AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis
File(s)
Published version
Author(s)
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.
Date Issued
2019-01-22
Date Acceptance
2018-11-09
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (4), pp.1414-1419
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/).
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000456336100049&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
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
Publication Status
Published
Date Publish Online
2019-01-22