1. Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis
- Author
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Natalia Garcia Escude, Hanafy M. Ismail, Mark I. Paine, Mariana Silva dos Santos, Vincent O. Adung'a, Raquel J. Vionette-Amaral, Shannon Quek, James I. MacRae, Clair Rose, Simon C. Wagstaff, Lee R. Haines, Daniel K. Masiga, Aitor Casas-Sanchez, Laith Yakob, Pedro L. Oliveira, Seth M. Barribeau, Alvaro Acosta-Serrano, Marcos Sterkel, and Besansky, Nora J.
- Subjects
Male ,Biología ,Enzyme Metabolism ,Pharmacology ,Biochemistry ,Mice ,Tyrosine aminotransferase ,0302 clinical medicine ,Medical Conditions ,wc_705 ,Biology (General) ,Amino Acids ,Enzyme Chemistry ,media_common ,Mammals ,0303 health sciences ,Organic Compounds ,Gene silencing ,Eukaryota ,Neglected Diseases ,Bees ,3. Good health ,Blood ,Physical Sciences ,Metabolic Pathways ,General Agricultural and Biological Sciences ,Drug ,Tsetse Flies ,QH301-705.5 ,media_common.quotation_subject ,Equines ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Hydroxyl Amino Acids ,Humans ,Horses ,Rats, Wistar ,Biology ,Cyclohexanones ,Organisms ,Chemical Compounds ,Drug Repositioning ,Biology and Life Sciences ,Proteins ,Models, Theoretical ,medicine.disease ,Virology ,Invertebrates ,030104 developmental biology ,Trypanosomiasis, African ,Nitrobenzoates ,Nitisinone ,Physiological Processes ,Trypanosomiasis ,0301 basic medicine ,Insecticides ,Orphan Drug Production ,Physiology ,4-Hydroxyphenylpyruvate Dioxygenase ,Aromatic Amino Acids ,RNA interference ,Medicine and Health Sciences ,African trypanosomiasis ,qx_505 ,Tyrosine ,Transmission (medicine) ,General Neuroscience ,Ingestion ,wc_695 ,Body Fluids ,Insects ,Chemistry ,Infectious Diseases ,Vertebrates ,Metabolome ,Female ,Anatomy ,medicine.drug ,Research Article ,wc_20 ,Arthropoda ,Infectious Disease Control ,030231 tropical medicine ,Orphan drug ,Toxicity Tests ,medicine ,Animals ,030304 developmental biology ,Infection Control ,General Immunology and Microbiology ,qu_4 ,Organic Chemistry ,Rats ,Metabolism ,Amniotes ,Enzymology ,Rna interference ,Zoology ,Entomology - 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., This study shows that tsetse flies, vectors of African trypanosomiasis, are highly susceptible to killing by nitisinone, a tyrosine catabolism inhibitor currently used to treat human metabolic diseases; this environment-friendly drug could facilitate elimination of African trypanosomiasis and other diseases transmitted by blood feeding insects.
- Published
- 2021