Nucleoside analogues for the treatment of animal trypanosomiasis

Dorien Mabille; Kayhan Ilbeigi; Sarah Hendrickx; Marzuq A Ungogo; Fabian Hulpia; Cai Lin; Louis Maes; Harry P de Koning; Serge Van Calenbergh; Guy Caljon

doi:10.1016/j.ijpddr.2022.05.001

Nucleoside analogues for the treatment of animal trypanosomiasis

Int J Parasitol Drugs Drug Resist. 2022 Aug:19:21-30. doi: 10.1016/j.ijpddr.2022.05.001. Epub 2022 May 6.

Authors

Affiliations

¹ Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium. Electronic address: dorien.mabille@uantwerpen.be.
² Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium. Electronic address: kayhan.ilbeigi@uantwerpen.be.
³ Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium. Electronic address: sarah.hendrickx@uantwerpen.be.
⁴ Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. Electronic address: 2226184U@student.gla.ac.uk.
⁵ Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium. Electronic address: FHulpia@ITS.JNJ.com.
⁶ Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium. Electronic address: cai.lin@ugent.be.
⁷ Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium. Electronic address: louis.maes@uantwerpen.be.
⁸ Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. Electronic address: harry.de-koning@glasgow.ac.uk.
⁹ Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium. Electronic address: serge.vancalenbergh@ugent.be.
¹⁰ Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium. Electronic address: guy.caljon@uantwerpen.be.

Abstract

Animal trypanosomiasis (AT) is a parasitic disease with high socio-economic impact. Given the limited therapeutic options and problems of toxicity and drug resistance, this study assessed redirecting our previously identified antitrypanosomal nucleosides for the treatment of AT. Promising hits were identified with excellent in vitro activity across all important animal trypanosome species. Compound 7, an inosine analogue, and our previously described lead compound, 3'-deoxytubercidin (8), showed broad spectrum anti-AT activity, metabolic stability in the target host species and absence of toxicity, but with variable efficacy ranging from limited activity to full cure in mouse models of Trypanosoma congolense and T. vivax infection. Several compounds show promise against T. evansi (surra) and T. equiperdum (dourine). Given the preferred target product profile for a broad-spectrum compound against AT, this study emphasizes the need to include T. vivax in the screening cascade given its divergent susceptibility profile and provides a basis for lead optimization towards such broad spectrum anti-AT compound.

Keywords: Animal trypanosomiasis; Nucleoside analogues.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Drug Resistance
Mice
Nucleosides / therapeutic use
Trypanosoma congolense*
Trypanosoma*
Trypanosomiasis* / drug therapy
Trypanosomiasis* / parasitology

Substances

Nucleosides