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

PLoS Neglected Tropical Diseases
Thomas W von GeldernDale J Kempf

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.

References

Apr 1, 1989·Chemical & Pharmaceutical Bulletin·K KiyoshimaT Takeuchi
Aug 27, 2010·Lancet·Mark J TaylorMoses Bockarie
Dec 30, 2014·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Martin WalkerMaría-Gloria Basáñez

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Citations

Aug 6, 2019·PLoS Neglected Tropical Diseases·Marc P HübnerAchim Hoerauf
May 19, 2020·Parasite : Journal De La Société Française De Parasitologie·Michel BoussinesqSamuel Wanji
Jul 22, 2019·Tropical Medicine and Infectious Disease·Malina A Bakowski, Case W McNamara
Dec 8, 2020·PLoS Neglected Tropical Diseases·Andrea SchieferAchim Hoerauf
Mar 29, 2021·Trends in Pharmacological Sciences·Rachel H ClareNicholas R Casewell
Aug 29, 2020·Acta Tropica·Norbert W BrattigRolf Garms
Jun 4, 2021·Research and Reports in Tropical Medicine·Thuy-Huong Ta-TangJosé M Rubio
Jul 8, 2021·Trends in Parasitology·Kelly L JohnstonMark J Taylor
Feb 25, 2020·ACS Infectious Diseases·Natalie A Hawryluk
Jun 20, 2020·ACS Medicinal Chemistry Letters·Dale J Kempf, Kennan C Marsh
Oct 14, 2021·Parasitology Research·Adela NgwewondoSabine Specht

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Methods Mentioned

BETA
MDA
acylation
PCR

Software Mentioned

Operetta

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