ADP-ribosyltransferases of the PARP family encompass a group of enzymes with variegated regulatory functions in cells, ranging from DNA damage repair to the control of cell-cycle progression and immune response. Over the years, this knowledge has led to the use of PARP1/2 inhibitors as mainstay pharmaceutical strategies for the treatment of ovarian, pancreatic, prostate and breast cancers, holding mutations in genes encoding for proteins involved in the DNA repair mechanisms (synthetic lethality). Meanwhile, the last decade has witnessed significant progress in comprehending cellular pathways regulated by mono-ADP-ribosylation, with a huge effort in the development of novel selective compounds to inhibit those PARPs endowed with mono-ADP-ribosylation activity. This review focuses on the progress achieved in the cancer field, delving into most recent findings regarding the role of a subset of enzymes - the interferon-stimulated PARPs - in cancer progression.
PARP 家族的 ADP 核糖转移酶包括一组在细胞中具有各种调节功能的酶,从 DNA 损伤修复到控制细胞周期进展和免疫反应。多年来,这些知识促使人们将 PARP1/2 抑制剂作为治疗卵巢癌、胰腺癌、前列腺癌和乳腺癌的主要药物策略,因为 DNA 修复机制(合成致死)涉及的蛋白质编码基因发生了突变。与此同时,在过去十年中,人们在理解受单 ADP 核糖基化调控的细胞通路方面取得了重大进展,并在开发新型选择性化合物以抑制具有单 ADP 核糖基化活性的 PARPs 方面做出了巨大努力。本综述将重点关注癌症领域取得的进展,深入探讨有关干扰素刺激的 PARPs 这一类酶在癌症进展中所起作用的最新发现。
{"title":"PARP enzymes and mono-ADP-ribosylation: advancing the connection from interferon-signalling to cancer biology.","authors":"Barbara Morone, Giovanna Grimaldi","doi":"10.1017/erm.2024.13","DOIUrl":"https://doi.org/10.1017/erm.2024.13","url":null,"abstract":"<p><p>ADP-ribosyltransferases of the PARP family encompass a group of enzymes with variegated regulatory functions in cells, ranging from DNA damage repair to the control of cell-cycle progression and immune response. Over the years, this knowledge has led to the use of PARP1/2 inhibitors as mainstay pharmaceutical strategies for the treatment of ovarian, pancreatic, prostate and breast cancers, holding mutations in genes encoding for proteins involved in the DNA repair mechanisms (synthetic lethality). Meanwhile, the last decade has witnessed significant progress in comprehending cellular pathways regulated by mono-ADP-ribosylation, with a huge effort in the development of novel selective compounds to inhibit those PARPs endowed with mono-ADP-ribosylation activity. This review focuses on the progress achieved in the cancer field, delving into most recent findings regarding the role of a subset of enzymes - the interferon-stimulated PARPs - in cancer progression.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery of the millennium, as it was identified in 1999. Although PARP2 was described initially as a DNA repair factor, it is now evident that PARP2 partakes in the regulation or execution of multiple biological processes as inflammation, carcinogenesis and cancer progression, metabolism or oxidative stress-related diseases. Hereby, we review the involvement of PARP2 in these processes with the aim of understanding which processes are specific for PARP2, but not for other members of the ART family. A better understanding of the specific functions of PARP2 in all of these biological processes is crucial for the development of new PARP-centred selective therapies.
{"title":"Specific and shared biological functions of PARP2 – is PARP2 really a lil’ brother of PARP1?","authors":"Magdolna Szántó, José Yélamos, Péter Bai","doi":"10.1017/erm.2024.14","DOIUrl":"https://doi.org/10.1017/erm.2024.14","url":null,"abstract":"PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery of the millennium, as it was identified in 1999. Although PARP2 was described initially as a DNA repair factor, it is now evident that PARP2 partakes in the regulation or execution of multiple biological processes as inflammation, carcinogenesis and cancer progression, metabolism or oxidative stress-related diseases. Hereby, we review the involvement of PARP2 in these processes with the aim of understanding which processes are specific for PARP2, but not for other members of the ART family. A better understanding of the specific functions of PARP2 in all of these biological processes is crucial for the development of new PARP-centred selective therapies.","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Long non-coding RNAs (lncRNAs) are progressively being perceived as prominent molecular agents controlling multiple aspects of neuronal (patho)physiology. Amongst these is the HOX transcript antisense intergenic RNA, often abbreviated as HOTAIR. HOTAIR epigenetically regulates its target genes via its interaction with two different chromatin-modifying agents; histone methyltransferase polycomb-repressive complex 2 and histone demethylase lysine-specific demethylase 1. Parenthetically, HOTAIR elicits trans-acting sponging function against multiple micro-RNA species. Oncological research studies have confirmed the pathogenic functions of HOTAIR in multiple cancer types, such as gliomas and proposed it as a pro-oncological lncRNA. In fact, its expression has been suggested to be a predictor of the severity/grade of gliomas, and as a prognostic biomarker. Moreover, a propound influence of HOTAIR in other aspects of brain heath and disease states is just beginning to be unravelled. The objective of this review is to recapitulate all the relevant data pertaining to the regulatory roles of HOTAIR in neuronal (patho)physiology. To this end, we discuss the pathogenic mechanisms of HOTAIR in multiple neuronal diseases, such as neurodegeneration, traumatic brain injury and neuropsychiatric disorders. Finally, we also summarize the results from the studies incriminating HOTAIR in the pathogeneses of gliomas and other brain cancers. Implications of HOTAIR serving as a suitable therapeutic target in neuropathologies are also discussed.
{"title":"The multifaceted functions of long non-coding RNA HOTAIR in neuropathologies and its potential as a prognostic marker and therapeutic biotarget","authors":"Faraz Ahmad, Ravi Sudesh, Atheeq Toufeeq Ahmed, Mohanapriya Arumugam, Darin Mansor Mathkor, Shafiul Haque","doi":"10.1017/erm.2024.11","DOIUrl":"https://doi.org/10.1017/erm.2024.11","url":null,"abstract":"<p>Long non-coding RNAs (lncRNAs) are progressively being perceived as prominent molecular agents controlling multiple aspects of neuronal (patho)physiology. Amongst these is the HOX transcript antisense intergenic RNA, often abbreviated as <span>HOTAIR</span>. <span>HOTAIR</span> epigenetically regulates its target genes via its interaction with two different chromatin-modifying agents; histone methyltransferase polycomb-repressive complex 2 and histone demethylase lysine-specific demethylase 1. Parenthetically, <span>HOTAIR</span> elicits trans-acting sponging function against multiple micro-RNA species. Oncological research studies have confirmed the pathogenic functions of <span>HOTAIR</span> in multiple cancer types, such as gliomas and proposed it as a pro-oncological lncRNA. In fact, its expression has been suggested to be a predictor of the severity/grade of gliomas, and as a prognostic biomarker. Moreover, a propound influence of <span>HOTAIR</span> in other aspects of brain heath and disease states is just beginning to be unravelled. The objective of this review is to recapitulate all the relevant data pertaining to the regulatory roles of <span>HOTAIR</span> in neuronal (patho)physiology. To this end, we discuss the pathogenic mechanisms of <span>HOTAIR</span> in multiple neuronal diseases, such as neurodegeneration, traumatic brain injury and neuropsychiatric disorders. Finally, we also summarize the results from the studies incriminating <span>HOTAIR</span> in the pathogeneses of gliomas and other brain cancers. Implications of <span>HOTAIR</span> serving as a suitable therapeutic target in neuropathologies are also discussed.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140809433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rhys E. De Sota, Stephen R. Quake, John J. Sninsky, Shusuke Toden
Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform. With mRNAs packaged in a myriad of extracellular vesicles and particles, these signals may be used to develop clinically actionable, non-invasive disease biomarkers. Here, we summarize the recent scientific developments of extracellular mRNA, biology of extracellular mRNA carriers, clinical utility of cf-mRNA as disease biomarkers, as well as proposed functions in cell and tissue pathophysiology.
