Cargando…
Suramin action in African trypanosomes involves a RuvB-like DNA helicase
Suramin is one of the oldest drugs in use today. It is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense, and it is also used for surra in camels caused by Trypanosoma evansi. Yet despite one hundred years of use, suramin&...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520940/ https://www.ncbi.nlm.nih.gov/pubmed/37757728 http://dx.doi.org/10.1016/j.ijpddr.2023.09.003 |
_version_ | 1785110032390553600 |
---|---|
author | Albisetti, Anna Hälg, Silvan Zoltner, Martin Mäser, Pascal Wiedemar, Natalie |
author_facet | Albisetti, Anna Hälg, Silvan Zoltner, Martin Mäser, Pascal Wiedemar, Natalie |
author_sort | Albisetti, Anna |
collection | PubMed |
description | Suramin is one of the oldest drugs in use today. It is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense, and it is also used for surra in camels caused by Trypanosoma evansi. Yet despite one hundred years of use, suramin's mode of action is not fully understood. Suramin is a polypharmacological molecule that inhibits diverse proteins. Here we demonstrate that a DNA helicase of the pontin/ruvB-like 1 family, termed T. brucei RuvBL1, is involved in suramin resistance in African trypanosomes. Bloodstream-form T. b. rhodesiense under long-term selection for suramin resistance acquired a homozygous point mutation, isoleucine-312 to valine, close to the ATP binding site of T. brucei RuvBL1. The introduction of this missense mutation, by reverse genetics, into drug-sensitive trypanosomes significantly decreased their sensitivity to suramin. Intriguingly, the corresponding residue of T. evansi RuvBL1 was found mutated in a suramin-resistant field isolate, in that case to a leucine. RuvBL1 (Tb927.4.1270) is predicted to build a heterohexameric complex with RuvBL2 (Tb927.4.2000). RNAi-mediated silencing of gene expression of either T. brucei RuvBL1 or RuvBL2 caused cell death within 72 h. At 36 h after induction of RNAi, bloodstream-form trypanosomes exhibited a cytokinesis defect resulting in the accumulation of cells with two nuclei and two or more kinetoplasts. Taken together, these data indicate that RuvBL1 DNA helicase is involved in suramin action in African trypanosomes. |
format | Online Article Text |
id | pubmed-10520940 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-105209402023-09-27 Suramin action in African trypanosomes involves a RuvB-like DNA helicase Albisetti, Anna Hälg, Silvan Zoltner, Martin Mäser, Pascal Wiedemar, Natalie Int J Parasitol Drugs Drug Resist Regular article Suramin is one of the oldest drugs in use today. It is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense, and it is also used for surra in camels caused by Trypanosoma evansi. Yet despite one hundred years of use, suramin's mode of action is not fully understood. Suramin is a polypharmacological molecule that inhibits diverse proteins. Here we demonstrate that a DNA helicase of the pontin/ruvB-like 1 family, termed T. brucei RuvBL1, is involved in suramin resistance in African trypanosomes. Bloodstream-form T. b. rhodesiense under long-term selection for suramin resistance acquired a homozygous point mutation, isoleucine-312 to valine, close to the ATP binding site of T. brucei RuvBL1. The introduction of this missense mutation, by reverse genetics, into drug-sensitive trypanosomes significantly decreased their sensitivity to suramin. Intriguingly, the corresponding residue of T. evansi RuvBL1 was found mutated in a suramin-resistant field isolate, in that case to a leucine. RuvBL1 (Tb927.4.1270) is predicted to build a heterohexameric complex with RuvBL2 (Tb927.4.2000). RNAi-mediated silencing of gene expression of either T. brucei RuvBL1 or RuvBL2 caused cell death within 72 h. At 36 h after induction of RNAi, bloodstream-form trypanosomes exhibited a cytokinesis defect resulting in the accumulation of cells with two nuclei and two or more kinetoplasts. Taken together, these data indicate that RuvBL1 DNA helicase is involved in suramin action in African trypanosomes. Elsevier 2023-09-19 /pmc/articles/PMC10520940/ /pubmed/37757728 http://dx.doi.org/10.1016/j.ijpddr.2023.09.003 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Regular article Albisetti, Anna Hälg, Silvan Zoltner, Martin Mäser, Pascal Wiedemar, Natalie Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
title | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
title_full | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
title_fullStr | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
title_full_unstemmed | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
title_short | Suramin action in African trypanosomes involves a RuvB-like DNA helicase |
title_sort | suramin action in african trypanosomes involves a ruvb-like dna helicase |
topic | Regular article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520940/ https://www.ncbi.nlm.nih.gov/pubmed/37757728 http://dx.doi.org/10.1016/j.ijpddr.2023.09.003 |
work_keys_str_mv | AT albisettianna suraminactioninafricantrypanosomesinvolvesaruvblikednahelicase AT halgsilvan suraminactioninafricantrypanosomesinvolvesaruvblikednahelicase AT zoltnermartin suraminactioninafricantrypanosomesinvolvesaruvblikednahelicase AT maserpascal suraminactioninafricantrypanosomesinvolvesaruvblikednahelicase AT wiedemarnatalie suraminactioninafricantrypanosomesinvolvesaruvblikednahelicase |