title: Design and synthesis of high-affinity dimeric inhibitors targeting the interactions between gephyrin and inhibitory neurotransmitter receptors.
abstract: 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.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark).
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Maric
authors.forename: Vikram Babu
authors.initials: VB
authors.lastname: Kasaragod
authors.forename: Linda
authors.initials: L
authors.lastname: Haugaard-Kedström
authors.forename: Torben Johann
authors.initials: TJ
authors.lastname: Hausrat
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.forename: Hermann
authors.initials: H
authors.lastname: Schindelin
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D017981:Receptors, Neurotransmitter / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D017981:Receptors, Neurotransmitter; C073441:gephyrin
keywords: calorimetry; drug design; medicinal chemistry; structural biology; structure-activity relationship