Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity.
Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity.
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DOI：
10.3390/ijms21239126
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发表时间：
2020-11-30
影响因子：
5.6
通讯作者：
Koziel J
中科院分区：
文献类型：
--
作者：
Bryzek D;Golda A;Budziaszek J;Kowalczyk D;Wong A;Bielecka E;Shakamuri P;Svoboda P;Pohl J;Potempa J;Koziel J
IL-37是人类唯一的哺乳动物长春新素成员，通过杀灭病原体和调节炎症反应，在先天性免疫中发挥重要作用。然而，在炎症部位，LL-37中的精氨酸残基可以通过肽基-精氨酸脱亚胺酶(PAD2和PAD4)催化的反应转化为瓜氨酸，PAD2和PAD4在中性粒细胞中表达，并在中性粒细胞外陷阱(Net)的形成过程中高度活跃。瓜氨酸化会削弱LL-37的杀菌活性，并使其免疫调节功能丧失。因此，我们假设，在PADS存在的情况下，抗瓜氨酸的LL-37变异体将保留天然多肽的功能。为了验证这一假设，我们合成了LL-37，其中精氨酸残基被高精氨酸取代(hArg-LL-37)。HArg-LL-37的杀菌活性与天然LL-37相当，但PAD4处理和Net暴露均不影响hArg-LL-37的抗菌和免疫调节活性。重要的是，LL-37和hArg-LL-37对蛋白酶降解的敏感性没有显著差异。总而言之，我们证明了抗瓜氨酸hArg-LL-37是一种有吸引力的先导化合物，可用于产生治疗细菌感染和其他与PAD活性增强相关的炎症性疾病的新药物。此外，我们的结果为使用高精氨酸合成治疗性多肽提供了概念验证。
LL-37, the only member of the mammalian cathelicidin in humans, plays an essential role in innate immunity by killing pathogens and regulating the inflammatory response. However, at an inflammatory focus, arginine residues in LL-37 can be converted to citrulline via a reaction catalyzed by peptidyl-arginine deiminases (PAD2 and PAD4), which are expressed in neutrophils and are highly active during the formation of neutrophil extracellular traps (NETs). Citrullination impairs the bactericidal activity of LL-37 and abrogates its immunomodulatory functions. Therefore, we hypothesized that citrullination-resistant LL-37 variants would retain the functionality of the native peptide in the presence of PADs. To test this hypothesis, we synthetized LL-37 in which arginine residues were substituted by homoarginine (hArg-LL-37). Bactericidal activity of hArg-LL-37 was comparable with that of native LL-37, but neither treatment with PAD4 nor exposure to NETs affected the antibacterial and immunomodulatory activities of hArg-LL-37. Importantly, the susceptibilities of LL-37 and hArg-LL-37 to degradation by proteases did not significantly differ. Collectively, we demonstrated that citrullination-resistant hArg-LL-37 is an attractive lead compound for the generation of new agents to treat bacterial infections and other inflammatory diseases associated with enhanced PAD activity. Moreover, our results provide a proof-of-concept for synthesis of therapeutic peptides using homoarginine.
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影响因子：
2
作者：
Chowdhury, Saiful M.;Munske, Gerhard R.;Yang, Jonathon;Zhukova, Daria;Hamilton Nguyen;Bruce, James E.
通讯作者：
Bruce, James E.
DOI：
10.4049/jimmunol.1303062
发表时间：
2014-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Koziel J;Bryzek D;Sroka A;Maresz K;Glowczyk I;Bielecka E;Kantyka T;Pyrć K;Svoboda P;Pohl J;Potempa J
通讯作者：
Potempa J
影响因子：
2.9
作者：
Liao, YF;Hsieh, HC;Hung, HC
通讯作者：
Hung, HC
影响因子：
4.6
作者：
Al-Adwani, Salma;Wallin, Cecilia;Bergman, Peter
通讯作者：
Bergman, Peter
影响因子：
4.1
作者：
Oren, Z;Lerman, JC;Shai, Y
通讯作者：
Shai, Y