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J. Biol. Chem., Vol. 277, Issue 9, 6771-6774, March 1, 2002

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ACCELERATED PUBLICATION
6-mer Peptide Selectively Anneals to a Pathogenic Serpin Conformation and Blocks Polymerization
IMPLICATIONS FOR THE PREVENTION OF Z ₁-ANTITRYPSIN-RELATED CIRRHOSIS^*

Ravi Mahadeva^§, Timothy R. Dafforn^¶, Robin W. Carrell^¶, and David A. Lomas

From the  Respiratory Medicine Unit, Department of Medicine and the ^¶ Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom

Conformational diseases such as amyloidosis, Alzheimer's disease, prion diseases, and the serpinopathies are all caused by structural rearrangements within a protein that transform it into a pathological species. These diseases are typified by the Z variant of ₁-antitrypsin (E342K), which causes the retention of protein within hepatocytes as inclusion bodies that are associated with neonatal hepatitis and cirrhosis. The inclusion bodies result from the Z mutation perturbing the conformation of the protein, which facilitates a sequential interaction between the reactive center loop of one molecule and -sheet A of a second. Therapies to prevent liver disease must block this reactive loop--sheet polymerization without interfering with other proteins of similar tertiary structure. We have used reactive loop peptides to explore the differences between the pathogenic Z and normal M ₁-antitrypsin. The results show that the reactive loop is likely to be partially inserted into -sheet A in Z ₁-antitrypsin. This conformational difference from M ₁-antitrypsin was exploited with a 6-mer reactive loop peptide (FLEAIG) that selectively and stably bound Z ₁-antitrypsin. The importance of this finding is that the peptide prevented the polymerization of Z ₁-antitrypsin and did not significantly anneal to other proteins (such as antithrombin, ₁-antichymotrypsin, and plasminogen activator inhibitor-1) with a similar tertiary structure. These findings provide a lead compound for the development of small molecule inhibitors that can be used to treat patients with Z ₁-antitrypsin deficiency. Furthermore they demonstrate how a conformational disease process can be selectively inhibited with a small peptide.

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