Shujing Xu, Shuo Wang, Yang Zhou, Nicholas Foley, Lin Sun, Laura Walsham, Kai Tang, Dazhou Shi, Xiaoyu Shi, Zhijiao Zhang, Xiangyi Jiang, Shenghua Gao, Xinyong Liu, Christophe Pannecouque*, David C. Goldstone*, Alexej Dick* and Peng Zhan*,
{"title":"高配体效率苯并噻唑类艾滋病毒噬菌体调制剂的 \"伪基质包膜\"/自由能扰动引导设计与机理研究","authors":"Shujing Xu, Shuo Wang, Yang Zhou, Nicholas Foley, Lin Sun, Laura Walsham, Kai Tang, Dazhou Shi, Xiaoyu Shi, Zhijiao Zhang, Xiangyi Jiang, Shenghua Gao, Xinyong Liu, Christophe Pannecouque*, David C. Goldstone*, Alexej Dick* and Peng Zhan*, ","doi":"10.1021/acs.jmedchem.4c0154410.1021/acs.jmedchem.4c01544","DOIUrl":null,"url":null,"abstract":"<p >Based on our proposed “pseudosubstrate envelope” concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, <b>IC-1k</b>, exhibited an EC<sub>50</sub> of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, <b>IC-1k</b> emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that <b>IC-1k</b> targeted HIV-1 CA within the chemical space of the “pseudosubstrate envelope”. Further mechanistic studies revealed a dual-stage inhibition profile: <b>IC-1k</b> disrupted early-stage capsid–host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for <b>IC-1k</b> (<i>T</i><sub>1/2</sub> = 91.3 min) compared to PF74 (<i>T</i><sub>1/2</sub> = 0.7 min), alongside a favorable safety profile. Overall, <b>IC-1k</b> presents a promising lead compound for further optimization.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19057–19076 19057–19076"},"PeriodicalIF":6.8000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"“Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency\",\"authors\":\"Shujing Xu, Shuo Wang, Yang Zhou, Nicholas Foley, Lin Sun, Laura Walsham, Kai Tang, Dazhou Shi, Xiaoyu Shi, Zhijiao Zhang, Xiangyi Jiang, Shenghua Gao, Xinyong Liu, Christophe Pannecouque*, David C. Goldstone*, Alexej Dick* and Peng Zhan*, \",\"doi\":\"10.1021/acs.jmedchem.4c0154410.1021/acs.jmedchem.4c01544\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Based on our proposed “pseudosubstrate envelope” concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, <b>IC-1k</b>, exhibited an EC<sub>50</sub> of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, <b>IC-1k</b> emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that <b>IC-1k</b> targeted HIV-1 CA within the chemical space of the “pseudosubstrate envelope”. Further mechanistic studies revealed a dual-stage inhibition profile: <b>IC-1k</b> disrupted early-stage capsid–host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for <b>IC-1k</b> (<i>T</i><sub>1/2</sub> = 91.3 min) compared to PF74 (<i>T</i><sub>1/2</sub> = 0.7 min), alongside a favorable safety profile. Overall, <b>IC-1k</b> presents a promising lead compound for further optimization.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"67 21\",\"pages\":\"19057–19076 19057–19076\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-10-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01544\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01544","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
“Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency
Based on our proposed “pseudosubstrate envelope” concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, IC-1k, exhibited an EC50 of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, IC-1k emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that IC-1k targeted HIV-1 CA within the chemical space of the “pseudosubstrate envelope”. Further mechanistic studies revealed a dual-stage inhibition profile: IC-1k disrupted early-stage capsid–host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for IC-1k (T1/2 = 91.3 min) compared to PF74 (T1/2 = 0.7 min), alongside a favorable safety profile. Overall, IC-1k presents a promising lead compound for further optimization.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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