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首页> 外文期刊>Biochimica et biophysica acta. Biomembranes >d -Peptides as inhibitors of PR3-membrane interactions
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d -Peptides as inhibitors of PR3-membrane interactions

机译：D- PR3膜相互作用的抑制剂

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Abstract Proteinase 3 (PR3) is a neutrophil serine protease present in cytoplasmic granules but also expressed at the neutrophil surface where it mediates proinflammatory effects. Studies of the underlying molecular mechanisms have been hampered by the lack of inhibitors of the PR3 membrane anchorage. Indeed while there exist inhibitors of the catalytic activity of PR3, its membrane interfacial binding site (IBS) is distinct from its catalytic site. The IBS has been characterized both by mutagenesis experiments and molecular modeling. Through docking and molecular dynamics simulations we have designed d -peptides targeting the PR3 IBS. We used surface plasmon resonance to evaluate their effect on the binding of PR3 to phospholipid bilayers. Next, we verified their ability of binding to PR3 via fluorescence spectroscopy and isothermal titration calorimetry. The designed peptides did not affect the catalytic activity of PR3. A few peptides bound to PR3 hydrophobic pockets and inhibited PR3 binding to lipids. While the (KFF) 3 K d -peptide inconveniently showed a significant affinity for the lipids, another d -peptide (SAKEAFFKLLAS) did not and it inhibited the PR3-membrane binding site with IC 50 of about 40μM. Our work puts forward d -peptides as promising inhibitors of peripheral protein-membrane interactions, which remain high-hanging fruits in drug design. Graphical abstract Display Omitted Highlights ? Membrane-expressed proteinase 3 (PR3) is a drug target for chronic inflammation. ? Computationally designed d -peptides interact in silico with PR3 membrane-binding site. ? d -Peptides bind to membrane binding site and do not affect PR3 catalytic activity. ? Surface plasmon resonance shows d -peptides to be inhibitors of PR3-vesicle binding. ? d -Peptides are promising inhibitors for peripheral protein-membrane interactions.
机译：摘要蛋白酶3（pr3）是存在于细胞质颗粒中的中性粒细胞丝氨酸蛋白酶，但在中性粒细胞表面表达，其中它介导促炎作用。通过缺乏PR3膜锚固抑制剂，对潜在的分子机制的研究受到阻碍。实际上，虽然存在PR3的催化活性的抑制剂，但其膜界面结合位点（IBS）不同于其催化位点。通过诱变实验和分子建模表征IBS。通过对接和分子动力学模拟，我们设计了靶向PR3 IBS的D-肽。我们使用表面等离子体共振来评估它们对PR3与磷脂双层的结合的影响。接下来，我们通过荧光光谱和等温滴定热法验证了它们与PR3结合的能力。设计的肽不影响PR3的催化活性。几种肽与Pr3疏水袋结合并抑制与脂质结合的PR3。虽然（KFF）3K D-肽对脂质的显着亲和力表现出对脂质的显着亲和力，但另一个D-肽（SakeaffKllas）没有，它抑制了IC 50约40μm的PR3膜结合位点。我们的工作提出了D-肽作为外周蛋白 - 膜相互作用的有前途抑制剂，其在药物设计中仍然是高悬垂的水果。图形抽象显示省略了亮点？膜表达蛋白酶3（PR3）是慢性炎症的药物靶标。还计算设计的D-肽在硅中与PR3膜结合位点相互作用。还D-肽与膜结合位点结合，不会影响PR3催化活性。还表面等离子体共振显示D-肽是PR3-囊泡结合的抑制剂。还D-丙肽是外周蛋白膜相互作用的有前途抑制剂。

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