Predicting drug penetration across the blood-brain barrier: comparison of different stationary phases for immobilized artificial membrane liquid chromatography

Several in vitro methods have been tested for their ability to predict drug penetration across the blood-brain barrier into the central nervous system. In this article, the performance of three stationary phases for immobilized artificial membrane (IAM) liquid chromatographic approaches were compared on a set of 49 compounds. IAM liquid chromatography measurements were performed with Dulbecco’s phosphate-buffered saline and methanol as organic modifier in the mobile phase. Transport across the blood-brain barrier (log BB) was predicted using computed descriptor data and the retention factor of all compounds. All data were correlated with experimental log BB values and the relative performance of the approaches was studied. The IAM.PC.DD2 column proved to be the best suited for prediction of log BB values, although all three columns performed very good

Into the first biomimetic sphingomyelin stationary phase: Suitability in drugs’ biopharmaceutic profiling and block relevance analysis of selectivity

State of the art: Sphingomyelin (SPH) is a type of sphingolipid found in animal nerve tissues, especially in the membranous myelin sheath that surrounds some nerve cell axons. Because of its characteristics, SPH stationary phase represents an ideal tool to mimic the interactions taking place between active pharmaceutical ingredients and neurons.Method: The IAM.SPH stationary phase (0.821 mg) was suspended in methanol (7.0 mL) and the resulting slurry packed (600 bar) in an HPLC column (10 cm x 2.1 mm). The column was operated at 300 μL min-1 at 25°C using a mobile phase consisting of 60/25/15 (v/v/v) Dulbecco's phosphate buffer saline pH 7.4/methanol/acetonitrile. The elution was achieved isocratically and monitored by UV detection at 220 nm. The investigated dataset consisted of 88 compounds (36 neutrals, 26 bases and 26 acids). The block relevance (BR) analysis was accomplished starting by calculating 82 descriptors using the software VS+ and submitting the data matrices to Matlab. Multiple linear regression and related descriptors were obtained with Vega ZZ 64.Results and discussion: The method developed allowed to achieve a solid and reproducible SPH affinity scale for the assayed compounds. Computational studies produced statistically significant models for the prediction and mechanism elucidation of the retentive behavior of pharmaceutically relevant compounds on the SPH stationary phase.Conclusions: For ionizable compounds, the IAM.SPH exhibited an original selectivity when compared to the commercially available IAM.PC. Moreover, apart from its suitability to surrogate log BB, IAM.SPH was also found relate significantly with the drugs' fraction unbound in plasma, a crucial parameter in pharmacokinetics

Patchwork protein chemistry: a practitioner's treatise on the advances in synthetic peptide stitchery

With the study of peptides and proteins at the heart of many scientific endeavors, the omics era heralded a multitude of opportunities for chemists and biologists alike. Across the interface with life sciences, peptide chemistry plays an indispensable role, and progress made over the past decades now allows proteins to be treated as molecular patchworks stitched together through synthetic tailoring. The continuous elaboration of sophisticated strategies notwithstanding, Merrifield's solid-phase methodology remains a cornerstone of chemical protein design. Although the non-practitioner might misjudge peptide synthesis as trivial, routine, or dull given its long history, we comment here on its many advances, obstacles, and prospects from a practitioner's point of view. While sharing our perspectives through thematic highlights across the literature, this treatise provides an interpretive overview as a guide to novices, and a recap for specialists