Preclinical development of an oral anti-Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis

Taylor, Mark ORCID: https://orcid.org/0000-0003-3396-9275, von Geldern, Thomas W, Ford, Louise, Hübner, Marc P, Marsh, Kennan, Johnston, Kelly, Sjoberg, Hanna, Specht, Sabine, Pionnier, Nicolas ORCID: https://orcid.org/0000-0002-2379-4945, Tyrer, Hayley, Clare, Rachel ORCID: https://orcid.org/0000-0002-3945-0530, Cook, Darren, Murphy, Emma ORCID: https://orcid.org/0000-0001-9421-7777, Steven, Andrew, Archer, John, Bloemker, Dominique, Lenz, Franziska, Koschel, Marianne, Ehrens, Alexandra, Metuge, Haelly M, Chunda, Valerinne C, Ndongmo Chounna, Patrick W, Njouendou, Abdel J, Fombad, Fanny F, Carr, Robert, Morton, Howard E, Aljayyoussi, Ghaith, Hoerauf, Achim, Wanji, Samuel, Kempf, Dale J, Turner, Joseph ORCID: https://orcid.org/0000-0002-2185-5476 and Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 (2019) 'Preclinical development of an oral anti-Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis'. Science Translational Medicine, Vol 11, Issue 483.

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Abstract

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis ( and ) and onchocerciasis (). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti- macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.

Item Type:	Article
Subjects:	QV Pharmacology > QV 38 Drug action. WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 885 Onchocerciasis
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1126/scitranslmed.aau2086
Depositing User:	Stacy Murtagh
Date Deposited:	26 Mar 2019 17:32
Last Modified:	01 Nov 2021 12:32
URI:	https://archive.lstmed.ac.uk/id/eprint/10493

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