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

Sterkel, MORCID logo; Haines, LR; Casas-Sánchez, AORCID logo; Owino Adung'a, VORCID logo; Vionette-Amaral, RJ; Quek, SORCID logo; Rose, CORCID logo; Silva Dos Santos, MORCID logo; García Escude, NORCID logo; Ismail, HMORCID logo; +8 more...Paine, MIORCID logo; Barribeau, SM; Wagstaff, SORCID logo; MacRae, JIORCID logo; Masiga, DORCID logo; Yakob, LORCID logo; Oliveira, PLORCID logo; Acosta-Serrano, ÁORCID logo and (2021) Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis. PLoS biology, 19 (1). e3000796-. ISSN 1544-9173 DOI: 10.1371/journal.pbio.3000796
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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.


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