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Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors

The lectin pathway (LP) of the complement system is an important antimicrobial defense mechanism, but it also contributes significantly to ischemia reperfusion injury (IRI) associated with myocardial infarct, stroke, and several other clinical conditions. Mannan-binding lectin–associated serine prot...

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Autores principales: Szakács, Dávid, Kocsis, Andrea, Szász, Róbert, Gál, Péter, Pál, Gábor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527154/
https://www.ncbi.nlm.nih.gov/pubmed/30952698
http://dx.doi.org/10.1074/jbc.RA119.008315
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author Szakács, Dávid
Kocsis, Andrea
Szász, Róbert
Gál, Péter
Pál, Gábor
author_facet Szakács, Dávid
Kocsis, Andrea
Szász, Róbert
Gál, Péter
Pál, Gábor
author_sort Szakács, Dávid
collection PubMed
description The lectin pathway (LP) of the complement system is an important antimicrobial defense mechanism, but it also contributes significantly to ischemia reperfusion injury (IRI) associated with myocardial infarct, stroke, and several other clinical conditions. Mannan-binding lectin–associated serine proteinase 2 (MASP-2) is essential for LP activation, and therefore, it is a potential drug target. We have previously developed the first two generations of MASP-2 inhibitors by in vitro evolution of two unrelated canonical serine proteinase inhibitors. These inhibitors were selective LP inhibitors, but their nonhuman origin rendered them suboptimal lead molecules for drug development. Here, we present our third-generation MASP-2 inhibitors that were developed based on a human inhibitor scaffold. We subjected the second Kunitz domain of human tissue factor pathway inhibitor 1 (TFPI1 D2) to directed evolution using phage display to yield inhibitors against human and rat MASP-2. These novel TFPI1-based MASP-2 inhibitor (TFMI-2) variants are potent and selective LP inhibitors in both human and rat serum. Directed evolution of the first Kunitz domain of TFPI1 had already yielded the potent kallikrein inhibitor, Kalbitor® (ecallantide), which is an FDA-approved drug to treat acute attacks of hereditary angioedema. Like hereditary angioedema, acute IRI is also related to the uncontrolled activation of a specific plasma serine proteinase. Therefore, TFMI-2 variants are promising lead molecules for drug development against IRI.
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spelling pubmed-65271542019-05-21 Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors Szakács, Dávid Kocsis, Andrea Szász, Róbert Gál, Péter Pál, Gábor J Biol Chem Immunology The lectin pathway (LP) of the complement system is an important antimicrobial defense mechanism, but it also contributes significantly to ischemia reperfusion injury (IRI) associated with myocardial infarct, stroke, and several other clinical conditions. Mannan-binding lectin–associated serine proteinase 2 (MASP-2) is essential for LP activation, and therefore, it is a potential drug target. We have previously developed the first two generations of MASP-2 inhibitors by in vitro evolution of two unrelated canonical serine proteinase inhibitors. These inhibitors were selective LP inhibitors, but their nonhuman origin rendered them suboptimal lead molecules for drug development. Here, we present our third-generation MASP-2 inhibitors that were developed based on a human inhibitor scaffold. We subjected the second Kunitz domain of human tissue factor pathway inhibitor 1 (TFPI1 D2) to directed evolution using phage display to yield inhibitors against human and rat MASP-2. These novel TFPI1-based MASP-2 inhibitor (TFMI-2) variants are potent and selective LP inhibitors in both human and rat serum. Directed evolution of the first Kunitz domain of TFPI1 had already yielded the potent kallikrein inhibitor, Kalbitor® (ecallantide), which is an FDA-approved drug to treat acute attacks of hereditary angioedema. Like hereditary angioedema, acute IRI is also related to the uncontrolled activation of a specific plasma serine proteinase. Therefore, TFMI-2 variants are promising lead molecules for drug development against IRI. American Society for Biochemistry and Molecular Biology 2019-05-17 2019-04-05 /pmc/articles/PMC6527154/ /pubmed/30952698 http://dx.doi.org/10.1074/jbc.RA119.008315 Text en © 2019 Szakács et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Immunology
Szakács, Dávid
Kocsis, Andrea
Szász, Róbert
Gál, Péter
Pál, Gábor
Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors
title Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors
title_full Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors
title_fullStr Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors
title_full_unstemmed Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors
title_short Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors
title_sort novel masp-2 inhibitors developed via directed evolution of human tfpi1 are potent lectin pathway inhibitors
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527154/
https://www.ncbi.nlm.nih.gov/pubmed/30952698
http://dx.doi.org/10.1074/jbc.RA119.008315
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