PLoS Neglected Tropical Diseases (Feb 2019)

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 L 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 D Turner,
  • Marc P Hübner,
  • Achim Hoerauf,
  • Mark J Taylor,
  • Stephen A Ward,
  • Kennan Marsh,
  • Dale J Kempf

DOI
https://doi.org/10.1371/journal.pntd.0007159
Journal volume & issue
Vol. 13, no. 2
p. e0007159

Abstract

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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.