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Bioactive recombinant human oncostatin M for NMR-based screening in drug discovery
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Journal Article
Bioactive recombinant human oncostatin M for NMR-based screening in drug discovery
2021
Overview
Oncostatin M (OSM) is a pleiotropic, interleukin-6 family inflammatory cytokine that plays an important role in inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer progression and metastasis. Recently, elevated OSM levels have been found in the serum of COVID-19 patients in intensive care units. Multiple anti-OSM therapeutics have been investigated, but to date no OSM small molecule inhibitors are clinically available. To pursue a high-throughput screening and structure-based drug discovery strategy to design a small molecule inhibitor of OSM, milligram quantities of highly pure, bioactive OSM are required. Here, we developed a reliable protocol to produce highly pure unlabeled and isotope enriched OSM from
E. coli
for biochemical and NMR studies. High yields (ca. 10 mg/L culture) were obtained in rich and minimal defined media cultures. Purified OSM was characterized by mass spectrometry and circular dichroism. The bioactivity was confirmed by induction of OSM/OSM receptor signaling through STAT3 phosphorylation in human breast cancer cells. Optimized buffer conditions yielded
1
H,
15
N HSQC NMR spectra with intense, well-dispersed peaks. Titration of
15
N OSM with a small molecule inhibitor showed chemical shift perturbations for several key residues with a binding affinity of 12.2 ± 3.9 μM. These results demonstrate the value of bioactive recombinant human OSM for NMR-based small molecule screening.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ COVID-19
/ E coli
/ Humanities and Social Sciences
/ Humans
/ Magnetic Resonance Spectroscopy - methods
/ Molecular Docking Simulation
/ NMR
/ Oncostatin M - antagonists & inhibitors
/ Proteins
/ Science
/ Severe acute respiratory syndrome coronavirus 2
/ Small Molecule Libraries - chemistry
/ Small Molecule Libraries - pharmacology
