ArticleScientific reports2021
Identification of an alpha-1 antitrypsin variant with enhanced specificity for factor XIa by phage display, bacterial expression, and combinatorial mutagenesis.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 11 citations in OpenAlex.
- Expression and purification of a broad-spectrum human protease inhibitor inBiochemistry and biophysics reports · 2025Article
- High-throughput amino acid-level characterization of the interactions of plasminogen activator inhibitor-1 with variably divergent proteases.Protein science : a publication of the Protein Society · 2025Article
- Enhancement of plasma kallikrein specificity of antitrypsin variants identified by phage display and partial reversion.BMC biotechnology · 2025Article
- The Crystal Structure of the Michaelis-Menten Complex of C1 Esterase Inhibitor and C1s Reveals Novel Insights into Complement Regulation.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
- Article
- Probing of the reactive center loop region of alpha-1-antitrypsin by mutagenesis predicts new type-2 dysfunctional variants.Cellular and molecular life sciences : CMLS · 2023Article
- Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis.Frontiers in cardiovascular medicine · 2022Review
- A reactive center loop-based prediction platform to enhance the design of therapeutic SERPINs.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Stepwise Reversion of Multiply Mutated Recombinant Antitrypsin Reveals a Selective Inhibitor of Coagulation Factor XIa as Active as the M358R Variant.Frontiers in cardiovascular medicine · 2021Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Coagulation Factor XIa (FXIa) is an emerging target for antithrombotic agent development. The M358R variant of the serpin alpha-1 antitrypsin (AAT) inhibits both FXIa and other proteases. Our aim was to enhance the specificity of AAT M358R for FXIa. We randomized two AAT M358R phage display libraries at reactive centre loop positions P13-P8 and P7-P3 and biopanned them with FXIa. A bacterial expression library randomized at P2'-P3' was also probed. Resulting novel variants were expressed as recombinant proteins in E. coli and their kinetics of FXIa inhibition determined. The most potent FXIa-inhibitory motifs were: P13-P8, HASTGQ; P7-P3, CLEVE; and P2-P3', PRSTE (respectively, novel residues bolded). Selectivity for FXIa over thrombin was increased up to 34-fold versus AAT M358R for these single motif variants. Combining CLEVE and PRSTE motifs in AAT-RC increased FXIa selectivity for thrombin, factors XIIa, Xa, activated protein C, and kallikrein by 279-, 143-, 63-, 58-, and 36-fold, respectively, versus AAT M358R. AAT-RC lengthened human plasma clotting times less than AAT M358R. AAT-RC rapidly and selectively inhibits FXIa and is worthy of testing in vivo. AAT specificity can be focused on one target protease by selection in phage and bacterial systems coupled with combinatorial mutagenesis.
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