Peptide hydrogels for affinity-controlled release of therapeutic cargo: Current and potential strategies.

The development of devices for the precise and controlled delivery of therapeutics has grown rapidly over the last few decades. Drug delivery materials must provide a depot with delivery profiles that satisfy pharmacodynamic and pharmacokinetic requirements resulting in clinical benefit. Therapeutic efficacy can be limited due to short half-life and poor stability. Thus, to compensate for this, frequent administration and high doses are often required to achieve therapeutic effect, which in turn increases potential side effects and systemic toxicity. This can potentially be mitigated by using materials that can deliver drugs at controlled rates, and material design principles that allow this are continuously evolving. Affinity-based release strategies incorporate a myriad of reversible interactions into a gel network, which have affinities for the therapeutic of interest. Reversible binding to the gel network impacts the release profile of the drug. Such affinity-based interactions can be modulated to control the release profile to meet pharmacokinetic benchmarks. Much work has been done developing affinity-based control in the context of polymer-based materials. However, this strategy has not been widely implemented in peptide-based hydrogels. Herein, we present recent advances in the use of affinity-controlled peptide gel release systems and their associated mechanisms for applications in drug delivery.

Conservation of Cdc14 phosphatase specificity in plant fungal pathogens: implications for antifungal development.

Cdc14 protein phosphatases play an important role in plant infection by several fungal pathogens. This and other properties of Cdc14 enzymes make them an intriguing target for development of new antifungal crop treatments. Active site architecture and substrate specificity of Cdc14 from the model fungus Saccharomyces cerevisiae (ScCdc14) are well-defined and unique among characterized phosphatases. Cdc14 appears absent from some model plants. However, the extent of conservation of Cdc14 sequence, structure, and specificity in fungal plant pathogens is unknown. We addressed this by performing a comprehensive phylogenetic analysis of the Cdc14 family and comparing the conservation of active site structure and specificity among a sampling of plant pathogen Cdc14 homologs. We show that Cdc14 was lost in the common ancestor of angiosperm plants but is ubiquitous in ascomycete and basidiomycete fungi. The unique substrate specificity of ScCdc14 was invariant in homologs from eight diverse species of dikarya, suggesting it is conserved across the lineage. A synthetic substrate mimetic inhibited diverse fungal Cdc14 homologs with similar low µM Ki values, but had little effect on related phosphatases. Our results justify future exploration of Cdc14 as a broad spectrum antifungal target for plant protection.

Self-Assembling Coiled-Coil Peptide Nanotubes with Biomolecular Cargo Encapsulation.

We report a coiled-coil trimeric peptide based on the known GCN4 zipper motif that self-assembles into nanotubes with diameters on the order of a few hundred nanometers to a micron. The dimensional morphology of these tubular structures was observed to be tunable by altering the properties of the buffer during assembly. Structural evidence from X-ray scattering and electron microscopy suggest that tube assembly takes place in structural tiers leading to a hexagonal close-packed arrangement of the coiled-coils. The hollow tubes were observed to selectively encapsulate fluorescein-labeled anionic dextran, as a result of electrostatic interactions between the inner tube surface and negatively charged cargo. The ability of these nanotubes to house biomolecular cargo endows them with potential for molecular storage and drug delivery applications.

Reversible Hierarchical Assembly of Trimeric Coiled-Coil Peptides into Banded Nano- and Microstructures.

We report a set of coiled-coil peptides, radially functionalized with bipyridines, that demonstrate hierarchical assembly into banded rectangular nano- and microstructures, the dimensions of which vary with the strategic placement and number of aromatic groups on the monomer backbone. Finer structural aspects of the hexagonal packing of the individual trimers were determined by X-ray scattering, including intertrimer aromatic interactions between bipyridine moieties. The ease of formation of these biomaterials under physiological conditions and the use of pH to reversibly modulate assembly demonstrate future potential for a range of biological applications, such as drug delivery in a pH-controlled manner.