
A camelid single-domain antibody (sdAb42) selectively binds and stabilizes the inactive T-state conformation of trypanosomatid pyruvate kinases, thereby inhibiting their enzymatic activity through an allosteric mechanism.


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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. We propose that these results pinpoint a site of vulnerability on trypanosomatid pyruvate kinases that may be exploited for the design of novel chemotherapeutics.

### Competing Interest Statement

The authors have declared no competing interest.

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

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


Allosteric Inhibition of Trypanosomatid Pyruvate Kinases by a Camelid Single-Domain Antibody
