The making of a potent L-lactate transport inhibitor

L-lactate is an important metabolite, energy source, and signaling molecule in health and disease. In mammals, its transport across biological membranes is mediated by monocarboxylate transporters (MCTs) of the solute carrier 16 (SLC16) family. Malfunction, overexpression or absence of transporters of this family are associated with diseases such as cancer and type 2 diabetes. Moreover, lactate acts as a signaling molecule and virulence factor in certain bacterial infections. Here, we report the rational, structure-guided identification of potent, nanomolar affinity inhibitors acting on an L-lactate-specific SLC16 homologue from the bacterium Syntrophobacter fumaroxidans (SfMCT).

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Fig: Identification of SfMCT inhibitors: A Screening for L-lactate transport inhibitors using a transport inhibition assay (final inhibitor concentrations are indicated). Full names and molecular structures of the used compounds are given in Supplementary Fig. For compounds highlighted by a starKi values were determined. Residual uptake in the presence of competitor is normalized with respect to control samples without competitor (control). B–J Ki determination of selected inhibitors with displayed structures. The determined Ki values and the 95% confidence intervals are indicated in the corresponding panels. Data are represented as mean ± SEM from three to five independent experiments, each in triplicate. If not visible, error bars are smaller than symbols. Individual data points are shown as open circles.

High-resolution crystal structures of SfMCT with bound inhibitors uncovered their interaction mechanism on an atomic level and the role of water molecules in inhibitor binding. The presented systematic approach is a valuable procedure for the identification of L-lactate transport inhibitors. Furthermore, identified inhibitors represent potential tool compounds to interfere with monocarboxylate transport across biological membranes mediated by MCTs.

Bosshart, P.D., Kalbermatter, D., Bonetti, S. et al. The making of a potent L-lactate transport inhibitor. Commun Chem 4, 128 (2021). https://doi.org/10.1038/s42004-021-00564-5

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