keking929

Roger Y. Tsien, professor at the University of California, San Diego and Howard Hughes Medical Institute Investigator, passed away on August 24, 2016. Tsien shared the 2008 Nobel Prize in Chemistry for his work on the discovery and development of the green fluorescent protein, and developed a whole series of colored fluorescent proteins, as well as widely used small-molecule probes for Ca²⁺ ions.

A fundamentally simple, mild, and practical procedure for peptide bond formation is reported that employs a stoichiometric amount of easy-to-access 9-silafluorenyl dichlorides as the coupling agent. Without initial preactivation or elaboration of the carboxylic acid or amine termini of the amino acids, the developed reagent is proposed to act through an unprecedented chemical ligation mechanism, bringing the two coupling partners together before being subsequently eliminated. The desired amides or peptide bonds are thus furnished in good yields and with low to no epimerization.

A chemical ligation mechanism was proposed for amide bond formation with 9-silafluorenyl dichlorides as new coupling reagents. This approach enabled the synthesis of peptides in a simple and unprecedented manner without preactivation of either the carboxylic acid or amine termini of the amino acids.

Self-assembling coiled coils, which occur commonly in native proteins, have received significant interest for the design of new biomaterials-based medical therapies. Considerable effort over recent years has led to a detailed understanding of the self-assembly process of coiled coils, and a diverse collection of strategies have been developed for designing functional materials using this motif. The ability to engineer the interface between coiled coils allows one to achieve variously connected components, leading to precisely defined structures such as nanofibers, nanotubes, nanoparticles, networks, gels, and combinations of these. Currently these materials are being developed for a range of biotechnological and medical applications, including drug delivery systems for controlled release, targeted nanomaterials, ‘drug-free’ therapeutics, vaccine delivery systems, and others. WIREs Nanomed Nanobiotechnol 2017, 9:e1424. doi: 10.1002/wnan.1424

For further resources related to this article, please visit the WIREs website.

Coiled coils are oligomerizing structures useful for designing nanomaterials such as particles, fibers, and networks within biomedical applications.

We report on the design of a polymeric prodrug of the anticancer agent paclitaxel (PTX) by a grafting-from-drug approach. A chain transfer agent for reversible addition fragmentation chain transfer (RAFT) polymerization was efficiently and regioselectively linked to the C2′ position of paclitaxel, which is crucial for its bioactivity. Subsequent RAFT polymerization of a hydrophilic monomer yielded well-defined paclitaxel–polymer conjugates with high drug loading, water solubility, and stability. The versatility of this approach was further demonstrated by ω-end post-functionalization with a fluorescent tracer. In vitro experiments showed that these conjugates are readily taken up into endosomes where native PTX is efficiently cleaved off and then reaches its subcellular target. This was confirmed by the cytotoxicity profile of the conjugate, which matches those of commercial PTX formulations based on mere physical encapsulation.

Visible effects: Well-defined paclitaxel–polymer conjugates with high drug loading, water solubility, and stability were obtained by a grafting-from approach. They are readily taken up into endosomes where native paclitaxel is efficiently released. The versatility of this approach was further demonstrated by post-functionalization with a fluorescent tracer.

Clinical translation of nucleic acids drugs has been stunted by limited delivery options. Herein, we report a synthetic polymer designed to mimic viral mechanisms of delivery called VIPER (virus-inspired polymer for endosomal release). VIPER is composed of a polycation block for condensation of nucleic acids, and a pH-sensitive block for acid-triggered display of a lytic peptide to promote trafficking to the cell cytosol. VIPER shows superior efficiencies compared to commercial agents when delivering genes to multiple immortalized cell lines. Importantly, in murine models, VIPER facilitates effective gene transfer to solid tumors.

A virus-inspired polymer is reported as an effective gene transfer vehicle. The polymer, called VIPER (virus-inspired polymer for endosomal release), is composed of a polycation block for nucleic acids condensation and a pH-sensitive block for acid-triggered display of a lytic peptide to promote trafficking to the cell cytosol both in vitro and in vivo.

Poly-proline type II (PPII) helical PXXP motifs are the recognition elements for a variety of protein–protein interactions that are critical for cellular signaling. Despite development of protocols for locking peptides into α-helical and β-strand conformations, there remains a lack of analogous methods for generating mimics of PPII helical structures. We describe herein a strategy to enforce PPII helical secondary structure in the 19-residue TrpPlexus miniature protein. Through sequence variation, we showed that a network of cation–π interactions could drive the formation of PPII helical conformations for both peptide and N-substituted glycine peptoid residues. The achievement of chemically diverse PPII helical scaffolds provides a new route towards discovering peptidomimetic inhibitors of protein–protein interactions mediated by PXXP motifs.

PPII helices on lockdown: A network of cation–π interactions was used to template peptide and peptoid residues into left-handed poly-proline type II (PPII) helices, covalently locking the secondary structure with an engineered disulfide bridge. These chemically diverse PPII helical structures provide a new route toward peptidomimetic protein–protein interaction inhibitors.