Synthesis and activity of thioether-containing analogues of the complement inhibitor compstatin.
Synthesis and activity of thioether-containing analogues of the complement inhibitor compstatin.
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DOI：
10.1021/cb2000378
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发表时间：
2011-07-15
影响因子：
4
通讯作者：
Lambris, John D.
中科院分区：
文献类型：
--
作者：
Knerr, Patrick J.;Tzekou, Apostolia;Ricklin, Daniel;Qu, Hongchang;Chen, Hui;van der Donk, Wilfred A.;Lambris, John D.
二硫键对于许多生物活性肽的结构稳定性和生物活性是必不可少的。然而，这些键对还原剂是不稳定的，这可能限制此类肽的治疗效用。用抗还原的胱硫醚桥取代二硫键是改善稳定性同时对肽施加最小结构扰动的有吸引力的手段。我们已经将这种方法应用于治疗性补体抑制剂坎普他汀（compstatin），坎普他汀是一种含二硫键的肽，目前正在进行年龄相关性黄斑变性的临床试验，以努力保持其有效活性，同时提高其生物稳定性。含硫醚的坎普他汀类似物通过固相肽合成利用正交保护的胱硫醚氨基酸结构单元和固体支持的肽环化来产生。总的来说，与含二硫化物的母体肽相比，这些类似物对其生物靶标的亲和力和对补体激活的有效抑制在很大程度上得以维持。因此，由硫醚键赋予的对还原的改善的稳定性使得这类新的坎普他汀肽成为治疗应用的有希望的替代物。此外，这种合成的多功能性允许在各种其他治疗肽中探索这种二硫化物到硫醚的取代。
Disulfide bonds are essential for the structural stability and biological activity of many bioactive peptides. However, these bonds are labile to reducing agents, which can limit the therapeutic utility of such peptides. Substitution of a disulfide bond with a reduction-resistant cystathionine bridge is an attractive means of improving stability while imposing minimal structural perturbation to the peptide. We have applied this approach to the therapeutic complement inhibitor compstatin, a disulfide-containing peptide currently in clinical trials for age-related macular degeneration, in an effort to maintain its potent activity while improving its biological stability. Thioether-containing compstatin analogues were produced via solid-phase peptide synthesis utilizing orthogonally-protected cystathionine amino acid building blocks and solid-supported peptide cyclization. Overall, the affinity of these analogues for their biological target and potent inhibition of complement activation were largely maintained when compared to those of the parent disulfide-containing peptides. Thus, the improved stability to reduction conferred by the thioether bond makes this new class of compstatin peptides a promising alternative for therapeutic applications. Additionally, the versatility of this synthesis allows for exploration of this disulfide-to-thioether substitution in a variety of other therapeutic peptides.
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