{"title":"小分子蛋白质伙伴的鉴定重塑了对非酒精性脂肪性肝炎和药物发现的认识。","authors":"","doi":"10.1016/j.lfs.2024.123031","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><p>Nonalcoholic steatohepatitis (NASH) is the severe subtype of nonalcoholic fatty diseases (NAFLD) with few options for treatment. Patients with NASH exhibit partial responses to the current therapeutics and adverse effects. Identification of the binding proteins for the drugs is essential to understanding the mechanism and adverse effects of the drugs and fuels the discovery of potent and safe drugs. This paper aims to critically discuss recent advances in covalent and noncovalent approaches for identifying binding proteins that mediate NASH progression, along with an in-depth analysis of the mechanisms by which these targets regulate NASH.</p></div><div><h3>Materials and methods</h3><p>A literature search was conducted to identify the relevant studies in the database of PubMed and the American Chemical Society. The search covered articles published from January 1990 to July 2024, using the search terms with keywords such as NASH, benzophenone, diazirine, photo-affinity labeling, thermal protein profiling, CETSA, target identification.</p></div><div><h3>Key findings</h3><p>The covalent approaches utilize drugs modified with diazirine and benzophenone to covalently crosslink with the target proteins, which facilitates the purification and identification of target proteins. In addition, they map the binding sites in the target proteins. By contrast, noncovalent approaches identify the binding targets of unmodified drugs in the intact cell proteome. The advantages and limitations of both approaches have been compared, along with a comprehensive analysis of recent innovations that further enhance the efficiency and specificity.</p></div><div><h3>Significance</h3><p>The analyses of the applicability of these approaches provide novel tools to delineate NASH pathogenesis and promote drug discovery.</p></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of protein partners for small molecules reshapes the understanding of nonalcoholic steatohepatitis and drug discovery\",\"authors\":\"\",\"doi\":\"10.1016/j.lfs.2024.123031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Aims</h3><p>Nonalcoholic steatohepatitis (NASH) is the severe subtype of nonalcoholic fatty diseases (NAFLD) with few options for treatment. Patients with NASH exhibit partial responses to the current therapeutics and adverse effects. Identification of the binding proteins for the drugs is essential to understanding the mechanism and adverse effects of the drugs and fuels the discovery of potent and safe drugs. This paper aims to critically discuss recent advances in covalent and noncovalent approaches for identifying binding proteins that mediate NASH progression, along with an in-depth analysis of the mechanisms by which these targets regulate NASH.</p></div><div><h3>Materials and methods</h3><p>A literature search was conducted to identify the relevant studies in the database of PubMed and the American Chemical Society. The search covered articles published from January 1990 to July 2024, using the search terms with keywords such as NASH, benzophenone, diazirine, photo-affinity labeling, thermal protein profiling, CETSA, target identification.</p></div><div><h3>Key findings</h3><p>The covalent approaches utilize drugs modified with diazirine and benzophenone to covalently crosslink with the target proteins, which facilitates the purification and identification of target proteins. In addition, they map the binding sites in the target proteins. By contrast, noncovalent approaches identify the binding targets of unmodified drugs in the intact cell proteome. The advantages and limitations of both approaches have been compared, along with a comprehensive analysis of recent innovations that further enhance the efficiency and specificity.</p></div><div><h3>Significance</h3><p>The analyses of the applicability of these approaches provide novel tools to delineate NASH pathogenesis and promote drug discovery.</p></div>\",\"PeriodicalId\":18122,\"journal\":{\"name\":\"Life sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0024320524006210\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320524006210","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Identification of protein partners for small molecules reshapes the understanding of nonalcoholic steatohepatitis and drug discovery
Aims
Nonalcoholic steatohepatitis (NASH) is the severe subtype of nonalcoholic fatty diseases (NAFLD) with few options for treatment. Patients with NASH exhibit partial responses to the current therapeutics and adverse effects. Identification of the binding proteins for the drugs is essential to understanding the mechanism and adverse effects of the drugs and fuels the discovery of potent and safe drugs. This paper aims to critically discuss recent advances in covalent and noncovalent approaches for identifying binding proteins that mediate NASH progression, along with an in-depth analysis of the mechanisms by which these targets regulate NASH.
Materials and methods
A literature search was conducted to identify the relevant studies in the database of PubMed and the American Chemical Society. The search covered articles published from January 1990 to July 2024, using the search terms with keywords such as NASH, benzophenone, diazirine, photo-affinity labeling, thermal protein profiling, CETSA, target identification.
Key findings
The covalent approaches utilize drugs modified with diazirine and benzophenone to covalently crosslink with the target proteins, which facilitates the purification and identification of target proteins. In addition, they map the binding sites in the target proteins. By contrast, noncovalent approaches identify the binding targets of unmodified drugs in the intact cell proteome. The advantages and limitations of both approaches have been compared, along with a comprehensive analysis of recent innovations that further enhance the efficiency and specificity.
Significance
The analyses of the applicability of these approaches provide novel tools to delineate NASH pathogenesis and promote drug discovery.
期刊介绍:
Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed.
The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.