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The majority of the thesis concerns the work conducted on nisin-derived semisynthetic lipopeptides. These compounds were evaluated for their antimicrobial activity and a selection of compounds showed to be as active as the parent compound nisin, while having superior stability, lower charge and lower molecular weight, making for an overall more drug-like entity. Further work was done on PRMT (Protein Arginine Methyl Transferase) peptide substrates comprising unnatural amino acids and their ability to tune PRMT activity. Finally, the synthesis of a fluorescent amino acid suitable for solid phase peptide synthesis is described, as well as a photocleavable linker, that can be of use in activity based protein profiling.

Rationale Airway hyperresponsiveness is a principle feature of asthma, explained in part by remodeling of airway smooth muscle (ASM), including muscle thickening and increased extracellular matrix (ECM) protein production by the ASM. Current therapies are largely successful in targeting the inflammatory component of asthma, but lack the necessary means to reverse or prevent the remodeling process. β-catenin is a potential therapeutic target in this regard, as we have shown previously its critical role in the regulation of ASM proliferation and ECM production. Accordingly we have tested several small-molecule signaling modulators that attenuate the nuclear functions of β-catenin. Methods Three small-molecule compounds were employed in this study that each selectively target different components of β-catenin signaling: ICG-001 (inhibits β-catenin/CBP interaction), IQ-1 (prevents β-catenin/p300 interaction) and XAV-939 (a WNT-specific β-catenin antagonist that inhibits Tankyrase 1 and 2 to stabilize Axin). Immortalized human bronchial smooth muscle cell lines were treated with Fetal Bovine Serum (FBS) or Transforming Growth Factor-β1 (TGF-β1) in combination with increasing concentrations of ICG-001, IQ-1 or XAV-939. We assessed cell proliferation using an Alamar Blue conversion assay and Western blotting. ECM production was determined via RT-qPCR and Western blotting. Results ICG-001 dose dependently (0,1-10 μM) inhibited FBS-induced airway smooth muscle proliferation (58% at 3 μM, p

Administration of adenosine-5′-monophosphate (5′-AMP) can induce an artificial but endogenously reversible torpor-like state in mice. The dynamics of body temperature and the relation between body temperature and metabolic rate may indicate the (dis)similarity of this artificial torpor-like state to natural torpor in intact animals. We investigated these in C57BL/6J mice by (1) comparing cooling rates during 5′-AMP induced hypothermia to cooling rates during high workload induced torpor, and by (2) estimating the relative contributions of metabolic suppression and passive temperature (Q 10) effects in the 5′-AMP induced hypothermic state. We did the latter by back-extrapolating the relation between body temperature and metabolic rate in hypothermic conditions to the euthermic temperature level, using calculated Q 10-values. The data indicate that (1) cooling rate in 5′-AMP induced hypothermia is about 1.8 times faster than in natural torpor in workload conditions, and that (2) Q 10 effects can entirely explain the metabolic reduction of 5′-AMP induced hypothermia, indicating that active metabolic suppression may be lacking. Together, this suggests fundamental differences between 5′-AMP induced hypothermia and natural torpor, limiting the validity of the paradigm to the study of effects of hypothermic conditions and temperature related metabolic effects.