A modular toolkit to inhibit proline-rich motif-mediated protein-protein interactions

作者：Opitz Robert; Mueller Matthias; Reuter Cedric; Barone Matthias; Soicke Arne; Roske Yvette; Piotukh Kirill; Huy Peter; Beerbaum Monika; Wiesner Burkhard; Beyermann Michael; Schmieder Peter; Freund Christian; Volkmer Rudolf; Oschkinat Hartmut; Schmalz Hans Guenther^*; Kuehne Ronald

来源：Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(16): 5011-5016.

DOI：10.1073/pnas.1422054112

• Ena
• VASP
• protein-protein interaction
• actin cytoskeleton
• cell migration

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 recognitionmotifs. 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.

• 出版日期2015-4-21