title: A modular toolkit to inhibit proline-rich motif-mediated protein-protein interactions.
abstract: Small-molecule competitors of protein-protein interactions are urgently needed for functional analysis of large-scale genomics and proteomics data. Particularly abundant, yet so far undruggable, targets include domains specialized in recognizing proline-rich segments, including Src-homology 3 (SH3), WW, GYF, and Drosophila enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Here, we present a modular strategy to obtain an extendable toolkit of chemical fragments (ProMs) designed to replace pairs of conserved prolines in recognition motifs. As proof-of-principle, we developed a small, selective, peptidomimetic inhibitor of Ena/VASP EVH1 domain interactions. Highly invasive MDA MB 231 breast-cancer cells treated with this ligand showed displacement of VASP from focal adhesions, as well as from the front of lamellipodia, and strongly reduced cell invasion. General applicability of our strategy is illustrated by the design of an ErbB4-derived ligand containing two ProM-1 fragments, targeting the yes-associated protein 1 (YAP1)-WW domain with a fivefold higher affinity.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Robert
authors.initials: R
authors.lastname: Opitz
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department für Chemie, Universität zu Köln, 50939 Köln, Germany;
authors.forename: Cédric
authors.initials: C
authors.lastname: Reuter
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Barone
authors.affiliation: Department für Chemie, Universität zu Köln, 50939 Köln, Germany;
authors.forename: Arne
authors.initials: A
authors.lastname: Soicke
authors.affiliation: Max Delbrück Centrum für Molekulare Medizin, 13125 Berlin, Germany; and.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Roske
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Kirill
authors.initials: K
authors.lastname: Piotukh
authors.affiliation: Department für Chemie, Universität zu Köln, 50939 Köln, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Huy
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Monika
authors.initials: M
authors.lastname: Beerbaum
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Burkhard
authors.initials: B
authors.lastname: Wiesner
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Beyermann
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Oschkinat
authors.affiliation: Department für Chemie, Universität zu Köln, 50939 Köln, Germany; schmalz@uni-koeln.de kuehne@fmp-berlin.de.
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Schmalz
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany; schmalz@uni-koeln.de kuehne@fmp-berlin.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kühne
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004331:Drosophila melanogaster / Q000378:metabolism; D004951:Esterification; D005455:Fluorescent Antibody Technique; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008840:Microfilament Proteins / Q000737:chemistry; D008958:Models, Molecular; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry; D055232:Proline-Rich Protein Domains; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011554:Pseudopodia; D022502:Stress Fibers / Q000378:metabolism; D060589:Zyxin / Q000737:chemistry; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008024:Ligands; D008840:Microfilament Proteins; D010455:Peptides; D010750:Phosphoproteins; D060589:Zyxin; D000098662:Vasodilator-Stimulated Phosphoprotein; C011083:polyproline
keywords: Ena; VASP; actin cytoskeleton; cell migration; protein–protein interaction
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