ArticleProtein science : a publication of the Protein Society2002
alpha(1)-Proteinase inhibitor mutants with specificity for plasma kallikrein and C1s but not C1.
Article in Protein science : a publication of the Protein Society, 2002. 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, 16 citations in OpenAlex.
- Reactive Centre Loop Mutagenesis of SerpinB3 to Target TMPRSS2 and Furin: Inhibition of SARS-CoV-2 Cell Entry and Replication.International journal of molecular sciences · 2022Article
- Targeted SERPIN (TaSER): A dual-action antithrombotic agent that targets platelets for SERPIN delivery.Journal of thrombosis and haemostasis : JTH · 2022Article
- Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis.Frontiers in cardiovascular medicine · 2022Review
- Therapeutic SERPINs: Improving on Nature.Frontiers in cardiovascular medicine · 2021Review
- Engineering the serpin αProtein science : a publication of the Protein Society · 2020Review
- Inhibition of post-mortem fish muscle softening and degradation using legume seed proteinase inhibitors.Journal of food science and technology · 2020Review
- Article
- SERPINs-From Trap to Treatment.Frontiers in medicine · 2019Review
- Therapeutic approaches in hereditary angioedema.Clinical reviews in allergy & immunology · 2011Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Coagulation and complement proteinases are activated in sepsis, and one approach to therapy is to develop proteinase inhibitors that will specifically inhibit these proteinases without inhibiting activated protein C, a proteinase that is beneficial to survival. In this study, we made mutants of the serpin alpha(1)-PI, designed to mimic the specificity of C1-inhibitor. The P3-P2-P1 residues of alpha1-PI were changed from IPM to LGR and PFR, sequences preferred by C1s and kallikrein, respectively. Inhibition of C1s, kallikrein, factor XIIa, and activated protein C was assessed by SDS-PAGE, and by determination of the k(app) and SI. alpha(1)-PI-LGR inhibited C1s with a rate of 7790 M(-1)s(-1), but only minimal inhibition of C1 in a hemolytic assay was observed. Kallikrein, factor XIIa, and activated protein C were inhibited with rates of 382,180 M(-1)s(-1), 10,400 M(-1)s(-1), and 3500 M(-1)s(-1), respectively. alpha(1)-PI-PFR was a poor inhibitor of C1s, factor XIIa, and activated protein C, but had enhanced reactivity with kallikrein. Changing the P4' residue of alpha(1)-PI-LGR Pro to Glu reduced the activity with C1s, consistent with the idea that C1s requires hydrophobic residues in this region of the serpin for optimal interaction. The data provide insight into the requirements for kallikrein and C1s inhibition necessary for designing inhibitors with appropriate properties for further investigation as therapeutic agents.
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