Small‐molecule peptides inhibit Z α1‐antitrypsin polymerization
- 16 December 2008
- journal article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 13 (8b), 2304-2316
- https://doi.org/10.1111/j.1582-4934.2008.00608.x
Abstract
[[abstract]]The Z variant of α1-antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosis and the associated plasma deficiency leads to emphysema. In this work, a combinatorial approach based on the inhibitory mechanism of α1-AT was developed to arrest its pathogenic polymerization. One peptide, Ac-TTAI-NH2, emerged as the most tight-binding ligand for Z α1-AT. Characterization of this tetrapeptide by gel electrophoresis and biosensor analysis revealed its markedly improved binding specificity and affinity compared with all previously reported peptide inhibitors. In addition, the peptide is not cytotoxic to lung cell lines. A model of the peptide-protein complex suggests that the peptide interacts with nearby residues by hydrogen bonds, hydrophobic interactions, and cavity-filling stabilization. The combinatorially selected peptide not only effectively blocks the polymerization but also promotes dissociation of the oligomerized α1-AT. These results are a significant step towards the potential treatment of Z α1-AT related diseasesKeywords
This publication has 50 references indexed in Scilit:
- Small Molecules Block the Polymerization of Z α1-Antitrypsin and Increase the Clearance of Intracellular AggregatesJournal of Medicinal Chemistry, 2007
- Fluorescence Correlation Spectroscopic Study of Serpin Depolymerization by Computationally Designed PeptidesJournal of Molecular Biology, 2007
- A High-Throughput Screen for Compounds That Inhibit Aggregation of the Alzheimer’s PeptideACS Chemical Biology, 2006
- How Small Peptides Block and Reverse Serpin PolymerisationJournal of Molecular Biology, 2004
- Multiple sequence alignment with the Clustal series of programsNucleic Acids Research, 2003
- Combinatorial chemistry: 20 years on…Drug Discovery Today, 2002
- Pathogenic α1-Antitrypsin Polymers Are Formed by Reactive Loop-β-Sheet A LinkagePublished by Elsevier BV ,2000
- Implications for function and therapy of a 2.9 å structure of binary-complexed antithrombinJournal of Molecular Biology, 1998
- The classification of amino acid conservationJournal of Theoretical Biology, 1986