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001-es BibID:	BIBFORM094508
035-os BibID:	(WoS)000470656500020 (Scopus)85066156398
Első szerző:	Szakács Dávid
Cím:	Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors / Dávid Szakács, Andrea Kocsis, Róbert Szász, Péter Gál, Gábor Pál
Dátum:	2019
ISSN:	0021-9258 1083-351X
Megjegyzések:	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.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk MASP TFPI1 MASP-2 inhibitor
Megjelenés:	Journal Of Biological Chemistry. - 294 : 20 (2019), p. 8227-8237. -
További szerzők:	Kocsis Andrea Szász Róbert (1972-) (belgyógyász, haematológus) Gál Péter Pál Gábor
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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