2. Academic Validation
  3. AWZ1066S, a highly specific anti- Wolbachia drug candidate for a short-course treatment of filariasis

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

  • Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1414-1419. doi: 10.1073/pnas.1816585116.
W David Hong 1 2,  Farid Benayoud 3,  Gemma L Nixon 1,  Louise Ford 2,  Kelly L Johnston 2,  Rachel H Clare 2,  Andrew Cassidy 2,  Darren A N Cook 2,  Amy Siu 3,  Motohiro Shiotani 4,  Peter J H Webborn 5,  Stefan Kavanagh 5,  Ghaith Aljayyoussi 2,  Emma Murphy 2,  Andrew Steven 2,  John Archer 2,  Dominique Struever 6,  Stefan J Frohberger 6,  Alexandra Ehrens 6,  Marc P Hübner 6,  Achim Hoerauf 6,  Adam P Roberts 2,  Alasdair T M Hubbard 2,  Edward W Tate 7,  Remigiusz A Serwa 7,  Suet C Leung 1 2,  Li Qie 1,  Neil G Berry 1,  Fabian Gusovsky 3,  Janet Hemingway 8,  Joseph D Turner 2,  Mark J Taylor 2,  Stephen A Ward 9,  Paul M O'Neill 10
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Liverpool, L69 7ZD Liverpool, United Kingdom.
  • 2 Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom.
  • 3 Eisai AiM Institute, Eisai, Inc., Andover, MA 01810.
  • 4 Drug Safety, Eisai Co., Ltd., 300-2635 Tsukuba, Japan.
  • 5 Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca UK, CB2 0AA Cambridge, United Kingdom.
  • 6 Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, 53127 Bonn, Germany.
  • 7 Department of Chemistry, Imperial College London, SW7 2AZ London, United Kingdom.
  • 8 Department of International Health, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk pmoneill@liverpool.ac.uk.
  • 9 Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom; janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk pmoneill@liverpool.ac.uk.
  • 10 Department of Chemistry, University of Liverpool, L69 7ZD Liverpool, United Kingdom; janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk pmoneill@liverpool.ac.uk.
PMID: 30617067 DOI: 10.1073/pnas.1816585116
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.

Keywords

anti-Wolbachia; drug discovery; lymphatic filariasis; macrofilaricide; onchocerciasis.

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