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AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.

Proceedings of the National Academy of Sciences of the United States of America

Authors: W David Hong, Farid Benayoud, Gemma L Nixon, Louise Ford, Kelly L Johnston, Rachel H Clare, Andrew Cassidy, Darren A N Cook, Amy Siu, Motohiro Shiotani, Peter J H Webborn, Stefan Kavanagh, Ghaith Aljayyoussi, Emma Murphy, Andrew Steven, John Archer, Dominique Struever, Stefan J Frohberger, Alexandra Ehrens, Marc P Hübner, Achim Hoerauf, Adam P Roberts, Alasdair T M Hubbard, Edward W Tate, Remigiusz A Serwa, Suet C Leung, Li Qie, Neil G Berry, Fabian Gusovsky, Janet Hemingway, Joseph D Turner, Mark J Taylor, Stephen A Ward, Paul M O'Neill

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, , using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti- 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- 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.

Copyright © 2019 the Author(s). Published by PNAS.

PMID: 30617067

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