Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis
| Autor: | 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 |
|---|---|
| Přispěvatelé: | Besansky, Nora J. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | PLoS Biology SEDICI (UNLP) Universidad Nacional de La Plata instacron:UNLP PLOS BIOLOGY PLoS Biology, Vol 19, Iss 1, p e3000796 (2021) |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |