Proceedings of the National Academy of Sciences of the United States of America · 2019
AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Hong W David, Benayoud Farid, Nixon Gemma L, Ford Louise, Johnston Kelly L, Clare Rachel H, Cassidy Andrew, Cook Darren A N, Siu Amy, Shiotani Motohiro, Webborn Peter J H, Kavanagh Stefan, Aljayyoussi Ghaith, Murphy Emma, Steven Andrew, Archer John, Struever Dominique, Frohberger Stefan J, Ehrens Alexandra, Hübner Marc P, Hoerauf Achim, Roberts Adam P, Hubbard Alasdair T M, Tate Edward W, Serwa Remigiusz A, Leung Suet C, Qie Li, Berry Neil G, Gusovsky Fabian, Hemingway Janet, Turner Joseph D, Taylor Mark J, Ward Stephen A, O'Neill Paul M
Аннотация
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.