On the way to precision formulation additives: 2D-screening to select solubilizers with tailored host and release capabilities.

摘要: A 2-dimensional high-throughput screening method is presented to select peptide sequences from large libraries for precision formulation additives, having a high capacity specifically host drug of interest and provide tailored release properties. The identified are conjugated with poly(ethylene glycol) (PEG) obtain peptide-PEG conjugates that proved be valuable as solubilizers small organic molecule drugs overcome limitations poor water-solubility low bio-availability. 2D-screening selects on both (i) loading capacities (ii) preferred drug-release capabilities demonstrated an experimental Tau-protein aggregation inhibitor/Tau- deaggregator potentials anti-Alzheimer disease (BB17). To enable 2D-screening, one-bead one-compound (OBOC) library was immobilized glass slide, allocating individual beads permanent positions. While the first step involved incubation supported OBOC BB17 identify binding by fluorescence scanner readouts, second reveals properties binders blood plasma protein model solutions. Efficiently peptides either keeper or medium fast releaser can direct sequence readouts slide resin via matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. Four synthesized representing strong, medium, weak releasers non-binders. Loading reached up 1:3.4 (mol per mol carrier) kinetics (fast/medium/slow) in agreement selection process investigated anisotropy correlation spectroscopy. ability BB17/conjugate complexes inhibit Tau4RDΔK (four repeat Tau ((M)Q244-E372 deletion K280), 129 residues) N2a cells studied Tau-pelleting assay showing modulation cellular aggregation. Promising effects such reduction 55% total load observed strong additive. Studies vitro Thioflavin S Tau-aggregation assays show half-maximal inhibitory activities (IC50 values) BB17/conjugates micro-molar range.