Polymers for Disrupting Protein-Protein Interactions: Where Are We and Where Should We Be?

Protein-protein interactions (PPIs) are central to the cellular signaling and regulatory networks that underlie many physiological and pathophysiological processes. It is challenging to target PPIs using traditional small molecule or peptide-based approaches due to the frequent lack of well-defined binding pockets at the large and flat PPI interfaces. Synthetic polymers offer an opportunity to circumvent these challenges by providing unparalleled flexibility in tuning their physiochemical properties to achieve the desired binding properties. In this review, we summarize the current state of the field pertaining to polymer-protein interactions in solution, highlighting various polyelectrolyte systems, their tunable parameters, and their characterization. We provide an outlook on how these architectures can be improved by incorporating sequence control, foldability, and machine learning to mimic proteins at every structural level. Advances in these directions will enable the design of more specific protein-binding polymers and provide an effective strategy for targeting dynamic proteins, such as intrinsically disordered proteins.

X-ray Crystallographic Structure of a Giant Double-Walled Peptide Nanotube Formed by a Macrocyclic ß-Sheet Containing Aß16-22.

This paper describes the supramolecular assembly of a macrocyclic ß-sheet containing residues 16-22 of the ß-amyloid peptide, Aß. X-ray crystallography reveals that the macrocyclic ß-sheet assembles to form double-walled nanotubes, with an inner diameter of 7 nm and outer diameter of 11 nm. The inner wall is composed of an extended network of hydrogen-bonded dimers. The outer wall is composed of a separate extended network of ß-barrel-like tetramers. These large peptide nanotubes pack into a hexagonal lattice that resembles a honeycomb. The complexity and size of the peptide nanotubes rivals some of the largest tubular biomolecular assemblies, such as GroEL and microtubules. These observations demonstrate that small amyloidogenic sequences can be used to build large nanostructures.

Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke.

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.

Molecular bases for temperature sensitivity in supramolecular assemblies and their applications as thermoresponsive soft materials.

Thermoresponsive supramolecular assemblies have been extensively explored in diverse formats, from injectable hydrogels to nanoscale carriers, for a variety of applications including drug delivery, tissue engineering and thermo-controlled catalysis. Understanding the molecular bases behind thermal sensitivity of materials is fundamentally important for the rational design of assemblies with optimal combination of properties and predictable tunability for specific applications. In this review, we summarize the recent advances in this area with a specific focus on the parameters and factors that influence thermoresponsive properties of soft materials. We summarize and analyze the effects of structures and architectures of molecules, hydrophilic and lipophilic balance, concentration, components and external additives upon the thermoresponsiveness of the corresponding molecular assemblies.