PICKAPEP: An application for parameter calculation and visualization of cyclized and modified peptidomimetics.

The interest in peptides and especially in peptidomimetic structures has risen enormously in the past few years. Novel modification strategies including nonnatural amino acids, sophisticated cyclization strategies, and side chain modifications to improve the pharmacokinetic properties of peptides are continuously arising. However, a calculator tool accompanying the current development in peptide sciences towards modified peptides is missing. Herein, we present the application PICKAPEP, enabling the virtual construction and visualization of peptidomimetics ranging from well-known cyclized and modified peptides such as ciclosporin A up to fully self-designed peptide-based structures with custom amino acids. Calculated parameters include the molecular weight, the water-octanol partition coefficient, the topological polar surface area, the number of rotatable bonds, and the peptide SMILES code. To our knowledge, PICKAPEP is the first tool allowing users to add custom amino acids as building blocks and also the only tool giving the possibility to process large peptide libraries and calculate parameters for multiple peptides at once. We believe that PICKAPEP will support peptide researchers in their work and will find wide application in current as well as future peptide drug development processes. PICKAPEP is available open source for Windows and Mac operating systems (https://urldefense.com/v3/__https://www.research-collection.ethz.ch/handle/20.500.11850/681174__;!!N11eV2iwtfs!qt5f_2lNd6IZUDH1HVSVwg0zYzS8-nFazQ8c61jS5GaD5vkVS5C3igyfh3haJRnaX8ugW7o9VWUiCihPqcptmaWoqwYf9LvZTQ$).

A story of peptides, lipophilicity and chromatography - back and forth in time.

Peptides, as part of the beyond the rule of 5 (bRo5) chemical space, represent a unique class of pharmaceutical compounds. Because of their exceptional position in the chemical space between traditional small molecules (molecular weight (MW) < 500 Da) and large therapeutic proteins (MW > 5000 Da), peptides became promising candidates for targeting challenging binding sites, including even targets traditionally considered as undruggable - e.g. intracellular protein-protein interactions. However, basic knowledge about physicochemical properties that are important for a drug to be membrane permeable is missing but would enhance the drug discovery process of bRo5 molecules. Consequently, there is a demand for quick and simple lipophilicity determination methods for peptides. In comparison to the traditional lipophilicity determination methods via shake flask and in silico prediction, chromatography-based methods could have multiple benefits such as the requirement of low analyte amount, insensitivity to impurities and high throughput. Herein we elucidate the role of peptide lipophilicity and different lipophilicity values. Further, we summarize peptide analysis via common chromatographic techniques, in specific reversed phase liquid chromatography, hydrophilic interaction liquid chromatography and supercritical fluid chromatography and their role in drug discovery and development process.