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Cited by 2Trypanosoma species research and implicationsMonoclonal and Polyclonal Antibodies ResearchBiochemical and Molecular Research

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Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody

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Pinto Torres, Joar Esteban, Claes, Mathieu, Hendrickx, Rik, Yuan, Meng, Smiejkowska, Natalia, Van Wielendaele, Pieter, Hacisuleyman, Aysima, De Winter, Hans, Muyldermans, Serge, Michels, Paul AM, Walkinshaw, Malcolm D, Versées, Wim, Caljon, Guy, Magez, Stefan, Sterckx, Yann G-J·2025·eLife
DOI 10.7554/elife.100066PMC PMC11957543

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Abstract

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.

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Metadata

Authors
Pinto Torres, J. E., Claes, M., Hendrickx, R., Yuan, M., Smiejkowska, N., Van Wielendaele, P., Hacisuleyman, A., De Winter, H., Muyldermans, S., Michels, P. A., Walkinshaw, M. D., Versées, W., Caljon, G., Magez, S., & Sterckx, Y. G.-J.
Affiliations
  • Laboratory for Cellular and Molecular Immunology (CMIM), Vrije Universiteit Brussel (VUB)
  • University of Antwerp (BE)
  • University of Edinburgh (GB)
  • Laboratory of Medical Biochemistry (LMB) and the Infla-Med Centre of Excellence, University of Antwerp
  • University of Lausanne (CH)
  • Laboratory of Medicinal Chemistry, University of Antwerp
  • Vrije Universiteit Brussel (BE)
Corresponding author
Sterckx, Yann G-J
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-03-31
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.100066
PMC
PMC11957543
OpenAlex
W4401726653
Cited by
2
References
3
Citations by year
2026: 1 · 2025: 1
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • IRIS (submittedVersion, cc-by)
  • Lirias (KU Leuven) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Vrije Universiteit Brussel (SRP95)
  • Universiteit Gent (BOF.STG.2018.0009.01/01N01518)
  • Universiteit Antwerpen (41391)
  • Fonds Wetenschappelijk Onderzoek (G013518N, 1137622N)
  • COST Action CA21111 (CA21111)
Topics
  • Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
allosteric inhibition, nanobodies, African trypanosomes, trypanocidal drugs, glycolysis, parasite energy metabolism, enzyme kinetics, drug resistance
MeSH terms
Camelidae, Allosteric Regulation, Animals, Kinetics, Pyruvate Kinase, Trypanosoma brucei brucei, Protozoan Proteins, Single-Domain Antibodies

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