Small-molecule peptides inhibit Z alpha1-antitrypsin polymerization.
The Z variant of 1-antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosis and the associated plasma deficiency leads to emphysema. In this work, a combinatorial approach based on the inhibitory mechanism of (alpha1)-AT was developed to arrest its pathogenic polymerization. One peptide, Ac-TTAI-NH(2), emerged as the most tight-binding ligand for Z (alpha1)-AT. Characterization of this tetrapeptide by gel electrophoresis and biosensor analysis revealed its markedly improved binding specificity and affinity compared with all previously reported peptide inhibitors. In addition, the peptide is not cytotoxic to lung cell lines. A model of the peptide-protein complex suggests that the peptide interacts with nearby residues by hydrogen bonds, hydrophobic interactions, and cavity-filling stabilization. The combinatorially selected peptide not only effectively blocks the polymerization but also promotes dissociation of the oligomerized (alpha1)-AT. These results are a significant step towards the potential treatment of Z (alpha1)-AT related diseases.
Chang
Yi-Pin
YP
Department of Chemistry and Biochemistry, National Chung Cheng University,Chia-Yi, Taiwan, Republic of China.
Mahadeva
Ravi
R
Department of Medicine, University of Cambridge, Cambridge, UK.
Chang
Wun-Shaing W
WW
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan, Republic of China.
Lin
Sheng-Chieh
SC
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan, Republic of China.
Chu
Yen-Ho
YH
Department of Chemistry and Biochemistry, National Chung Cheng University,Chia-Yi, Taiwan, Republic of China.
D001704:Biopolymers / Q000037:antagonists & inhibitors*; D002460:Cell Line; D006801:Humans; D010455:Peptides / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000187:drug effects*
D001704:Biopolymers; D010455:Peptides; D000515:alpha 1-Antitrypsin