Chymase is a serine protease that is predominantly expressed by mast cells and has key roles in immune defense and the cardiovascular system. This enzyme has also emerged as a therapeutic target for cardiovascular disease due to its ability to remodel cardiac tissue and generate angiotensin II. Here, we used the nature-derived cyclic peptide sunflower trypsin inhibitor-1 (SFTI-1) as a template for designing novel chymase inhibitors. The key binding contacts of SFTI-1 were optimized by combining a peptide substrate library screen with structure-based design, which yielded several variants with potent activity. The lead variant was further modified by replacing the P1 Tyr residue with para-substituted Phe derivatives, generating new inhibitors with improved potency (Ki = 1.8 nM) and higher selectivity over closely related enzymes. Several variants were shown to block angiotensin I cleavage in vitro, highlighting their potential for further development and future evaluation as pharmaceutical leads.

中文翻译：

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环肽SFTI-1中的结合环取代产生有效的选择性琼脂糖酶抑制剂。

胸苷酶是一种丝氨酸蛋白酶，主要由肥大细胞表达，在免疫防御和心血管系统中起关键作用。由于该酶具有重塑心脏组织并产生血管紧张素II的能力，因此也已成为心血管疾病的治疗靶标。在这里，我们使用自然衍生的环肽向日葵胰蛋白酶抑制剂-1（SFTI-1）作为模板来设计新型食糜酶抑制剂。通过将肽底物文库筛选与基于结构的设计相结合，可以优化SFTI-1的关键结合接触，从而产生具有强大活性的多种变体。通过用对位取代的Phe衍生物取代P1 Tyr残基，进一步修饰了先导变体，产生了新的抑制剂，这些抑制剂的效价更高（Ki = 1.8 nM），并且比紧密相关的酶具有更高的选择性。