Improper regulation of complement is associated with various pathologies, and the clinical demand for compounds that can regulate complement activation is therefore imperative. Cp40, an analog of the peptide compstatin, inhibits all complement pathways at the level of the central component C3. We have further developed Cp40, using either PEGylation at the N-terminus or insertion of charged amino acids at the C-terminus. The PEGylated analogs are highly soluble and retained their inhibitory activity, with C3b binding affinity dependent on the length of the PEG chain. The addition of two or three residues of lysine, in turn, not only improved the peptide’s solubility but also increased the binding affinity for C3b while retaining its inhibitory potency. Three of the new derivatives showed improved pharmacokinetic profiles in vivo in non-human primates. Given their compelling solubility and pharmacokinetic profiles, these new Cp40 analogs should broaden the spectrum of administration routes, likely reducing dosing frequency during chronic treatment and potentially expanding their range of clinical application.

中文翻译：

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具有增加的溶解度和改善的药代动力学特征的补体C3抑制剂坎普他汀的新类似物

补体调节不当与多种病理相关，因此临床上对可调节补体激活的化合物的需求势在必行。肽坎普他汀的类似物Cp40在中央成分C3的水平抑制所有补体途径。我们使用N端的PEG化或在C端插入带电荷的氨基酸，进一步开发了Cp40。PEG化的类似物高度可溶并保留了其抑制活性，C3b结合亲和力取决于PEG链的长度。反过来，添加两个或三个赖氨酸残基，不仅提高了肽的溶解度，而且还增加了对C3b的结合亲和力，同时保留了其抑制能力。在非人灵长类动物中，三种新的衍生物在体内显示出改善的药代动力学特征。鉴于其令人信服的溶解性和药代动力学特性，这些新的Cp40类似物应拓宽给药途径的范围，可能会降低慢性治疗期间的给药频率，并有可能扩大其临床应用范围。