Molecular recognition of fibroblast activation protein for diagnostic and therapeutic applications

0523934 - ÚOCHB 2021 RIV NL eng J - Journal Article
Šimková, Adéla - Bušek, P. - Šedo, A. - Konvalinka, Jan
Molecular recognition of fibroblast activation protein for diagnostic and therapeutic applications.
Biochimica Et Biophysica Acta-Proteins and Proteomics. Roč. 1868, č. 7 (2020), č. článku 140409. ISSN 1570-9639. E-ISSN 1878-1454
R&D Projects: GA MZd(CZ) NV15-31379A; GA MŠMT(CZ) LM2015064; GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : fibroblast activation protein * FAP inhibitors * FAP substrates * cancer tissue targeting * activity-based probes
OECD category: Biochemistry and molecular biology
Impact factor: 3.036, year: 2020
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/abs/pii/S1570963920300546

Fibroblast activation protein (FAP) is a non-classical serine protease expressed predominantly in conditions accompanied by tissue remodeling, particularly cancer. Due to its plasma membrane localization, FAP represents a promising molecular target for tumor imaging and treatment. The unique enzymatic activity of FAP facilitates development of diagnostic and therapeutic tools based on molecular recognition of FAP by substrates and small-molecule inhibitors, in addition to conventional antibody-based strategies. In this review, we provide background on the pathophysiological role of FAP and discuss its potential for diagnostic and therapeutic applications. Furthermore, we present a detailed analysis of the structural patterns crucial for substrate and inhibitor recognition by the FAP active site and determinants of selectivity over the related proteases dipeptidyl peptidase IV and prolyl endopeptidase. We also review published data on targeting of the tumor microenvironment with FAP antibodies, FAP-targeted prodrugs, activity-based probes and small-molecule inhibitors. We describe use of a recently developed, selective FAP inhibitor with low-nanomolar potency in inhibitor-based targeting strategies including synthetic antibody mimetics based on hydrophilic polymers and inhibitor conjugates for PET imaging. In conclusion, recent advances in understanding of the molecular structure and function of FAP have significantly contributed to the development of several tools with potential for translation into clinical practice.
Permanent Link: http://hdl.handle.net/11104/0308229