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

Autor:	Szakács D; Department of Biochemistry, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest., Kocsis A; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest., Szász R; Department of Hematology, Institute of Internal Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen., Gál P; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest., Pál G; Department of Biochemistry, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest; EvolVeritas Biotechnology Ltd., Somogyi Béla u. 17, H-6600 Szentes, Hungary. Electronic address: gabor.pal@ttk.elte.hu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2019 May 17; Vol. 294 (20), pp. 8227-8237. Date of Electronic Publication: 2019 Apr 05.
DOI:	10.1074/jbc.RA119.008315
Abstrakt:	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. (© 2019 Szakács et al.)
Databáze:	MEDLINE
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