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Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis

Sterkel, Marcos, Haines, Lee ORCID: https://orcid.org/0000-0001-8821-6479, Casas Sanchez, Aitor, Owino Adung’a, Vincent, Vionette-Amaral, Raquel, Quek, Shannon, Rose, Clair ORCID: https://orcid.org/0000-0001-7782-5359, Silva dos Santos, Mariana, Garcia Escude, Natalia, Ismail, Hanafy, Paine, Mark ORCID: https://orcid.org/0000-0003-2061-7713, Barribeau, Seth M., Wagstaff, Simon ORCID: https://orcid.org/0000-0003-0577-5537, MacRae, James I., Masiga, Daniel, Yakob, Laith, Oliveira, Pedro L. and Acosta-Serrano, Alvaro ORCID: https://orcid.org/0000-0002-2576-7959 (2021) 'Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis'. PLoS Biology, Vol 19, Issue 1, e3000796.

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Abstract

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce populations of insect pollinator species. Here we present a promising, environment-friendly alternative to current insecticides that targets the insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded and eliminated. RNA interference (RNAi) of either the first two enzymes in the tyrosine degradation pathway (tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD)) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, oral administration of NTBC to bumblebees did not affect their survival. Using a novel mathematical model, we show that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current disease elimination programmes.

Item Type: Article
Uncontrolled Keywords: Research Article, Biology and life sciences, Physical sciences, Medicine and health sciences
Subjects: QU Biochemistry > QU 4 General works
QX Parasitology > Insects. Other Parasites > QX 505 Diptera
WC Communicable Diseases > WC 20 Research (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 695 Parasitic diseases (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 705 Trypanosomiasis
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.pbio.3000796
SWORD Depositor: JISC Pubrouter
Depositing User: Stacy Murtagh
Date Deposited: 27 Jan 2021 10:24
Last Modified: 27 Jan 2021 10:24
URI: https://archive.lstmed.ac.uk/id/eprint/16788

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