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Proc Natl Acad Sci U S A. 2019 Jan 7. pii: 201816585. doi: 10.1073/pnas.1816585116. [Epub ahead of print]

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

Author information

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.

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

PMID:
30617067
DOI:
10.1073/pnas.1816585116
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Conflict of interest statement

Conflict of interest statement: An international patent (WO2018134685) that includes chemical compounds described in this manuscript has been filed by the authors (W.D.H., F.B., M.J.T., P.M.O., and S.A.W.). Some authors (F.B., A. Siu, M.S., and F.G.) of this manuscript are full-time employees of Eisai, Inc.

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