Using the Cyclotide Scaffold for Targeting Biomolecular Interactions in Drug Development.

This review provides an overview of the properties of cyclotides and their potential for developing novel peptide-based therapeutics. The selective disruption of protein-protein interactions remains challenging, as the interacting surfaces are relatively large and flat. However, highly constrained polypeptide-based molecular frameworks with cell-permeability properties, such as the cyclotide scaffold, have shown great promise for targeting those biomolecular interactions. The use of molecular techniques, such as epitope grafting and molecular evolution employing the cyclotide scaffold, has shown to be highly effective for selecting bioactive cyclotides.

Chemical Synthesis of a Potent Antimicrobial Peptide Murepavadin Using a Tandem Native Chemical Ligation/Desulfurization Reaction.

Classical approaches for the backbone cyclization of polypeptides require conditions that may compromise the chirality of the C-terminal residue during the activation step of the cyclization reaction. Here, we describe an efficient epimerization-free approach for the Fmoc-based synthesis of murepavadin using intramolecular native chemical ligation in combination with a concomitant desulfurization reaction. Using this approach, bioactive murepavadin was produced in a good yield in two steps. The synthetic peptide antibiotic showed potent activity against different clinical isolates of P. aeruginosa. This approach can be easily adapted for the production of murepavadin analogues and other backbone-cyclized peptides.

Use of Microfluidics to Prepare Lipid-Based Nanocarriers.

Lipid-based nanoparticles (LBNPs) are an important tool for the delivery of a diverse set of drug cargoes, including small molecules, oligonucleotides, and proteins and peptides. Despite their development over the past several decades, this technology is still hindered by issues with the manufacturing processes leading to high polydispersity, batch-to-batch and operator-dependent variability, and limits to the production volumes. To overcome these issues, the use of microfluidic techniques in the production of LBNPs has sharply increased over the past two years. Microfluidics overcomes many of the pitfalls seen with conventional production methods, leading to reproducible LBNPs at lower costs and higher yields. In this review, the use of microfluidics in the preparation of various types of LBNPs, including liposomes, lipid nanoparticles, and solid lipid nanoparticles for the delivery of small molecules, oligonucleotides, and peptide/protein drugs is summarized. Various microfluidic parameters, as well as their effects on the physicochemical properties of LBNPs, are also discussed.