2006
DOI: 10.1165/rcmb.2005-0207oc
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Identification of a 4-mer Peptide Inhibitor that Effectively Blocks the Polymerization of Pathogenic Z α1-Antitrypsin

Abstract: alpha(1)-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) polymerizes within the liver and lung, resulting in hepatic aggregation of AT and tissue deficiency, predisposing to early onset of cirrhosis and emphysema, respectively. Polymerization of the aberrant protein can be prevented in vitro by specific peptides such as FLEAIG. This peptide serves as a lead molecule to design a shorter peptide that may be effective as a therapeutic agent. In this study we employed … Show more

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Cited by 45 publications
(49 citation statements)
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“…The resulting polymers lead to aggregation in hepatocytes and subsequent plasma deficiency [25]. A strategy to try and prevent polymerization has been the use of small peptides to compete with reactive loops and bind to β-sheet A [125][126][127][128][129]. Although in vitro tests are promising, challenges to this approach being translated to humans have included how to deliver the peptides to the ER of hepatocytes and the fact that they inactivate Z A1AT [127], therefore potentially worsening plasma deficiency, emphysema risk and progression.…”
Section: Polymerization Prevention Strategies and Chemical Chaperonesmentioning
confidence: 99%
“…The resulting polymers lead to aggregation in hepatocytes and subsequent plasma deficiency [25]. A strategy to try and prevent polymerization has been the use of small peptides to compete with reactive loops and bind to β-sheet A [125][126][127][128][129]. Although in vitro tests are promising, challenges to this approach being translated to humans have included how to deliver the peptides to the ER of hepatocytes and the fact that they inactivate Z A1AT [127], therefore potentially worsening plasma deficiency, emphysema risk and progression.…”
Section: Polymerization Prevention Strategies and Chemical Chaperonesmentioning
confidence: 99%
“…This approach could potentially ameliorate the liver disease, and defend respiratory epithelial surface, providing antielastase protection and avoiding the proinflammatory effects of polymerized Z A1AT. Currently, there is some progress in development of synthetic peptide designed to selectively inhibit Z polymerisation Parfrey et al, 2004;Chang et al, 2006;Mallya et al, 2007;Chang et al, 2009). …”
Section: Z Variantmentioning
confidence: 99%
“…These methods reduce intracellular aggregation of Z-AT but do not increase the secretion Z-AT. Use of short synthetic peptides targeting -sheet A may show therapeutic potential for Z-AT related liver and lung disease (Figure 3) (Chang et al, 2006; Unpublished observation).…”
Section: Treatment Of Z α1-antitrypsin-associated Liver Diseasementioning
confidence: 99%