Institute for Molecular Bioscience , The University of Queensland , Brisbane , QLD 4072 , Australia.
J Med Chem. 2020 Jan 23;63(2):816-826. doi: 10.1021/acs.jmedchem.9b01811. Epub 2020 Jan 9.
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 -substituted Phe derivatives, generating new inhibitors with improved potency ( = 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.
糜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具有关键作用。由于其能够重塑心肌组织并生成血管紧张素 II，该酶已成为心血管疾病的治疗靶点。在这里，我们以天然来源的环肽向日葵胰蛋白酶抑制剂-1（SFTI-1）为模板来设计新型糜酶抑制剂。通过将肽底物文库筛选与基于结构的设计相结合，优化了 SFTI-1 的关键结合接触点，得到了几种具有强活性的变体。通过用 -取代的 Phe 衍生物取代先导变体的 P1 Tyr 残基，进一步修饰了先导变体，生成了新的抑制剂，其效力提高（ = 1.8 nM），对密切相关的酶具有更高的选择性。几种变体被证明可以在体外阻断血管紧张素 I 的切割，突出了它们作为药物先导物进一步开发和未来评估的潜力。
