Triangular prism-shaped β-peptoid helices as unique biomimetic scaffolds

β-Peptoids are peptidomimetics based on N-alkylated β-aminopropionic acid residues (or N-alkyl-β-alanines). This type of peptide mimic has previously been incorporated in biologically active ligands and has been hypothesized to be able to exhibit foldamer properties. Here we show, for the first time, that β-peptoids can be tuned to fold into stable helical structures. We provide high-resolution X-ray crystal structures of homomeric β-peptoid hexamers, which reveal right-handed helical conformations with exactly three residues per turn and a helical pitch of 9.6–9.8 Å between turns. The presence of folded conformations in solution is supported by circular dichroism spectroscopy showing length- and solvent dependency, and molecular dynamics simulations provide further support for a stabilized helical secondary structure in organic solvent. We thus outline a framework for future design of novel biomimetics that display functional groups with high accuracy in three dimensions, which has potential for development of new functional materials

Chemical tools for unraveling the substrate specificity of the lysine deacylase enzymes

The lysine deacylase (KDAC) enzymes catalyze hydrolytic removal of acyl functionalities from theε-amino group of lysine residues ina variety of proteins including histones, and KDAC-mediated deacetylation of proteins has been established as a key epigeneticandmetabolic regulator. Recent studies have highlighted lysine acetylation as a general post-translational modification (PTM), andagrowing list of non-histone proteins has been identified as substrates for the KDACs, thereby extending their potential impactoncellular function. Furthermore, other acyl groups (e.g., crotonyl, malonyl, succinyl, glutaryl, myristoyl and 3-phosphoglyceroyl) havebeen identified as lysine PTMs, and both zinc- and NAD+-dependent KDACs have demonstrated capability to remove suchmodifications. These findings suggest that KDACs with impaired deacetylase activity might in fact be functional deacylases catalyzinghydrolysis of other acylamides. To address these interesting observations, we have synthesized a library of substrates containing different peptide scaffolds functionalized with a number of N - ε -acyl moieties. Library synthesis and its evaluation against a panel of human KDACs including zinc-dependent HDACs 1–11 as well as NAD + -dependent sirtuins (SIRT1–7) will be discussed

The <i>agr</i> inhibitors solonamide B and analogues alter immune responses to <i>Staphylococccus aureus</i> but do not exhibit adverse effects on immune cell functions

Staphylococcus aureus infections are becoming increasingly difficult to treat due to antibiotic resistance with the community-associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300 being of particular concern. The inhibition of bacterial virulence has been proposed as an alternative approach to treat multi-drug resistant pathogens. One interesting anti-virulence target is the agr quorum-sensing system, which regulates virulence of CA-MRSA in response to agr-encoded autoinducing peptides. Agr regulation confines exotoxin production to the stationary growth phase with concomitant repression of surface-expressed adhesins. Solonamide B, a non-ribosomal depsipeptide of marine bacterial origin, was recently identified as a putative anti-virulence compound that markedly reduced expression of α-hemolysin and phenol-soluble modulins. To further strengthen solonamide anti-virulence candidacy, we report the chemical synthesis of solonamide analogues, investigation of structure-function relationships, and assessment of their potential to modulate immune cell functions. We found that structural differences between solonamide analogues confer significant differences in interference with agr, while immune cell activity and integrity is generally not affected. Furthermore, treatment of S. aureus with selected solonamides was found to only marginally influence the interaction with fibronectin and biofilm formation, thus addressing the concern that application of compounds inducing an agr-negative state may have adverse interactions with host factors in favor of host colonization

Is Virtual Fencing an Effective Way of Enclosing Cattle? Personality, Herd Behaviour and Welfare

In modern nature conservation and rewilding there is a need for controlling the movements of large grazers in extensively managed areas. The inflexibility of physical fencing can be a limitation in nature management, and the physical boundaries created by physical fencing can have detrimental effects on wildlife. Virtual fencing systems provide boundaries without physical structures. These systems utilise collars with GPS technology to track animals and deliver auditory or electric cues to encourage the animals to stay within the predefined boundaries. This study aims to assess the use of virtual fencing (Nofence&copy;) to keep twelve Angus cows (Bos taurus) within a virtual enclosure without compromising their welfare. As such, the study examines inter-individual differences between the cows as well as their herd behaviour, when reacting and learning to respond appropriately to virtual fencing. Moreover, the activity of the cows was used as an indicator of welfare. The virtual fencing was successful in keeping the herd within the designated area. Moreover, the cattle learned to avoid the virtual border and respond to auditory cues, where the cows received significantly more auditory warning and electric impulses per week throughout the first 14 days than the remaining 125 days (p &lt; 0.001). The cows were found to express both inter-individual differences (p &lt; 0.001) and herd behaviour. The cattle did not express any significant changes in their activity upon receiving an electrical impulse from the collar. Thus, indicating that there were little to no acute welfare implications associated with the use of virtual fencing in this study. This study clearly supports the potential for virtual fencing as a viable alternative to physical electric fencing. However, it also shows that both individual differences in personality and herd structure should be considered when selecting individuals for virtual fencing