Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Developing clinically relevant synthetic agents that are capable of modulating protein-protein interactions (PPIs) has been recognized as a central goal in the Post-Genomic era. Specific control of the large and flexible PPI interfaces requires multivalent large agents. Mid-sized molecules provide a promising scaffold for designing PPI inhibitors, however, their large size often limits cell permeation, and the requirement of appropriate spatial distribution of many functional groups leads the issue of chemical tractability. In an effort to explore a new methodology of designing mid-sized PPI inhibitors to target intracellular targets, we have studied the strategy based on assembling small module compounds to create multivalent mid-sized agents. Herein, I describe three particular approaches based on the module assembly; metal-coordination-based ligand assembly, assembly of two modules for a pocket and a local surface, and intracellular assembly to generate an inhibitor in cells. These agents were shown to possess abilities to recognize targeted protein surfaces selectively and inhibit their PPIs in cells. This strategy may open a general approach that are applicable for regulation of intracellular PPIs by synthetic molecules.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
A series of imidazole-containing peptidomimetic PFTase inhibitors and their co-crystal structures bound to PFTase and FPP are reported. The structures reveal that the peptidomimetics adopt a similar conformation to that of the extended CVIM tetrapeptide, with the imidazole group coordinating to the catalytic zinc ion. Both mono- and bis-imidazole-containing derivatives, 13 and 16, showed remarkably high enzyme inhibition activity against PFTase in vitro with IC50 values of 0.86 and 1.7 nM, respectively. The peptidomimetics were also highly selective for PFTase over PGGTase-I both in vitro and in intact cells. In addition, peptidomimetics 13 and 16 were found to suppress tumor growth in nude mouse xenograft models with no gross toxicity at a daily dose of 25 mg kg−1.
Abstract Diterpene glucoside fusicoccin A (FC-A) is a phytotoxic fungal metabolite that stabilizes the interactions between 14-3-3 protein and phosphorylated ligand protein. 14-3-3-mediated protein binding is central to the regulation of the serine/threonine kinase signaling pathway in all eukaryotic cells and is essential for controlling numerous biological processes. Thus, fusicoccins could serve as a robust platform for developing new chemical probes and pharmaceuticals. This review describes recent progress toward understanding the biosynthetic pathways of fusicoccins and the rational design of 14-3-3 inhibitors and stabilizers, as well as their antitumor activities.
Abstract Synthetic chemical probes designed to simultaneously targeting multiple sites of protein surfaces are of interest owing to their potential application as site specific modulators of protein–protein interactions. A new approach toward bivalent inhibitors of mammalian type I geranylgeranyltransferase (GGTase I) based on module assembly for simultaneous recognition of both interior and exterior protein surfaces is reported. The inhibitors synthesized in this study consist of two modules linked by an alkyl spacer; one is the tetrapeptide CVIL module for binding to the interior protein surface (active pocket) and the other is a 3,4,5‐alkoxy substituted benzoyl motif that contains three aminoalkyl groups designed to bind to the negatively charged protein exterior surface near the active site. The compounds were screened by two distinct enzyme inhibition assays based on fluorescence spectroscopy and incorporation of a [ 3 H]‐labeled prenyl group onto a protein substrate. The bivalent inhibitors block GGTase I enzymatic activity with K i values in the submicromolar range and are approximately one order of magnitude and more than 150 times more effective than the tetrapeptide CVIL and the methyl benzoate derivatives, respectively. The bivalent compounds 6 and 8 were shown to be competitive inhibitors, suggesting that the CVIL module anchors the whole molecule to the GGTase I active site and delivers the other module to the targeting protein surface. Thus, our module‐assembly approach resulted in simultaneous multiple‐site recognition, and as a consequence, synergetic inhibition of GGTase I activity, thereby providing a new approach in designing protein‐surface‐directed inhibitors for targeting protein–protein interactions.
Summary (1) Plant cell growth require the elongation of cells mediated by cell wall remodelling and turgor pressure changes. The plasma membrane (PM) H + -ATPase facilitates both cell wall remodelling and turgor pressure changes, by acidifying the apoplast of cells, referred to as acid growth. The acid growth theory is mostly established on the auxin-induced activation of PM H + -ATPase in non-photosynthetic tissues. However, how PM H + -ATPase affect the growth in photosynthetic tissues of Arabidopsis remains unclear. (2) Here, a combination of transcriptomics and cis-regulatory element analysis was conducted to identify the impact of PM H + -ATPase on global transcript levels and the molecular mechanism downstream of the PM H + -ATPase. (3) The PM H + -ATPase activation increased transcript levels globally, especially cell wall modification-related genes. The transcript level changes were in PM H + -ATPase-dependent manner. Involvement of Ca 2+ was suggested as CAMTA motif was enriched in the promoter of PM H + -ATPase-induced genes and cytosolic Ca 2+ elevated upon PM H + -ATPase activation. (4) PM H + -ATPase activation in photosynthetic tissues promote the expression of cell wall modification enzymes and shoot growth, adding a novel perspective of photosynthesis-dependent PM H + -ATPase activation in photosynthetic tissues to the acid growth theory that has primarily based on findings from non-photosynthetic tissues.
