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Novel MicroScale Solutions for Biophysical Characterization in Drug Discovery and Development
Author(s) -
Heffern Charles
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb597
Subject(s) - microscale thermophoresis , microscale chemistry , drug discovery , chemistry , small molecule , drug development , biomolecule , characterization (materials science) , transmembrane protein , computational biology , nanotechnology , combinatorial chemistry , drug , biochemistry , materials science , biology , mathematics education , mathematics , receptor , pharmacology
Here we present 2 unique and proprietary technologies for biophysical characterization of biomolecules to facilitate the drug discovery and drug development process: MicroScale Thermophoresis (MST) monitors the movement of molecules through μm‐sized temperature gradients to quantify interactions of any kind of molecule. Recent results from automated high‐throughput primary and secondary screening campaigns by MST will be presented. In a collaboration project with Sanofi R&D, MST identified several hits which were not detected by orthogonal techniques. In addition, MST detected secondary effects such as protein aggregation and denaturation, and could thus be used to reliably rule‐out false positives and measurement artifacts. nanoDSF technology is specifically tailored for thermal and chemical unfolding studies. By monitoring fluorescence shifts of the amino acid tryptophan or tyrosine, unfolding profiles of multidomain proteins, transmembrane proteins or low‐abundant drug targets can be obtained in an entirely label‐free approach. Here, we present buffer and detergent screening campaigns for membrane proteins as well as for antibodies and antibody‐drug conjugates, highlighting the sensitivity and resolution of this method. In addition, the fully‐automated protein stability platform using the novel Prometheus NT.Plex in combination with NT.Robotic Autosampler enables high‐throughput measurements as required in formulation development. Thermal and chemical unfolding data correlate with long‐term turbidity and monomer content over time, showing that the Prometheus NT.Plex can be used to rapidly predict the long‐term stability of biologics within 1 day.