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金属触发的化合物CDPDP通过下调炎性细胞因子，并在具有广泛的药物代谢动力学、药物相似性、药物动力学、药物代谢和毒性（ADMET）、对接和模拟研究的小鼠模型中调节氧化应激风暴，从而表现出抗关节炎行为。

Metals-triggered compound CDPDP exhibits anti-arthritic behavior by downregulating the inflammatory cytokines, and modulating the oxidative storm in mice models with extensive ADMET, docking and simulation studies.

作者信息

Hassan Syed Shams Ul, Abbas Syed Qamar, Muhammad Ishaq, Wu Jia-Jia, Yan Shi-Kai, Ali Fawad, Majid Muhammad, Jin Hui-Zi, Bungau Simona

机构信息

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.

Department of Natural Product Chemistry, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.

出版信息

Front Pharmacol. 2022 Nov 23;13:1053744. doi: 10.3389/fphar.2022.1053744. eCollection 2022.

DOI:10.3389/fphar.2022.1053744
PMID:36506587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9727203/
Abstract

Triggering through abiotic stress, including chemical triggers like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metal Nickel on actinobacteria SH-1327 to obtain a stress-derived compound was firstly investigated. A new compound cyclo-(D)-Pro-(D)-Phe (CDPDP) was triggered from the actinobacteria strain SH-1327 with the addition of nickel ions 1 mM. The stress compound was further evaluated for its anti-oxidant, analgesic, and anti-inflammatory activity against rheumatoid arthritis through and assays in albino mice. A remarkable anti-oxidant potential of CDPDP was recorded with the IC value of 30.06 ± 5.11 μg/ml in DPPH, IC of 18.98 ± 2.91 against NO free radicals, the IC value of 27.15 ± 3.12 against scavenging ability and IC value of 28.40 ± 3.14 μg/ml for iron chelation capacity. Downregulation of pro-inflammatory mediators (NO and MDA), suppressed levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-Iβ) and upregulation of expressions of anti-oxidant enzymes (GSH, catalase, and GST) unveiled its anti-inflammatory potential. CDPDP was analyzed in human chondrocyte cell line CHON-001 and the results demonstrated that CDPDP significantly increased cell survival, and inhibited apoptosis of IL-1β treated chondrocytes and IL-1β induced matrix degrading markers. In addition, to evaluate the mitochondrial fitness of CHON-001 cells, CDPDP significantly upregulated pgc1-α, the master regulator of mitochondrial biogenesis, indicating that CDPDP provides protective effects in CHON-001 cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of the CDPDP showed that CDPDP is safe in cases of hepatotoxicity, cardiotoxicity, and cytochrome inhibition. Furthermore, docking results showed good binding of CDPDP with IL-6-17.4 kcal/mol, and the simulation studies proved the stability between ligand and protein. Therefore, the findings of the current study prospect CDPDP as a potent anti-oxidant and a plausible anti-arthritic agent with a strong pharmacokinetic and pharmacological profile.

摘要

通过非生物胁迫触发，包括重金属等化学触发因素，是一种新的药物发现技术。在本研究中，首先研究了重金属镍对放线菌SH - 1327的影响，以获得一种应激衍生化合物。在添加1 mM镍离子的情况下，从放线菌菌株SH - 1327中触发了一种新的化合物环 - (D)-脯氨酸-(D)-苯丙氨酸（CDPDP）。通过对白化病小鼠的实验和分析，进一步评估了该应激化合物对类风湿性关节炎的抗氧化、镇痛和抗炎活性。在DPPH实验中，CDPDP的抗氧化潜力显著，IC值为30.06±5.11μg/ml；对NO自由基的IC值为18.98±2.91；清除能力的IC值为27.15±3.12；铁螯合能力的IC值为28.40±3.14μg/ml。促炎介质（NO和MDA）的下调、促炎细胞因子（TNF-α、IL - 6、IL - 1β）水平的抑制以及抗氧化酶（GSH、过氧化氢酶和GST）表达的上调揭示了其抗炎潜力。在人软骨细胞系CHON - 001中对CDPDP进行了分析，结果表明CDPDP显著提高了细胞存活率，并抑制了IL - 1β处理的软骨细胞的凋亡以及IL - 1β诱导的基质降解标志物。此外，为了评估CHON - 001细胞的线粒体适应性，CDPDP显著上调了线粒体生物发生的主要调节因子pgc1 - α，表明CDPDP在CHON - 001细胞中提供了保护作用。CDPDP的吸收、分布、代谢、排泄和毒性（ADMET）概况表明，CDPDP在肝毒性、心脏毒性和细胞色素抑制方面是安全的。此外，对接结果显示CDPDP与IL - 6的结合良好，结合能为-17.4 kcal/mol，模拟研究证明了配体与蛋白质之间的稳定性。因此，本研究结果表明CDPDP是一种有效的抗氧化剂和一种有潜力的抗关节炎药物，具有强大的药代动力学和药理学特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b319/9727203/b06b412c0887/fphar-13-1053744-g013.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b319/9727203/e05b02d71ed4/fphar-13-1053744-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b319/9727203/e073854be667/fphar-13-1053744-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b319/9727203/a470e71f552b/fphar-13-1053744-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b319/9727203/b9e88ca082e2/fphar-13-1053744-g011.jpg
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