{"title":"Decoding bioactive signals of the RNA secretome: the cell-free messenger RNA catalogue","authors":"Rhys E. De Sota, Stephen R. Quake, John J. Sninsky, Shusuke Toden","doi":"10.1017/erm.2024.12","DOIUrl":"https://doi.org/10.1017/erm.2024.12","url":null,"abstract":"<p>Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform. With mRNAs packaged in a myriad of extracellular vesicles and particles, these signals may be used to develop clinically actionable, non-invasive disease biomarkers. Here, we summarize the recent scientific developments of extracellular mRNA, biology of extracellular mRNA carriers, clinical utility of cf-mRNA as disease biomarkers, as well as proposed functions in cell and tissue pathophysiology.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140809736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Baoqiang Yang, D. Ma, Xue-Jun Zhu, Zewen Wu, Qingwu An, Jingwen Zhao, Xinnan Gao, Liyun Zhang
Autoimmune diseases are pathological autoimmune reactions in the body caused by various factors, which can lead to tissue damage and organ dysfunction. They can be divided into organ-specific and systemic autoimmune diseases. These diseases usually involve various body systems, including the blood, muscles, bones, joints and soft tissues. The transient receptor potential (TRP) and PIEZO receptors, which resulted in David Julius and Ardem Patapoutian winning the Nobel Prize in Physiology or Medicine in 2021, attracted people's attention. Most current studies on TRP and PIEZO receptors in autoimmune diseases have been carried out on animal model, only few clinical studies have been conducted. Therefore, this study aimed to review existing studies on TRP and PIEZO to understand the roles of these receptors in autoimmune diseases, which may help elucidate novel treatment strategies.
{"title":"Roles of TRP and PIEZO receptors in autoimmune diseases.","authors":"Baoqiang Yang, D. Ma, Xue-Jun Zhu, Zewen Wu, Qingwu An, Jingwen Zhao, Xinnan Gao, Liyun Zhang","doi":"10.1017/erm.2023.23","DOIUrl":"https://doi.org/10.1017/erm.2023.23","url":null,"abstract":"Autoimmune diseases are pathological autoimmune reactions in the body caused by various factors, which can lead to tissue damage and organ dysfunction. They can be divided into organ-specific and systemic autoimmune diseases. These diseases usually involve various body systems, including the blood, muscles, bones, joints and soft tissues. The transient receptor potential (TRP) and PIEZO receptors, which resulted in David Julius and Ardem Patapoutian winning the Nobel Prize in Physiology or Medicine in 2021, attracted people's attention. Most current studies on TRP and PIEZO receptors in autoimmune diseases have been carried out on animal model, only few clinical studies have been conducted. Therefore, this study aimed to review existing studies on TRP and PIEZO to understand the roles of these receptors in autoimmune diseases, which may help elucidate novel treatment strategies.","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140657403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathryn Pennel, Louise Dutton, Lydia Melissourgou-Syka, Campbell S D Roxburgh, Joanna Birch, Joanne Edwards
{"title":"Novel radiation and targeted therapy combinations for improving rectal cancer outcomes.","authors":"Kathryn Pennel, Louise Dutton, Lydia Melissourgou-Syka, Campbell S D Roxburgh, Joanna Birch, Joanne Edwards","doi":"10.1017/erm.2024.15","DOIUrl":"https://doi.org/10.1017/erm.2024.15","url":null,"abstract":"","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140696744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Role of the Cytochrome P450 Superfamily in the Skin.","authors":"Qianqian Chen, Tuan Wang, Hong Pan, Xia Wu, Huipu Yuan, Jianling Mo, Yuan Wei, Ying Xiao","doi":"10.1017/erm.2024.5","DOIUrl":"https://doi.org/10.1017/erm.2024.5","url":null,"abstract":"","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140702359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brenda Castro, Jason C. Steel, Christopher J. Layton
Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.
{"title":"AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?","authors":"Brenda Castro, Jason C. Steel, Christopher J. Layton","doi":"10.1017/erm.2024.4","DOIUrl":"https://doi.org/10.1017/erm.2024.4","url":null,"abstract":"Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140572974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shi Rui Seow, Sumaiyah Mat, Amalina Ahmad Azam, Nor Fadilah Rajab, Intan Safinar Ismail, Devinder Kaur Ajit Singh, Suzana Shahar, Maw Pin Tan, Francis Berenbaum
Osteoarthritis (OA) commonly affects the knee and hip joints and accounts for 19.3% of disability-adjusted life years and years lived with disability worldwide (Refs 1, 2). Early management is important in order to avoid disability uphold quality of life (Ref. 3). However, a lack of awareness of subclinical and early symptomatic stages of OA often hampers early management (Ref. 4). Moreover, late diagnosis of OA among those with severe disease, at a stage when OA management becomes more complicated is common (Refs 5, 6, 7, 8). Established risk factors for the development and progression of OA include increasing age, female, history of trauma and obesity (Ref. 9). Recent studies have also drawn a link between OA and metabolic syndrome, which is characterized by insulin resistance, dyslipidaemia and hypertension (Refs 10, 11).
