Identification of Novel Phospholipid Transfer Protein Inhibitors by High-Throughput Screening
| Autor: | Tomohiro Sotani, Yu Takahashi, Yoshiji Hantani, Rie Hantani |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cardiotonic Agents Apolipoprotein B High-throughput screening 030204 cardiovascular system & hematology Biochemistry Analytical Chemistry law.invention 03 medical and health sciences Mice 0302 clinical medicine law Risk Factors Phospholipid transfer protein medicine Animals Humans Secretion Phospholipid Transfer Proteins Apolipoproteins B Dyslipidemias chemistry.chemical_classification biology Chemistry Hep G2 Cells Surface Plasmon Resonance medicine.disease Atherosclerosis High-Throughput Screening Assays 030104 developmental biology Enzyme Cardiovascular Diseases biology.protein Recombinant DNA Molecular Medicine lipids (amino acids peptides and proteins) Carrier Proteins Dyslipidemia Biotechnology Lipoprotein Protein Binding |
| Zdroj: | SLAS discovery : advancing life sciences RD. 24(5) |
| ISSN: | 2472-5560 |
| Popis: | Atherogenesis has been recognized as a risk factor for lethal cardiovascular diseases. Plasma low-density lipoprotein levels are correlated to the occurrence of atherosclerosis, and their control is critical for both the prevention and treatment of these diseases. Phospholipid transfer protein (PLTP) is one of the key regulators of lipoprotein metabolism; PLTP-deficient mice exhibit decreased apolipoprotein B (apoB)-containing lipoprotein secretion and atherosclerosis, indicating the validity of PLTP as a promising therapeutic target. Here, we demonstrate a high-throughput screening (HTS) method to identify a novel chemotype of PLTP inhibitors. Instead of using recombinant proteins, we used human plasma as a source of enzymes in the first screening, so as to efficiently exclude promiscuous inhibitors. The selected compounds were further confirmed to target PLTP both biochemically and biophysically and were shown to inhibit apoB secretion from hepatic cells with no apparent toxicity. We believe that our approach is suitable for filtering out nonspecific inhibitors at an earlier stage of screening campaigns and that these compounds should have potential to be developed into drugs to treat dyslipidemia. |
| Databáze: | OpenAIRE |
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