Non-peptide G-protein activators as promising tools in cell biology and potential drug leads

Heterotrimeric G proteins are molecular switches connecting cell surface receptors with effecters but also eliciting modulatory functions on various endomembranes. A hallmark of G proteins is their guanine nucleotide sensitivity. While GDP is bound to Ga in its inactive form, ligand bound receptors stimulate Ga to release GDP and to bind GTP which triggers activation of the G protein. In addition to heptahelical receptors, other cellular proteins, some bacterial and insect toxins, and an array of pharmaceutical compounds were reported to activate or inhibit G proteins. Based on these observations low molecular weighs alkyl-substituted amino acid amides and analogues were designed as potent G protein activators. This review details the development of non-peptide receptormimetics from the lead compound 2-(3-chlorophenyl)histamine 3 to compounds like N-(2,5-diaminopentyl)dodecylamine 42 indicating first selectivity among G-protein isoforms, These compounds act similar to heptahelical receptors by catalyzing the release of GDP from Ga. Therefore the successful development of G-protein activators supports the concept of employing specifically designed pharmaceutical tools for direct G protein modulation. (C) Elsevier, Paris.