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

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Title: AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis
Authors: Hong, WD
Benayoud, F
Nixon, GL
Ford, L
Johnston, KL
Clare, RH
Cassidy, A
Cook, DAN
Siu, A
Shiotani, M
Webborn, PJH
Kavanagh, S
Aljayyoussi, G
Murphy, E
Steven, A
Archer, J
Struever, D
Frohberger, SJ
Ehrens, A
Huebner, MP
Hoerauf, A
Roberts, AP
Hubbard, ATM
Tate, EW
Serwa, RA
Leung, SC
Qie, L
Berry, NG
Gusovsky, F
Hemingway, J
Turner, JD
Taylor, MJ
Ward, SA
O'Neill, PM
Item Type: Journal Article
Abstract: 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.
Issue Date: 22-Jan-2019
Date of Acceptance: 9-Nov-2018
URI: http://hdl.handle.net/10044/1/67498
DOI: https://dx.doi.org/10.1073/pnas.1816585116
ISSN: 0027-8424
Publisher: National Academy of Sciences
Start Page: 1414
End Page: 1419
Journal / Book Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 116
Issue: 4
Copyright Statement: © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND - https://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
onchocerciasis
lymphatic filariasis
anti-Wolbachia
drug discovery
macrofilaricide
MACROFILARICIDAL ACTIVITY
LITOMOSOIDES-SIGMODONTIS
BACTERIAL ENDOSYMBIONTS
WUCHERERIA-BANCROFTI
DOUBLE-BLIND
DOXYCYCLINE
ONCHOCERCIASIS
ENDOBACTERIA
ALBENDAZOLE
ELIMINATION
MD Multidisciplinary
Publication Status: Published
Open Access location: https://www.pnas.org/content/pnas/116/4/1414.full.pdf
Online Publication Date: 2019-01-22
Appears in Collections:Chemistry
Biological and Biophysical Chemistry