Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.

Thomas W. von Geldern; Howard E. Morton; Rick F. Clark; Brian S. Brown; Kelly Johnston; Louise Ford; Sabine Specht; Robert A. Carr; Deanne F. Stolarik; Junli Ma; Matthew J. Rieser; Dominique Struever; Stefan J. Frohberger; Marianne Koschel; Alexandra Ehrens; Joseph Turner; Marc P. Hübner; Achim Hoerauf; Mark Taylor; Steve Ward; Kennan Marsh; Dale J. Kempf

doi:10.1371/journal.pntd.0007159

Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.

Thomas W. von Geldern, Howard E. Morton, Rick F. Clark, Brian S. Brown, Kelly Johnston, Louise Ford, Sabine Specht, Robert A. Carr, Deanne F. Stolarik, Junli Ma, Matthew J. Rieser, Dominique Struever, Stefan J. Frohberger, Marianne Koschel, Alexandra Ehrens, Joseph Turner, Marc P. Hübner, Achim Hoerauf, Mark Taylor, Steve WardKennan Marsh, Dale J. Kempf

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32 Citations (Scopus)

Abstract

There is a significant need for improved treatments for onchocerciasis and lymphatic filariasis, diseases caused by filarial worm infection. In particular, an agent able to selectively kill adult worms (macrofilaricide) would be expected to substantially augment the benefits of mass drug administration (MDA) with current microfilaricides, and to provide a solution to treatment of onchocerciasis / loiasis co-infection, where MDA is restricted. We have identified a novel macrofilaricidal agent, Tylosin A (TylA), which acts by targeting the worm-symbiont Wolbachia bacterium. Chemical modification of TylA leads to improvements in anti-Wolbachia activity and oral pharmacokinetic properties; an optimized analog (ABBV-4083) has been selected for clinical evaluation.

Original language	English
Article number	e0007159
Pages (from-to)	e0007159
Journal	PLoS Neglected Tropical Diseases
Volume	13
Issue number	2
DOIs	https://doi.org/10.1371/journal.pntd.0007159
Publication status	Published - 28 Feb 2019

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Ward-PLOS-Mar-19Accepted author manuscript, 2.11 MBLicence: CC BY

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von Geldern, T. W., Morton, H. E., Clark, R. F., Brown, B. S., Johnston, K., Ford, L., Specht, S., Carr, R. A., Stolarik, D. F., Ma, J., Rieser, M. J., Struever, D., Frohberger, S. J., Koschel, M., Ehrens, A., Turner, J., Hübner, M. P., Hoerauf, A., Taylor, M., ... Kempf, D. J. (2019). Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity. PLoS Neglected Tropical Diseases, 13(2), e0007159. Article e0007159. https://doi.org/10.1371/journal.pntd.0007159

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title = "Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.",

abstract = "There is a significant need for improved treatments for onchocerciasis and lymphatic filariasis, diseases caused by filarial worm infection. In particular, an agent able to selectively kill adult worms (macrofilaricide) would be expected to substantially augment the benefits of mass drug administration (MDA) with current microfilaricides, and to provide a solution to treatment of onchocerciasis / loiasis co-infection, where MDA is restricted. We have identified a novel macrofilaricidal agent, Tylosin A (TylA), which acts by targeting the worm-symbiont Wolbachia bacterium. Chemical modification of TylA leads to improvements in anti-Wolbachia activity and oral pharmacokinetic properties; an optimized analog (ABBV-4083) has been selected for clinical evaluation.",

author = "\{von Geldern\}, \{Thomas W.\} and Morton, \{Howard E.\} and Clark, \{Rick F.\} and Brown, \{Brian S.\} and Kelly Johnston and Louise Ford and Sabine Specht and Carr, \{Robert A.\} and Stolarik, \{Deanne F.\} and Junli Ma and Rieser, \{Matthew J.\} and Dominique Struever and Frohberger, \{Stefan J.\} and Marianne Koschel and Alexandra Ehrens and Joseph Turner and H{\"u}bner, \{Marc P.\} and Achim Hoerauf and Mark Taylor and Steve Ward and Kennan Marsh and Kempf, \{Dale J.\}",

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von Geldern, TW, Morton, HE, Clark, RF, Brown, BS, Johnston, K , Ford, L, Specht, S, Carr, RA, Stolarik, DF, Ma, J, Rieser, MJ, Struever, D, Frohberger, SJ, Koschel, M, Ehrens, A, Turner, J, Hübner, MP, Hoerauf, A, Taylor, M , Ward, S, Marsh, K & Kempf, DJ 2019, 'Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.', PLoS Neglected Tropical Diseases, vol. 13, no. 2, e0007159, pp. e0007159. https://doi.org/10.1371/journal.pntd.0007159

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AU - Johnston, Kelly

AU - Ford, Louise

AU - Specht, Sabine

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AU - Frohberger, Stefan J.

AU - Koschel, Marianne

AU - Ehrens, Alexandra

AU - Turner, Joseph

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AU - Ward, Steve

AU - Marsh, Kennan

AU - Kempf, Dale J.

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Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.

Abstract

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