Structural characterization of peptidomimetics targeting fibroblast activation protein
The result's identifiers
Result code in 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>
Alternative codes found
RIV/86652036:_____/25:00640365
Result on the web
<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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Alternative languages
Result language
angličtina
Original language name
Structural characterization of peptidomimetics targeting fibroblast activation protein
Original language description
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.
Czech name
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Czech description
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Classification
Type
O - Miscellaneous
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/LX22NPO5102" target="_blank" >LX22NPO5102: National institute for cancer research</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů