The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors.

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.

Effect of polar amino acid incorporation on Fmoc-diphenylalanine-based tetrapeptides.

Peptide hydrogels show great promise as extracellular matrix mimics due to their tuneable, fibrous nature. Through incorporation of polar cationic, polar anionic or polar neutral amino acids into the Fmoc-diphenylalanine motif, we show that electrostatic charge plays a key role in the properties of the subsequent gelators. Specifically, we show that an inverse relationship exists for biocompatibility in the solution state versus the gel state for cationic and anionic peptides. Finally, we use tethered bilayer lipid membrane (tBLM) experiments to suggest a likely mode of cytotoxicity for tetrapeptides which exhibit cytotoxicity in the solution state.

Programmable enzymatic oxidation of tyrosine-lysine tetrapeptides.

The ability to control the response of self-assembled systems upon exposure to external stimuli has been a long-standing goal of supramolecular chemistry. Short peptides are an attractive platform to realise this objective due to their chemical diversity and modular nature. Here, we synthesise a library of Fmoc-capped tetrapeptides, each containing two tyrosine and two lysine residues and varying in their amino acid sequence. Despite having similar secondary structure, these tetrapeptides form structures which are highly sequence dependent, yielding aggregates, nanofibres or monomers. This in turn highly affects the rate and degree of oxidative polymerisation by the enzyme tyrosinase, with self-assembled nanofibres exhibiting a greater degree of polymerisation. We monitor the formation of tyrosine oxidation products over time, finding that the precipitation of polymers is driven by quinone-based species. This affects the electrochemical properties of the oxidised peptide polymers, as determined through electrical impedance spectroscopy. Finally, intrinsic fluorescence microscale thermophoresis studies confirm that the degree of oxidative polymerisation is highly dependent on tyrosine solvent accessibility and the presence of peptide monomers. The ability to tune the kinetics of enzymatically active substrates and understand their polymerisation pathways on a molecular level is important for the creation of programmable, enzyme responsive biomaterials.