Article(id=1198683367081345914, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628499750744699, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-1119, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1666022400000, receivedDateStr=2022-10-18, revisedDate=1668700800000, revisedDateStr=2022-11-18, acceptedDate=null, acceptedDateStr=null, onlineDate=1763717985172, onlineDateStr=2025-11-21, pubDate=1683820800000, pubDateStr=2023-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763717985172, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763717985172, creator=13701087609, updateTime=1763717985172, updator=13701087609, issue=Issue{id=1198628499750744699, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='5', pageStart='0', pageEnd='1400', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763704903781, creator=13701087609, updateTime=1766137655840, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208832201509172104, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628499750744699, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208832201509172105, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628499750744699, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1221, endPage=1231, ext={EN=ArticleExt(id=1198683367664354204, articleId=1198683367081345914, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress of targeted degradation of
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Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), is still one of the significant threats to human life. In recent years, the continuous exploration of small molecule inhibitors represented by bedaquinoline has brought new vitality into the field of tuberculosis. However, small molecule inhibitors will inevitably occur acquired drug resistance during clinical medication. As a new pharmacological mechanism, targeted protein degradation (TPD) achieves efficacy by destroying rather than inhibiting protein targets. It might be an excellent strategy to develop anti-tuberculosis drugs based on the TPD concept to solve drug resistance. This article reviews the protein degradation pathways of Mtb, such as the Pup proteasome system and the ClpP-ClpC1 complex enzyme system. The future development of these strategies into TPD drugs was prospected and summarized.
, correspAuthors=Li-fang YU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Wei-jun XU, Li-fang YU), CN=ArticleExt(id=1198683378208834021, articleId=1198683367081345914, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=靶向降解结核分枝杆菌蛋白技术的研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=
结核分枝杆菌所引起的传染性疾病结核病仍然是当前对人类生命安全的重大威胁之一。近年来以贝达喹啉为代表的小分子抑制剂的不断探索为结核病领域注入新的活力。但小分子抑制剂在临床用药过程中, 不可避免地都会发生获得性耐药, 靶向蛋白降解(TPD) 作为一种新的药理学机制, 通过降解而不是抑制蛋白质靶点来实现药效, 利用TPD理念发展抗结核药物对于解决耐药性可能会是一个优秀的策略。本文综述了结核分枝杆菌自身的蛋白降解途径如Pup-蛋白酶体系统、ClpP-ClpC1复合酶系统等, 并对上述策略未来进一步发展成TPD药物进行了归纳与展望。
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34: 815-831, articleTitle=Conformational control of the bacterial Clp protease by natural product antibiotics, refAbstract=null)], funds=[Fund(id=1198960134836810636, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, awardId=21778019, language=CN, fundingSource=国家自然科学基金资助项目(21778019), fundOrder=null, country=null), Fund(id=1198960134979416987, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, awardId=22107031, language=CN, fundingSource=国家自然科学基金资助项目(22107031), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1198960129166111063, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, xref=null, ext=[AuthorCompanyExt(id=1198960129178693978, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, companyId=1198960129166111063, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China), AuthorCompanyExt(id=1198960129195471195, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, companyId=1198960129166111063, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=华东师范大学化学与分子工程学院, 