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Identification of a 4-mer Peptide Inhibitor that Effectively Blocks the Polymerization of Pathogenic Z ₁-Antitrypsin

Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi; Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan, R.O.C.; Department of Medicine, University of Cambridge, Cambridge; and Department of Biosciences, University of Birmingham, Birmingham, United Kingdom

Correspondence and requests for reprints should be addressed to Yen-Ho Chu, Department of Chemistry and Biochemistry, National Chung Cheng University, 168 University Rd., Min-Hsiung, Chia-Yi, Taiwan 62102, R.O.C. E-mail: cheyhc{at}ccu.edu.tw

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 a systematic chemical approach using alanine scanning of Ac-FLEAIG-OH and subsequent peptide shortening to study the binding of shorter peptides to Z-AT. While two additional 6-mer peptides Ac-FLAAIG-OH and Ac-FLEAAG-OH were found to bind to Z-AT, their daughter peptides Ac-FLEAA-NH₂ and Ac-FLAA-NH₂ also bound avidly to Z-AT and prevented polymerization of the protein. Further comparative studies revealed that the binding of Ac-FLAA-NH₂ was more specific for Z-AT. The peptide–AT complex formation was enhanced by the presence of C-terminal amide group on the peptide, and circular dichroism analysis demonstrated that a random coil rather than a -helical conformation favored binding of the peptide to AT. In summary, this study has identified novel small peptides that inhibit Z-AT polymerization, and are a significant advance towards the treatment of Z-AT–related cirrhosis and emphysema.

Key Words: ₁-antitrypsin • ₁-proteinase inhibitor • alanine scanning • polymerization • serpin