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Inhibiting Polymerization

New Therapeutic Strategies for Z ₁-Antitrypsin–Related Emphysema

Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom

Address correspondence to: Helen Parfrey, Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, MRC/Wellcome Trust Building, Hills Road, Cambridge CB2 2XY, UK. E-mail: hp226{at}cam.ac.uk

The Z variant of ₁-antitrypsin (Z-AT) is present in 4% of Northern Europeans and is associated with liver cirrhosis and emphysema. Polymers accumulate within the hepatocyte and the subsequent plasma deficiency of AT renders the lungs susceptible to proteolysis and early onset emphysema. We have previously demonstrated that the Phe-Leu-Glu-Ala-Ile-Gly (6 mer) peptide specifically binds to Z-AT and inhibits polymerization. Here we present the first detailed biochemical study of the purified Z-AT-6 mer binary complex. Biochemical studies indicated that this complex was inactive as a proteinase inhibitor and the peptide annealed to ß-sheet A of Z-AT. Removal of the N-acetyl terminus of the 6 mer peptide did not affect the peptide's ability to prevent polymer formation. However, the nonacetylated 6 mer–Z-AT complex dissociated at a rate 2.75x faster than the acetylated 6 mer–Z-AT complex to yield an active inhibitor; K_off 5.5 ± 1.07 versus 2.0 ± 0.25 10⁶ s^–1, respectively. These biochemical data indicate a potential therapeutic approach whereby polymerization is prevented in the liver, with the gradual release of the peptide from the binary complex restoring proteinase inhibitory function within the tissues. Thus, it raises the novel prospect of ameliorating both the cirrhosis and the emphysema associated with Z-AT.

Abbreviations: ₁-antitrypsin, AT • acetylated 6 mer peptide, Ac-6 mer • nonacetylated 6 mer peptide, non-Ac-6 mer • acetylated 12 mer peptide, Ac-12 mer • binary complex, BC • Z variant of ₁-antitrypsin, Z-AT

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