上海分子治疗与新药创制工程技术研究中心, 上海 200062)])], figs=[ArticleFig(id=1198960132282479243, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=EN, label=null, caption=null, figureFileSmall=417RFW6A95O1a5k8pfJKeQ==, figureFileBig=Ht8Nrgb3lioe+tGXoTttlw==, tableContent=null), ArticleFig(id=1198960132433474207, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=CN, label=Figure 1, caption=
Mechanism of protein degradation by Pup-proteasome , figureFileSmall=417RFW6A95O1a5k8pfJKeQ==, figureFileBig=Ht8Nrgb3lioe+tGXoTttlw==, tableContent=null), ArticleFig(id=1198960132622217907, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=EN, label=null, caption=null, figureFileSmall=V8muS4lmGbRGzTg9wVimYg==, figureFileBig=UZ4cET0drAU9rYzQaduF7w==, tableContent=null), ArticleFig(id=1198960132789990079, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=CN, label=Figure 2, caption=
A: Protcolytic targeting chimera (PROTAC) structure diagram; B: ClpP precursor structure (left, PDB ID: 6VGN), ClpC precursor structure (right, PDB ID: 3J3S); C: ClpC hexamer (left) and ClpP1P2 tetramer (right); D: Concept map of action mechanism of ClpP-Clp ATPase complex enzyme , figureFileSmall=V8muS4lmGbRGzTg9wVimYg==, figureFileBig=UZ4cET0drAU9rYzQaduF7w==, tableContent=null), ArticleFig(id=1198960132982928085, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=EN, label=null, caption=null, figureFileSmall=y1vOs1l9LRP+Hg2EQTeQGg==, figureFileBig=7WmxbYCDLfff8oG7ZF94ZA==, tableContent=null), ArticleFig(id=1198960133188449003, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=CN, label=Figure 3, caption=
A: CymA binding pocket with ClpC1-NTD; B: CymA and ClpC1-NTD complex crystal (PDB ID: 3WDC), CymA is green, the key amino acid residues are cyan; C: Schematic diagram of the interaction between BacPROTAC-1 and ClpC1-NTD and structure of BacPROTAC-1; D: BacPROTAC-4; E: BacPROTAC-5 , figureFileSmall=y1vOs1l9LRP+Hg2EQTeQGg==, figureFileBig=7WmxbYCDLfff8oG7ZF94ZA==, tableContent=null), ArticleFig(id=1198960133393969913, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=EN, label=null, caption=null, figureFileSmall=LFJdMLUeiv8gJwURgaOEFQ==, figureFileBig=EWyFbHDZ19avF+91imWsSg==, tableContent=null), ArticleFig(id=1198960133528187652, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=CN, label=Figure 4, caption=
A and B are ClpC1-NTD ligands screened from the natural product library; C: The molecular docking model of ClpC1-NTD with compound A (R1 is cyclohexyl group), the compound structure is green, key amino acid residues are gray; D: The molecular docking model of ClpC1-NTDwith compound B (type 1), the compound structure is green, key amino acid residues are indigo , figureFileSmall=LFJdMLUeiv8gJwURgaOEFQ==, figureFileBig=EWyFbHDZ19avF+91imWsSg==, tableContent=null), ArticleFig(id=1198960133712737047, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
 |
| Compd. | R1 | R2 | R3 | R4 | MIC/μmol·L-1 a |
| Isoniazid | / | / | / | / | 0.9 |
| 1 |  |  |  | / | 0.1 |
| 2 | / | 0.1 |
| 3 | / | > 10 |
| 4 | / | 0.9 |
| 5 | / | 0.5 |
| 6 | / | 1.7 |
| 7 | iPr |  |  | / | 0.4 |
| 8 | Me | / | 0.9 |
| 9 | H | / | 1.5 |
| 10 |  |  |  | / | 21.2 |
| 11 | / | 1.7 |
| 12 | iPr |  |  | / | 0.4 |
| 13 | Me | / | 1.6 |
| 14 | H | / | 0.5 |
| 15 |  |  |  | / | 2.3 |
| 16 | / | > 32 |
| 17 | iPr |  |  | / | 1.8 |
| 18 | Me | / | 3.4 |
| 19 |  |  |  | / | 2.6 |
| 20 | / | 3.2 |
| 21 | H |  |  | / | 4.3 |
| 22 |  |  |  | NO2 | 0.13 |
