Design of Organo-Peptides As Bipartite PCSK9 Antagonists
| Autor: | Daniel J. Burdick, Monica Kong-Beltran, Huy Nguyen, Mark Ultsch, Nicholas J. Skelton, Yingnan Zhang, Wei Li, Maureen Beresini, Charles Eigenbrot, John G. Quinn, Daniel Kirchhofer |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Serine Proteinase Inhibitors Peptide Crystallography X-Ray 01 natural sciences Biochemistry 03 medical and health sciences Humans Binding site chemistry.chemical_classification Binding Sites Molecular Structure 010405 organic chemistry PCSK9 PCSK9 Inhibitors Subtilisin General Medicine Hep G2 Cells Proprotein convertase Small molecule 0104 chemical sciences 030104 developmental biology chemistry Drug Design LDL receptor Molecular Medicine Kexin lipids (amino acids peptides and proteins) Proprotein Convertase 9 Peptides Protein Binding |
| Zdroj: | ACS chemical biology. 15(2) |
| ISSN: | 1554-8937 |
| Popis: | Proprotein convertase subtilisin/kexin 9 (PCSK9) has become an important therapeutic target for lipid lowering, since it regulates low-density lipoprotein cholesterol (LDL-c) levels by binding to liver LDL receptors (LDLR) and effecting their intracellular degradation. However, the development of small molecule inhibitors is hampered by the lack of attractive PCSK9 target sites. We recently discovered helical peptides that are able to bind to a cryptic groove site on PCSK9, which is situated in proximity to the main LDLR binding site. Here, we designed potent bipartite PCSK9 inhibitors by appending organic moieties to a helical groove-binding peptide to reach a hydrophobic pocket in the proximal LDLR binding region. The ultimately designed 1-amino-4-phenylcyclohexane-1-carbonyl extension improved the peptide affinity by >100-fold, yielding organo-peptide antagonists that potently inhibited PCSK9 binding to LDLR and preserved cellular LDLR. These new bipartite antagonists have reduced mass and improved potency compared to the first-generation peptide antagonists, further validating the PCSK9 groove as a viable therapeutic target site. |
| Databáze: | OpenAIRE |
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