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.

中文翻译：

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成纤维细胞活化蛋白的分子识别，可用于诊断和治疗应用。

成纤维细胞活化蛋白（FAP）是一种非经典的丝氨酸蛋白酶，主要在伴随组织重塑，特别是癌症的状况下表达。由于其质膜定位，FAP代表了有希望的肿瘤成像和治疗分子靶标。FAP独特的酶活性，除了基于常规抗体的策略外，还基于底物和小分子抑制剂对FAP的分子识别，促进了诊断和治疗工具的开发。在这篇综述中，我们提供了FAP的病理生理作用背景，并讨论了其在诊断和治疗应用中的潜力。此外，我们提供了对FAP活性位点对底物和抑制剂识别至关重要的结构模式的详细分析，以及对相关蛋白酶二肽基肽酶IV和脯氨酰内肽酶的选择性的决定因素。我们还审查了有关用FAP抗体，FAP靶向的前药，基于活性的探针和小分子抑制剂靶向肿瘤微环境的公开数据。我们描述了基于抑制剂的靶向策略，包括基于亲水性聚合物的合成抗体模拟物和用于PET成像的抑制剂结合物的低纳摩尔效能的最新开发的选择性FAP抑制剂的使用。结论，