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Probing the Chemical Space of Guanidino-Carboxylic Acids to Identify the First Blockers of the Creatine-Transporter-1. | LitMetric

Probing the Chemical Space of Guanidino-Carboxylic Acids to Identify the First Blockers of the Creatine-Transporter-1.

Mol Pharmacol

Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (C.V.F., A.E-K., M.H., A.C., W.S., T.S., M.F.); Institute of Organic Chemistry, University of Vienna, Vienna, Austria (Y.X., M.S., G.dM., M.P.F., N.M.); CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (Y.X., M.S., N.M.); AOP Orphan Pharmaceuticals GmbH, Vienna, Austria (C.K.); Christian Doppler Laboratory for Entropy-Oriented Drug Design, Institute of Organic Chemistry, University of Vienna, Vienna, Austria (N.M.); and NeGeMac Research Platform for Next Generation Macrocycles, Vienna, Austria (N.M.)

Published: November 2024

AI Article Synopsis

Article Abstract

The creatine transporter-1 (CRT-1/SLC6A8) maintains the uphill transport of creatine into cells against a steep concentration gradient. Cellular creatine accumulation is required to support the ATP-buffering by phosphocreatine. More than 60 compounds have been explored in the past for their ability to inhibit cellular creatine uptake, but the number of active compounds is very limited. Here, we show that all currently known inhibitors are full alternative substrates. We analyzed their structure-activity relationship for inhibition of CRT-1 to guide a rational approach to the synthesis of novel creatine transporter ligands. Measurements of both inhibition of [H]creatine uptake and transport associated currents allowed for differentiating between full and partial substrates and true inhibitors. This combined approach led to a refined understanding of the structural requirements for binding to CRT-1, which translated into the identification of three novel compounds - i.e., compound 1 (2-(-benzylcarbamimidamido)acetic acid), MIPA572 (=carbamimidoylphenylalanine), and MIPA573 (=carbamimidoyltryptophane) that blocked CRT-1 transport, albeit with low affinity. In addition, we found two new alternative full substrates, namely MIPA574 (carbamimidoylalanine) and GiDi1257 (1-carbamimidoylazetidine-3-carboxylic acid), which was superior in affinity to all known CTR-1 ligands, and one partial substrate, namely GiDi1254 (1-carbamimidoylpiperidine-4-carboxylic acid). SIGNIFICANCE STATEMENT: The creatine transporter-1 (CRT-1) is required to maintain intracellular creatine levels. Inhibition of CRT-1 has been recently proposed as a therapeutic strategy for cancer, but pharmacological tools are scarce. In fact, all available inhibitors are alternative substrates. We tested existing and newly synthesized guanidinocarboxylic acids for CRT-1 inhibition and identified three blockers, one partial and two full substrates of CRT-1. Our results support a refined structural understanding of ligand binding to CRT-1 and provide a proof-of-principle for blockage of CRT-1.

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Source
http://dx.doi.org/10.1124/molpharm.124.000995DOI Listing

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