Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer's Disease Drug Candidate.

Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer's disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile.

Generating System-Level Responses from a Network of Simple Synthetic Replicators.

The creation of reaction networks capable of exhibiting responses that are properties of entire systems represents a significant challenge for the chemical sciences. The system-level behavior of a reaction network is linked intrinsically to its topology and the functional connections between its nodes. A simple network of chemical reactions constructed from four reagents, in which each reagent reacts with exactly two others, can exhibit up-regulation of two products even when only a single chemical reaction is addressed catalytically.

Diversification of self-replicating molecules.

How new species emerge in nature is still incompletely understood and difficult to study directly. Self-replicating molecules provide a simple model that allows us to capture the fundamental processes that occur in species formation. We have been able to monitor in real time and at a molecular level the diversification of self-replicating molecules into two distinct sets that compete for two different building blocks ('food') and so capture an important aspect of the process by which species may arise.

A recognition-mediated reaction drives amplification within a dynamic library.

A single, appropriately designed, recognition event targets and transforms one of two reactive members of an exchanging pool of compounds through a recognition-mediated irreversible cycloaddition reaction, altering dramatically the final composition and kinetic behaviour of the dynamic library.

Exponential self-replication enabled through a fibre elongation/breakage mechanism.

Self-replicating molecules are likely to have played a central role in the origin of life. Most scenarios of Darwinian evolution at the molecular level require self-replicators capable of exponential growth, yet only very few exponential replicators have been reported to date and general design criteria for exponential replication are lacking. Here we show that a peptide-functionalized macrocyclic self-replicator exhibits exponential growth when subjected to mild agitation.

Micelle to fibre biocatalytic supramolecular transformation of an aromatic peptide amphiphile.

We use a range of spectroscopic methods to provide mechanistic insight into a phosphatase-driven supramolecular transformation whereby an amphiphilic peptide building block, upon dephosphorylation, switches from a solution-phase, micellar structure to a gel-phase, chiral uni-directional nanofibre morphology.

Dynamic covalent chemistry in aid of peptide self-assembly.

Self-assembled peptide systems have been widely studied in the context of gaining understanding of the rules that govern biomolecular processes and increasingly as new bio-inspired nanomaterials. Such materials may be designed to be highly dynamic, displaying adaptive and self-healing properties. This review focuses on recent approaches, which exploit reversible covalent and noncovalent chemistry in combination with peptide-based self-assembly.

Locking an oxidation-sensitive dynamic peptide system in the gel state.

We describe an enzyme-driven dynamic supramolecular peptide system which displays multiple reversible pathways, giving rise to emergent properties that are dictated by environmental conditions and that can be locked in a gel-state.

Target-driven selection in a dynamic nitrone library.

Nitrones undergo dynamic exchange in chloroform at room temperature through two mechanisms-hydrolysis and recombination or hydroxylamine addition/elimination; this dynamic exchange is harnessed to select a nitrone-based bis(amidopyridine) receptor for diacids from a group of four nitrones through its binding to a glutaric acid-based target.