine to Enter Trypanosoma Brucei.” BIORXIV. doi:10.1101/2020.03.08.982751.
Vancouver
1.
Alghamdi AH, Munday JC, Campagnaro GD, Gurvic D, Svensson F, Okpara CE, et al. Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei. BIORXIV. 2020.
IEEE
[1]
A. H. Alghamdi et al., “Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei,” BIORXIV. 2020.
@misc{8675429,
  abstract     = {Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.},
  author       = {Alghamdi, Ali H. and Munday, Jane C. and Campagnaro, Gustavo D. and Gurvic, Dominik and Svensson, Fredrik and Okpara, Chinyere E. and Kumar, Arvind and Quintana, Juan F. and Martin Abril, Maria Esther and Milić, Patrik and Watson, Laura and Paape, Daniel and Settimo, Luca and Dimitriou, Anna and Wielinska, Joanna and Smart, Graeme and Anderson, Laura F. and Woodley, Christopher M. and Kelly, Siu Pui Ying and Ibrahim, Hasan M. S. and Hulpia, Fabian and Al-Salabi, Mohammed I. and Eze, Anthonius A. and Teka, Ibrahim A. and Gudin, Simon and Field, Mark C. and Dardonville, Christophe and Tidwell, Richard R. and Carrington, Mark and O'Neill, Paul M. and Boykin, David W. and Zachariae, Ulrich and De Koning, Harry P.},
  keywords     = {General Biochemistry,Genetics and Molecular Biology,General Immunology and Microbiology,General Neuroscience,General Medicine},
  language     = {eng},
  series       = {BIORXIV},
  title        = {Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei},
  url          = {http://dx.doi.org/10.1101/2020.03.08.982751},
  year         = {2020},
}

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