A switch in N-terminal capping of β-peptides creates novel self-assembled nanoparticles.

Small tripeptides composed entirely of β-amino acids have been shown to self-assemble into fibres following acylation of the N-terminus. Given the use of Fmoc as a strategy to initiate self-assembly in α-peptides, we hypothesized that the acyl cap can be replaced by an Fmoc without perturbation to the self-assembly and enable simpler synthetic protocols. We therefore replaced the -acyl cap for an Fmoc group and herein we show that these Fmoc-protected β-peptides produce regular spherical particles, rather than fibrous structures, that are stable and capable of encapsulating cargo.

Esterase-Mediated Sustained Release of Peptide-Based Therapeutics from a Self-Assembled Injectable Hydrogel.

A synthetic strategy for conjugating small molecules and peptide-based therapeutics, via a cleavable ester bond, to a lipidated β-tripeptide is presented. The drug-loaded β-peptide was successfully co-assembled with a functionally inert lipidated β-tripeptide to form a hydrogel. Quantitative release of lactose from the hydrogel, by the action of serum esterases, is demonstrated over 28 days.

TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes.

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 Diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents.

1,3-Dichloroacetone: A Robust Reagent for Preparing Bicyclic Peptides.

The chemical synthesis of cyclic peptides is a well-established area of research. This has been further expanded by development of bio-orthogonal reactions that enable access to peptides of greater structural complexity. One approach utilizes 1,3-dichloroacetone to selectively link free cysteine side-chains with an acetone-like bridge via an S2 reaction.