ABSTRACT
Fifty-five mono- and disaccharide analogues were prepared and used for the construction of microarrays to uncover lectin-selective ligands. The microarray study showed that two disaccharide analogues, 28' and 44', selectively bind to Solanum tuberosum lectin (STL) and wheat germ agglutinin (WGA), respectively. Cell studies indicated that 28' and 44' selectively block the binding of STL and WGA to mammalian cells, unlike the natural ligand LacNAc, which suppresses binding of both STL and WGA to cells.
Subject(s)
Disaccharides/pharmacology , Monosaccharides/pharmacology , Plant Lectins/metabolism , Wheat Germ Agglutinins/metabolism , Carbocyanines/chemistry , Carbohydrate Conformation , Disaccharides/chemistry , Dose-Response Relationship, Drug , Fluorescent Dyes/chemistry , HeLa Cells , Humans , Ligands , Microarray Analysis , Monosaccharides/chemistry , Plant Lectins/antagonists & inhibitors , Plant Lectins/chemistry , Plant Lectins/isolation & purification , Protein Binding/drug effects , Solanum tuberosum/chemistry , Staining and Labeling , Triticum/chemistry , Wheat Germ Agglutinins/antagonists & inhibitors , Wheat Germ Agglutinins/chemistry , Wheat Germ Agglutinins/isolation & purificationABSTRACT
p21-activated kinases (PAKs) are key regulators of actin dynamics, cell proliferation and cell survival. Deregulation of PAK activity contributes to the pathogenesis of various human diseases, including cancer and neurological disorders. Using an ELISA-based screening protocol, we identified naphtho(hydro)quinone-based small molecules that allosterically inhibit PAK activity. These molecules interfere with the interactions between the p21-binding domain (PBD) of PAK1 and Rho GTPases by binding to the PBD. Importantly, they inhibit the activity of full-length PAKs and are selective for PAK1 and PAK3 in vitro and in living cells. These compounds may potentially be useful for determining the details of the PAK signaling pathway and may also be used as lead molecules in the development of more selective and potent PAK inhibitors.
Subject(s)
Protein Interaction Domains and Motifs , Protein Kinase Inhibitors/pharmacology , p21-Activated Kinases/antagonists & inhibitors , p21-Activated Kinases/metabolism , Allosteric Regulation/drug effects , Cell Line , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Enzyme Activation/drug effects , Humans , Isoenzymes , Protein Binding , Protein Kinase Inhibitors/chemistry , Small Molecule Libraries , Structure-Activity Relationship , cdc42 GTP-Binding Protein/metabolism , p21-Activated Kinases/chemistryABSTRACT
Autophagy or self-eating is a complicated cellular process that is involved in protein and organelle digestion occurring via a lysosome-dependent pathway. This process is of great importance in maintaining normal cellular homeostasis. However, disruption of autophagy is closely associated with various human diseases such as cancer, neurodegenerative disorders, heart disease and pathogen infection. Therefore, small molecules that modulate autophagy can be employed to dissect this complex process and ultimately could have high potential for the treatment of a variety of diseases. This critical review discusses general aspects of autophagy, autophagy-associated diseases and autophagy regulators for biological research and therapeutic applications (207 references).