Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody
African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.
Authors
- Joar Esteban Pinto Torres
- Pieter Van Wielendaele (ORCID: https://orcid.org/0000-0003-1492-6165)
- Aysima Hacisuleyman (ORCID: https://orcid.org/0000-0003-2471-0296)
- Paul A.M. Michels (ORCID: https://orcid.org/0000-0003-3726-6104)
- Malcolm D. Walkinshaw (ORCID: https://orcid.org/0000-0001-5955-9325)
- Serge Muyldermans (ORCID: https://orcid.org/0000-0002-3678-3575)
- Rik Hendrickx (ORCID: https://orcid.org/0000-0002-6751-4909)
- Meng Yuan (ORCID: https://orcid.org/0000-0001-9754-4503)
- Hans De Winter
- Yann G.‐J. Sterckx (ORCID: https://orcid.org/0000-0002-7420-0983)
- Wim Versées (ORCID: https://orcid.org/0000-0002-4695-696X)
- Natalia Smiejkowska (ORCID: https://orcid.org/0000-0001-7488-6009)
- Guy Caljon (ORCID: https://orcid.org/0000-0002-4870-3202)
- Mathieu Claes (ORCID: https://orcid.org/0000-0001-6396-0963)
- Stefan Magez
Institutions
- Vrije Universiteit Brussel (BE)
- University of Antwerp (BE)
- Ghent University (BE)
- Ghent University Global Campus (KR)
- VIB-VUB Center for Structural Biology (BE)
- University of Lausanne (CH)
- University of Edinburgh (GB)
Publication Details
- Journal
- eLife
- Published
- 2024-08-21
- DOI
- https://doi.org/10.7554/elife.100066
- Citations
- 2
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 0.77
Funders
- Fonds Wetenschappelijk Onderzoek
- Universiteit Gent
- Vrije Universiteit Brussel
- Universiteit Antwerpen
- Vlaamse regering