國家衛生研究院 NHRI:Item 3990099045/2709
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    题名: Identification of a 4-mer peptide inhibitor that effectively blocks the polymerization of pathogenic Z alpha(1)-antitrypsin
    作者: Chang, YP;Mahadeva, R;Chang, WSW;Shukla, A;Dafforn, TR;Chu, YH
    贡献者: National Institute of Cancer Research
    摘要: 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 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 p-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.
    关键词: Biochemistry & Molecular Biology;Cell Biology;Respiratory System
    日期: 2006-11
    關聯: American Journal of Respiratory Cell and Molecular Biology. 2006 Nov;35(5):540-548.
    Link to: http://dx.doi.org/10.1165/rcmb.2005-0207OC
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1044-1549&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000241813300004
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33750725161
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