Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors

Research output: Contribution to journalJournal articleResearchpeer-review

Hans-Michael Maric, Vikram Babu Kasaragod, Linda Maria Haugaard Kedström, Torben Johann Hausrat, Matthias Kneussel, Hermann Schindelin, Kristian Strømgaard

Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD =6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay.

Original languageEnglish
JournalAngewandte Chemie (International ed. in English)
Volume54
Issue number2
Pages (from-to)490-4
Number of pages5
ISSN1433-7851
DOIs
Publication statusPublished - 7 Jan 2015

ID: 131462538