The experimental power of FR900359 to study Gq-regulated biological processes.

Despite the discovery of heterotrimeric αßγ G proteins ∼25 years ago, their selective perturbation by cell-permeable inhibitors remains a fundamental challenge. Here we report that the plant-derived depsipeptide FR900359 (FR) is ideally suited to this task. Using a multifaceted approach we systematically characterize FR as a selective inhibitor of Gq/11/14 over all other mammalian Gα isoforms and elaborate its molecular mechanism of action. We also use FR to investigate whether inhibition of Gq proteins is an effective post-receptor strategy to target oncogenic signalling, using melanoma as a model system. FR suppresses many of the hallmark features that are central to the malignancy of melanoma cells, thereby providing new opportunities for therapeutic intervention. Just as pertussis toxin is used extensively to probe and inhibit the signalling of Gi/o proteins, we anticipate that FR will at least be its equivalent for investigating the biological relevance of Gq.

Novel insights into appropriate encapsulation methods for bioactive compounds into polymers: a study with peptides and HDAC inhibitors.

The use of different nanoparticles (NPs) for successful encapsulation of bioactive substances is discussed. The inclusion efficiency into liposomes, acetalated dextran (Ac-Dex), and variants of poly[(lactic acid)-co-(glycolic acid)] (PLGA) NPs is analyzed after chemical degradation. Efficient inclusion of SIRT1 inhibitor Ex527 in liposomes, Ac-Dex- and PLGA-NPs is observed for all procedures used. Activity of Ex527 is demonstrated by monitoring the acetylation status of SIRT1-target p53. In contrast, small peptides are only incorporated into acid-terminated PLGA-NPs and marginally into Ac-Dex-NPs. The yield depends on peptide sequence and terminal modifications. Activity is exemplified for angiotensin II using the dynamic mass redistribution technology.