Structural characterization of peptidomimetics targeting fibroblast activation protein

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00640365" target="_blank" >RIV/61388963:_____/25:00640365 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/86652036:_____/25:00640365

Výsledek na webu

<a href="https://hdl.handle.net/11104/0370774" target="_blank" >https://hdl.handle.net/11104/0370774</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Structural characterization of peptidomimetics targeting fibroblast activation protein

Popis výsledku v původním jazyce

Fibroblast activation protein (FAP) is a membrane-bound serine protease that has emerged as a promising tumor marker. FAP is overexpressed in the tumor stroma of most carcinomas, and has been linked to promoting angiogenesis, tumor cell invasion, and immunosuppression. Despite great interest in FAP targeting, limited structural information on FAP–inhibitor complexes has hampered further elaboration of inhibitor structures through rational design. In our recent work, we conducted a structure–activity relationship study to explore the chemical space in the P1′ and P2′ positions and developed a new class of peptidomimetic inhibitors bearing an α-ketoamide warhead. Besides other lead-like properties, the compound I22AP446 outperformed the most potent inhibitor published to that date. To gain insight into the binding mode of the α-ketoamide derivative, we determined a crystal structure of FAP in complex with I22AP446 at 1.75 Å resolution revealing key interaction features between the inhibitor and the enzyme. We thus present the first reported crystal structure of FAP bound to a peptidomimetic. Our findings provide a basis for structure-guided modifications of our lead compound and will fuel the development of FAP inhibitors with fine-tuned properties.

Název v anglickém jazyce

Structural characterization of peptidomimetics targeting fibroblast activation protein

Popis výsledku anglicky

Fibroblast activation protein (FAP) is a membrane-bound serine protease that has emerged as a promising tumor marker. FAP is overexpressed in the tumor stroma of most carcinomas, and has been linked to promoting angiogenesis, tumor cell invasion, and immunosuppression. Despite great interest in FAP targeting, limited structural information on FAP–inhibitor complexes has hampered further elaboration of inhibitor structures through rational design. In our recent work, we conducted a structure–activity relationship study to explore the chemical space in the P1′ and P2′ positions and developed a new class of peptidomimetic inhibitors bearing an α-ketoamide warhead. Besides other lead-like properties, the compound I22AP446 outperformed the most potent inhibitor published to that date. To gain insight into the binding mode of the α-ketoamide derivative, we determined a crystal structure of FAP in complex with I22AP446 at 1.75 Å resolution revealing key interaction features between the inhibitor and the enzyme. We thus present the first reported crystal structure of FAP bound to a peptidomimetic. Our findings provide a basis for structure-guided modifications of our lead compound and will fuel the development of FAP inhibitors with fine-tuned properties.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5102" target="_blank" >LX22NPO5102: Národní ústav pro výzkum rakoviny</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů