Anti-Wolbachia drugs for filariasis

• Published in: Trends in parasitology Vol. 37; no. 12; pp. 1068 - 1081
• Main Authors: Johnston, Kelly L., Hong, W. David, Turner, Joseph D., O’Neill, Paul M., Ward, Stephen A., Taylor, Mark J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2021
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Bancroftian filariasis; Drug Discovery; Elephantiasis, Filarial - drug therapy; endosymbionts; Humans; lymphatic filariasis; Nematoda; Nematode Infections - drug therapy; onchocerciasis; Onchocerciasis - drug therapy; parasitology; pharmacodynamics; pharmacokinetics; Wolbachia; lymphatic filariasis; onchocerciasis; drug discovery; Wolbachia
• ISSN: 1471-4922; 1471-5007; 1471-5007
• DOI: 10.1016/j.pt.2021.06.004

The mutualistic association between Wolbachia endosymbionts and their filarial nematode hosts has been exploited as a validated drug target delivering macrofilaricidal outcomes. Limitations of existing antibiotics to scale-up have driven the search for new drugs, which are effective in shorter regimens of 7 days or less. Here, we review the last 14 years of anti-Wolbachia drug discovery by the anti-Wolbachia (A·WOL) consortium, which has screened more than two million compounds, delivering thousands of hit compounds. Refined screening models integrated with robust pharmacokinetic/pharmacodynamic (PK/PD) driven optimisation and selection strategies have delivered the first two drug candidates specifically designed to target Wolbachia. AWZ1066S and ABBV-4083 are currently progressing through clinical trials with the aim of delivering safe and effective macrofilaricides to support the elimination of onchocerciasis and lymphatic filariasis. Wolbachia bacterial endosymbionts are a validated drug target for onchocerciasis and lymphatic filariasis delivering macrofilaricidal outcomes.The need for a macrofilaricide is recognised as a critical requirement for onchocerciasis elimination by the World Health Organization (WHO) neglected tropical disease (NTD) roadmap 2021–2030.The anti-Wolbachia (A·WOL) consortium has screened >two million compounds delivering 20 000+ hits and dozens of new chemical series.Two A·WOL clinical candidates – AWZ1066S and ABBV-4083 – are currently progressing through Phase I and Phase II clinical trials.