Geometrically Precise Building Blocks: the Self-Assembly of beta-Peptides

Peptides comprised entirely of b-amino acids, or b-peptides, have attracted substantial interest over the past 25 years due to their unique structural and chemical characteristics. b-Peptides form well-defined secondary structures that exhibit different geometries compared with their a-peptide counterparts, giving rise to their foldamer classification. b-Peptide foldamers can be functionalized easily and are metabolically stable and, together with the predictable side-chain topography, have led to the design of a growing number of bioactive b-peptides with a range of biological targets. The strategic engineering of chemical and topographic properties has also led to the design of b-peptide mimics of higher-order oligomers. More recently, the ability of these peptides to self-assemble into complex structures of controlled geometries has been exploited in materials applications. The focus of thismini-review is on how the unique structural features of b-peptide assemblies have been exploited in the design of self-assembled proteomimetic bundles and nanomaterials

Synthesis of “stapled” 14 - helical β3 - peptides

To understand how folded polymers, such as proteins behave has inspired widespread interest in unnatural oligomers that are known to display similar folding patterns and are referred to as foldamers1. β3-Peptides foldamers, (oligomers of β3-amino acids) are among the most widely studied foldamers at present, and have been reported to adopt discrete and stable secondary helical structures. Of the many types of helices formed by β3-peptides, 14-helices are particularly interesting as they have almost 3 residues per helical turn (with a pitch of 5.0Å). This allows the side chains to be aligned perfectly in three faces. The residues at i/i+3 positions are not only on the same face of the helix but are also are relatively close in proximity to each other. The aim of this study was to explore synthetic strategies for the synthesis of novel β3-peptides on which further functionalisation on specific faces of the helix can be performed and used to create novel foldamer assemblies. β3-Peptides were synthesised incorporating O-allyl-β3-serines and allyl-β3-glycines at i/i+3 positions and efficiently “stapled” the allyl groups on β3-serines and β3-glycines via Ring Closing Metathesis (RCM) on a solid support. The CD and 2D NMR analysis showed that β3-peptides, “stapled” as well as “unstapled”, exhibited spectra in various solvents consistent with 14 helix signature. Thus, the “stapled” side chains on the β-peptides can now be used as a template to attach functional groups to generate new molecules of biological significance

Conformational stability studies of a stapled hexa-β3-peptide library

A library of 14-helical hexa β(3)-peptides was synthesized in order to determine the influence of sequence variation as well as staple size and location on conformational stability. From this study we show that appropriately stapled hexa-β(3)-peptides can allow for a number of variations without significant perturbation of the 14-helix

Synthesis of stapled beta3 - peptides through ring - closing metathesis

The first synthesis of carbon-stapled beta(3)-peptides is reported. The precursor beta(3)-peptides, with O-allyl beta-serines located in an i/i+3 relationship, were prepared on solid phase. We show that efficient ring-closing metathesis (RCM) of these new beta(3)-peptides proceeds smoothly either in solution or on an appropriate solid support. All products were generated with high selectivity for the E-isomer

Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT1R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM. © 2020 Elsevier Inc