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首页> 外文期刊>Journal of Medicinal Chemistry >Hydrophobic effect and hydrogen bonds account for the improved activity of a complement inhibitor, compstatin
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Hydrophobic effect and hydrogen bonds account for the improved activity of a complement inhibitor, compstatin

机译：疏水作用和氢键可改善补体抑制剂坎普他汀的活性

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摘要

Tryptophans at positions 4 and 7 of compstatin, a peptide complement inhibitor, are crucial for its interaction with C3. However, the nature of their involvement has not been studied to date. Here we investigate the molecular forces involved in the C3- compstatin interactions, mediated by aromatic residues, by incorporating in these two positions various tryptophan analogues (5-methyltryptophan, 5-fluorotryptophan, 1-methyltryptophan, and 2-naphthylalanine) and assessing the resulting peptides for activity by enzyme-linked immunosorbent assay (ELISA) and binding by isothermal titration calorimetry (ITC). Of all the compstatin analogues, peptides containing 1-methyltryptophan at position 4 exhibited the highest binding affinity (K-d = 15 nM) and activity (IC50 = 0.205 mu M), followed by a peptide containing 5-fluorotryptophan at position 7. Our observations suggest that hydrophobic interactions involving residues at position 4 and the hydrogen bond initiated by the indole nitrogen are primarily responsible and crucial for the increase in activity. These findings have important implications for the design of clinically useful complement inhibitors.
机译：肽补体抑制剂坎普他汀第4和7位的色氨酸对于其与C3的相互作用至关重要。但是，迄今为止尚未研究其参与的性质。在这里，我们通过将两个色氨酸类似物（5-甲基色氨酸，5-氟色氨酸，1-甲基色氨酸和2-萘丙氨酸）并入这两个位置，来研究由芳香族残基介导的C3-坎普他汀相互作用中涉及的分子力。通过酶联免疫吸附测定（ELISA）获得活性肽，并通过等温滴定量热（ITC）结合。在所有坎普他汀类似物中，在4位含有1-甲基色氨酸的肽表现出最高的结合亲和力（Kd = 15 nM）和活性（IC50 = 0.205μM），其次是在7位含有5-氟色氨酸的肽。涉及第4位残基和由吲哚氮引发的氢键的疏水性相互作用是活性增加的主要原因，并且是至关重要的。这些发现对临床上有用的补体抑制剂的设计具有重要意义。

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