| 23 | Br | 0.25 |
| 24 | N3 | 4.09 |
| 25 | NH2 | 0.26 |
), ArticleFig(id=1198960133943423792, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=CN, label=Table 1, caption=
Antimicrobial activity (MIC) of CymA derivatives against H37Rv/Erdman strain. aCompounds 1-21 were tested for MIC using the H37Rv strain and compounds 22-25 were tested for MIC using the Erdman strain
, figureFileSmall=null, figureFileBig=null, tableContent=
|
| Compd. | R1 | R2 | R3 | R4 | MIC/μmol·L-1 a |
| Isoniazid | / | / | / | / | 0.9 |
| 1 | | | | / | 0.1 |
| 2 | / | 0.1 |
| 3 | / | > 10 |
| 4 | / | 0.9 |
| 5 | / | 0.5 |
| 6 | / | 1.7 |
| 7 | iPr | | | / | 0.4 |
| 8 | Me | / | 0.9 |
| 9 | H | / | 1.5 |
| 10 | | | | / | 21.2 |
| 11 | / | 1.7 |
| 12 | iPr | | | / | 0.4 |
| 13 | Me | / | 1.6 |
| 14 | H | / | 0.5 |
| 15 | | | | / | 2.3 |
| 16 | / | > 32 |
| 17 | iPr | | | / | 1.8 |
| 18 | Me | / | 3.4 |
| 19 | | | | / | 2.6 |
| 20 | / | 3.2 |
| 21 | H | | | / | 4.3 |
| 22 | | | | NO2 | 0.13 |
| 23 | Br | 0.25 |
| 24 | N3 | 4.09 |
| 25 | NH2 | 0.26 |
), ArticleFig(id=1198960134220247883, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
 |
| Compd. | | R1 | R2 | R3 | ClpC1-NTD KD/nmol·L-1 | MIC Mtb H37Rv/μmol·L-1 |
| 26 | Monomer | H |  |  | 1.2 | 0.42 |
| 27 | Me | 12.1 | n.d. |
| 28 | Monomer | H | Me |  | 4 | 3.13 |
| 29 | Me | 13.9 | > 50 |
| 30 | Monomer | H | Me | A | 4.6 | n.d. |
| 31 | Me | 26.1 | 6.25 |
| 32 | Dimer | H | Me | B | 0.2 | 0.097 |
| 33 | Me | 0.9 | 3.13 |
| 34 | Monomer | H |  | iPr | 3.5 | 1.56 |
| 35 | Me | 14.6 | 6.25 |
| 36 | Dimer | H | E | iPr | 0.4 | 0.37 |
| 37 | Me | 0.4 | 0.097 |
| 38 | Dimer | H | C | iPr | 0.6 | 0.366 |
| 39 | Dimer | H | Me | D | 0.4 | 0.097 |
| 40 | Dimer | H |  | iPr | 1.2 | 0.196 |
| 41 | Me | 1.8 | n.d. |
), ArticleFig(id=1198960134329299799, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=CN, label=Table 2, caption=
Structure-activity relationships of monomeric dCym derivatives and homo-BacPROTACs
, figureFileSmall=null, figureFileBig=null, tableContent=
|
| Compd. | | R1 | R2 | R3 | ClpC1-NTD KD/nmol·L-1 | MIC Mtb H37Rv/μmol·L-1 |
| 26 | Monomer | H | | | 1.2 | 0.42 |
| 27 | Me | 12.1 | n.d. |
| 28 | Monomer | H | Me | | 4 | 3.13 |
| 29 | Me | 13.9 | > 50 |
| 30 | Monomer | H | Me | A | 4.6 | n.d. |
| 31 | Me | 26.1 | 6.25 |
| 32 | Dimer | H | Me | B | 0.2 | 0.097 |
| 33 | Me | 0.9 | 3.13 |
| 34 | Monomer | H | | iPr | 3.5 | 1.56 |
| 35 | Me | 14.6 | 6.25 |
| 36 | Dimer | H | E | iPr | 0.4 | 0.37 |
| 37 | Me | 0.4 | 0.097 |
| 38 | Dimer | H | C | iPr | 0.6 | 0.366 |
| 39 | Dimer | H | Me | D | 0.4 | 0.097 |
| 40 | Dimer | H | | iPr | 1.2 | 0.196 |
| 41 | Me | 1.8 | n.d. |
), ArticleFig(id=1198960134429963106, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
 |
| Compd. | R1 | R2 | R3 | R4 | R5 | MIC/μmol·L-1 |
| 42 | OH(23S) | CH3(22R) | NO2 | CH3 |  | 0.01 |
| 43 | OH(23S) | CH3(22S) | NO2 | CH3 | 0.05 |
| 44 | H | CH3 | NO2 | CH3 | 1.0 |
| 45 | H |  | NO2 | H | 0.58 |
| 46 | H | NO2 | CH3 | 0.07 |
| 47 | H | H | CH3 | > 50 |
| 48 | H | NO2 | CH3 | 1.0 |
), ArticleFig(id=1198960134568375153, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198683367081345914, language=CN, label=Table 3, caption=
Antimicrobial activity (MIC) of RUFI derivatives against H37Rv strain
, figureFileSmall=null, figureFileBig=null, tableContent=
|
| Compd. | R1 | R2 | R3 | R4 | R5 | MIC/μmol·L-1 |
| 42 | OH(23S) | CH3(22R) | NO2 | CH3 | | 0.01 |
| 43 | OH(23S) | CH3(22S) | NO2 | CH3 | 0.05 |
| 44 | H | CH3 | NO2 | CH3 | 1.0 |
| 45 | H | | NO2 | H | 0.58 |
| 46 | H | NO2 | CH3 | 0.07 |
| 47 | H | H | CH3 | > 50 |
| 48 | H | NO2 | CH3 | 1.0 |
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