骨关节炎(OA)通常影响膝关节和髋关节,占全球残疾调整寿命年数和残疾生活年数的19.3%(参考文献1、2)。为了避免残疾,提高生活质量,早期治疗非常重要(参考文献 3)。然而,由于缺乏对OA亚临床和早期症状阶段的认识,往往阻碍了早期治疗(参考文献4)。此外,在病情严重的患者中,OA诊断较晚的情况也很常见,因为此时OA的治疗变得更加复杂(参考文献5、6、7、8)。导致 OA 发生和恶化的既定风险因素包括年龄增长、女性、外伤史和肥胖(参考文献 9)。最近的研究还发现,OA 与代谢综合征之间存在联系,代谢综合征的特征是胰岛素抵抗、血脂异常和高血压(参考文献 10、11)。
{"title":"Impact of diabetes mellitus on osteoarthritis: a scoping review on biomarkers","authors":"Shi Rui Seow, Sumaiyah Mat, Amalina Ahmad Azam, Nor Fadilah Rajab, Intan Safinar Ismail, Devinder Kaur Ajit Singh, Suzana Shahar, Maw Pin Tan, Francis Berenbaum","doi":"10.1017/erm.2024.7","DOIUrl":"https://doi.org/10.1017/erm.2024.7","url":null,"abstract":"Osteoarthritis (OA) commonly affects the knee and hip joints and accounts for 19.3% of disability-adjusted life years and years lived with disability worldwide (Refs 1, 2). Early management is important in order to avoid disability uphold quality of life (Ref. 3). However, a lack of awareness of subclinical and early symptomatic stages of OA often hampers early management (Ref. 4). Moreover, late diagnosis of OA among those with severe disease, at a stage when OA management becomes more complicated is common (Refs 5, 6, 7, 8). Established risk factors for the development and progression of OA include increasing age, female, history of trauma and obesity (Ref. 9). Recent studies have also drawn a link between OA and metabolic syndrome, which is characterized by insulin resistance, dyslipidaemia and hypertension (Refs 10, 11).","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amy L. George, Maria Emilia Dueñas, José Luis Marín-Rubio, Matthias Trost
Target deconvolution can help understand how compounds exert therapeutic effects and can accelerate drug discovery by helping optimise safety and efficacy, revealing mechanisms of action, anticipate off-target effects and identifying opportunities for therapeutic expansion. Chemoproteomics, a combination of chemical biology with mass spectrometry has transformed target deconvolution. This review discusses modification-free chemoproteomic approaches that leverage the change in protein thermodynamics induced by small molecule ligand binding. Unlike modification-based methods relying on enriching specific protein targets, these approaches offer proteome-wide evaluations, driven by advancements in mass spectrometry sensitivity, increasing proteome coverage and quantitation methods. Advances in methods based on denaturation/precipitation by thermal or chemical denaturation, or by protease degradation are evaluated, emphasising the evolving landscape of chemoproteomics and its potential impact on future drug-development strategies.
{"title":"Stability-based approaches in chemoproteomics","authors":"Amy L. George, Maria Emilia Dueñas, José Luis Marín-Rubio, Matthias Trost","doi":"10.1017/erm.2024.6","DOIUrl":"https://doi.org/10.1017/erm.2024.6","url":null,"abstract":"<p>Target deconvolution can help understand how compounds exert therapeutic effects and can accelerate drug discovery by helping optimise safety and efficacy, revealing mechanisms of action, anticipate off-target effects and identifying opportunities for therapeutic expansion. Chemoproteomics, a combination of chemical biology with mass spectrometry has transformed target deconvolution. This review discusses modification-free chemoproteomic approaches that leverage the change in protein thermodynamics induced by small molecule ligand binding. Unlike modification-based methods relying on enriching specific protein targets, these approaches offer proteome-wide evaluations, driven by advancements in mass spectrometry sensitivity, increasing proteome coverage and quantitation methods. Advances in methods based on denaturation/precipitation by thermal or chemical denaturation, or by protease degradation are evaluated, emphasising the evolving landscape of chemoproteomics and its potential impact on future drug-development strategies.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140572976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}