Discovery of an Inhibitor of Z-Alpha1 Antitrypsin Polymerization
- Univ. of Tennessee Health Science Center, Knoxville, TN (United States). Dept. of Medicine; Univ. of Tennessee, Knoxville, TN (United States). Gradate School of Genome Science and Technology
- Univ. of Tennessee, Knoxville, TN (United States). Gradate School of Genome Science and Technology; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics
- Univ. of Tennessee, Knoxville, TN (United States). Gradate School of Genome Science and Technology and Dept. of Biochemistry and Cellular and Molecular Biology; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics
Polymerization of the Z variant alpha-1-antitrypsin (Z-α1AT) results in the most common and severe form of α1AT deficiency (α1ATD), a debilitating genetic disorder whose clinical manifestations range from asymptomatic to fatal liver and/or lung disease. As the altered conformation of Z-α1AT and its attendant aggregation are responsible for pathogenesis, the polymerization process per se has become a major target for the development of therapeutics. Based on the ability of Z-alpha 1AT to aggregate by recruiting the reactive center loop (RCL) of another Z-α1AT into its s4A cavity, we developed a high-throughput screening assay that uses a modified 6-mer peptide mimicking the RCL to screen for inhibitors of Z-α1AT polymer growth. We used a subset of compounds from the Library of Pharmacologically Active Compounds (LOPAC) with molecular weights ranging from 300 to 700 Da, to evaluate the assay's capabilities. The inhibitor S-(4-nitrobenzyl)-6-thioguanosine was identified as a lead compound and its ability to prevent Z-α1AT polymerization confirmed by secondary assays. In order to further investigate the binding location of S-(4-nitrobenzyl)-6-thioguanosine, an in silico strategy was pursued and the intermediate alpha 1AT M* state modeled to allow molecular docking simulations and explore various potential binding sites. Docking results predict that S-(4-nitrobenzyl)-6-thioguanosine can bind at the s4A cavity and at the edge of beta-sheet A. The former binding site would directly block RCL insertion whereas the latter site would prevent beta-sheet A from expanding between s3A/s5A, and thus indirectly impede RCL insertion. Our investigations have revealed a novel compound that inhibits the formation of Z-α1AT polymers, as well as in vitro and in silico strategies for identifying and characterizing additional blocking molecules of Z-α1AT polymerization.
- Research Organization:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Organization:
- USDOE
- Grant/Contract Number:
- AC05-00OR22725
- OSTI ID:
- 1334442
- Journal Information:
- PLoS ONE, Vol. 10, Issue 5; ISSN 1932-6203
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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