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Exploiting the S4–S5 Specificity of Human Neutrophil Proteinase 3 to Improve the Potency of Peptidyl Di(chlorophenyl)-phosphonate Ester Inhibitors: A Kinetic and Molecular Modeling Analysis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-14 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01416 Carla Guarino 1 , Natalia Gruba 2 , Renata Grzywa 3 , Edyta Dyguda-Kazimierowicz 4 , Yveline Hamon 1 , Monika Łȩgowska 2 , Marcin Skoreński 3 , Sandrine Dallet-Choisy 1 , Sylvain Marchand-Adam 1 , Christine Kellenberger 5 , Dieter E. Jenne 6 , Marcin Sieńczyk 3 , Adam Lesner 2 , Francis Gauthier 1 , Brice Korkmaz 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-14 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01416 Carla Guarino 1 , Natalia Gruba 2 , Renata Grzywa 3 , Edyta Dyguda-Kazimierowicz 4 , Yveline Hamon 1 , Monika Łȩgowska 2 , Marcin Skoreński 3 , Sandrine Dallet-Choisy 1 , Sylvain Marchand-Adam 1 , Christine Kellenberger 5 , Dieter E. Jenne 6 , Marcin Sieńczyk 3 , Adam Lesner 2 , Francis Gauthier 1 , Brice Korkmaz 1
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The neutrophilic serine protease proteinase 3 (PR3) is involved in inflammation and immune response and thus appears as a therapeutic target for a variety of infectious and inflammatory diseases. Here we combined kinetic and molecular docking studies to increase the potency of peptidyl-diphenyl phosphonate PR3 inhibitors. Occupancy of the S1 subsite of PR3 by a nVal residue and of the S4–S5 subsites by a biotinylated Val residue as obtained in biotin-VYDnVP(O-C6H4-4-Cl)2 enhanced the second-order inhibition constant kobs/[I] toward PR3 by more than 10 times (kobs/[I] = 73000 ± 5000 M–1 s–1) as compared to the best phosphonate PR3 inhibitor previously reported. This inhibitor shows no significant inhibitory activity toward human neutrophil elastase and resists proteolytic degradation in sputa from cystic fibrosis patients. It also inhibits macaque PR3 but not the PR3 from rodents and can thus be used for in vivo assays in a primate model of inflammation.
中文翻译：
利用人类嗜中性粒细胞蛋白酶3的S4–S5特异性来提高肽基二（氯苯基）膦酸酯抑制剂的动力学和分子模型分析
中性丝氨酸蛋白酶3（PR3）参与炎症和免疫反应，因此似乎是各种传染性和炎性疾病的治疗目标。在这里，我们结合了动力学和分子对接研究，以提高肽基二苯基膦酸酯PR3抑制剂的效力。如在生物素-VYDnV P（OC 6 H 4 -4-Cl）2中获得的，nVal残基对PR3的S1亚位占据，而生物素化的Val残基对S4-S5亚位的占据，提高了二级抑制常数k obs / [I]朝向PR3的距离超过10倍（k obs / [I] = 73000±5000 M –1 s –1与先前报道的最佳膦酸酯PR3抑制剂相比。该抑制剂对人中性粒细胞弹性蛋白酶没有明显的抑制活性，并且能抵抗囊性纤维化患者痰液中的蛋白水解降解。它也抑制猕猴PR3但不抑制啮齿动物的PR3，因此可用于灵长类动物炎症模型的体内分析。
更新日期：2018-02-14
中文翻译：
利用人类嗜中性粒细胞蛋白酶3的S4–S5特异性来提高肽基二（氯苯基）膦酸酯抑制剂的动力学和分子模型分析
中性丝氨酸蛋白酶3（PR3）参与炎症和免疫反应，因此似乎是各种传染性和炎性疾病的治疗目标。在这里，我们结合了动力学和分子对接研究，以提高肽基二苯基膦酸酯PR3抑制剂的效力。如在生物素-VYDnV P（OC 6 H 4 -4-Cl）2中获得的，nVal残基对PR3的S1亚位占据，而生物素化的Val残基对S4-S5亚位的占据，提高了二级抑制常数k obs / [I]朝向PR3的距离超过10倍（k obs / [I] = 73000±5000 M –1 s –1与先前报道的最佳膦酸酯PR3抑制剂相比。该抑制剂对人中性粒细胞弹性蛋白酶没有明显的抑制活性，并且能抵抗囊性纤维化患者痰液中的蛋白水解降解。它也抑制猕猴PR3但不抑制啮齿动物的PR3，因此可用于灵长类动物炎症模型的体内分析。
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