Cyplecksins Are Covalent Inhibitors of the Pleckstrin Homology Domain of Cytohesin

The covalent grip: A new class of 5-bromobarbiturates (Cyplecksins; see structure) act by a covalent mechanism to inhibit the biological function of the pleckstrin homology domain of cytohesins, small guanine nucleotide exchange factors for the Ras-like ARF-GTPases. In cells, Cyplecksins interfere with the phosphoinositol-dependent membrane recruitment of cytohesins. Cyplecksins may be useful in validating cytohesins as potential drug targets.