Medicinal Research Reviews最新文献

{"title":"Controlling Protein Functionalities With Temporal and Cellular/Subcellular Dimensions of Spatial Resolution With Molecular Photoswitches","authors":"Saugata Sahu,&nbsp;Ammathnadu S. Amrutha,&nbsp;Nobuyuki Tamaoki","doi":"10.1002/med.22106","DOIUrl":"10.1002/med.22106","url":null,"abstract":"<div>\u0000 \u0000 <p>The use of photoswitchable ligand to control the protein functionalities and related downstream effects in an on-off manner is an active research area in photopharmacology and medicinal chemistry. Temporal control grants a privilege to identify the crucial role of a particular receptor in biological occurrences without destroying the protein permanently. Additionally, light can be applied site-selectively to regulate protein functionality with cellular and sub-cellular levels of spatial resolutions. The spatiotemporal resolution enables the probing of a specific receptor, a receptor isoform, or a particular signalling pathway. This reversible and fast spatiotemporal control is highly beneficial in studying protein functionalities in highly dynamic biological processes, including but not limited to signal transduction, neurotransmission, cell divisions, immune response, protein folding, and protein degradation. Though several light-active ligands have been developed to control protein functionality in an on-off manner efficiently, only a few reports on protein functionality with spatial resolution exist in the literature. Major challenges to achieve efficient photoswitches to study protein functionalities are efficient synthesis strategy, photostability of the ligand, bidirectional visible light switching ability and most importantly precise controlling of the local concentration of desired photoisomer using light. The site-specific localization of the active photoisomer depends on multiple factors like the nature of the photoswitch, the binding affinity of both photoisomers, molecular diffusion and light irradiation conditions. The present review discusses suitable techniques and the role of different factors in achieving cellular and subcellular dimension control in protein functionality. Multiple strategies are discussed, along with their advantages and limitations, to explore the enormous potentiality of these approaches in manipulating protein functionality.</p>\u0000 </div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 4","pages":"1142-1162"},"PeriodicalIF":10.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Energy Metabolism Supports Molecular and Functional Heterogeneity of Reactive Astrocytes in Central Nervous System Disorders","authors":"Jie Song,&nbsp;Jianning Kang,&nbsp;Ying Zhang,&nbsp;Yinghui Wang,&nbsp;Rui Yang,&nbsp;Bin Ning","doi":"10.1002/med.22103","DOIUrl":"10.1002/med.22103","url":null,"abstract":"<div>\u0000 \u0000 <p>Astrocytes undergo a reactive transformation in central nervous system (CNS) disorders, manifesting significant heterogeneity in morphology, molecules, function, and spatial distribution. Just like all cells, astrocytes necessitate energy for their basic functions. Energy production proves critical for the survival and development of astrocytes, as well as their fate determination and functional diversity. The activation process of astrocytes involves a metabolic shift in energy, yet our understanding of how this change impacts the heterogeneity of reactive astrocytes remains limited. In this comprehensive review, we begin by outlining the advancements in research on reactive astrocytes in CNS disorders, establishing a crucial association between the energy metabolism of reactive astrocytes and their molecular and functional aspects. Following this, we delve into a thorough analysis of the energy metabolic transitions of reactive astrocytes within the context of CNS diseases. Starting from the essential pathways of energy metabolism, we present a novel perspective, shedding light on the molecular and functional heterogeneity of reactive astrocytes by considering the heterogeneity in energy metabolism. In conclusion, we propose that the modulation of energy metabolism in reactive astrocytes, coupled with the promotion of their functionality toward disease recovery, represents a cutting-edge and promising strategy for the treatment of CNS diseases.</p>\u0000 </div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 4","pages":"1126-1141"},"PeriodicalIF":10.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Emerging Landscape of Tubercular Targets: A Medicinal Chemistry Approach","authors":"Baji Baba Shaik,&nbsp;Kimeshni Moodley,&nbsp;Safiyah Ghumran,&nbsp;Muhammad D. Bala,&nbsp;Parvesh Singh,&nbsp;Rajshekhar Karpoormath","doi":"10.1002/med.22100","DOIUrl":"10.1002/med.22100","url":null,"abstract":"<div>\u0000 \u0000 <p>Antitubercular drug discovery progress in the last decade, especially research on the biological function, target inhibition and diagnosis of tuberculosis (TB) diagnosis has considerably advanced. The application of target-based drug discovery techniques have become a more powerful tool for medicinal chemists in developing new therapeutic strategies, such as its application in the identification/validation of new targets, new leads, and drug candidates with optimized efficacy. This has been further evidenced by the recent approval of delamanid and bedaquiline for the treatment of MDR-TB and XDR-TB, respectively. While a TB drug pipeline has shown great development, high attrition rates must constantly replenish the pipeline with high-quality leads acting through the inhibition of new targets. This review provides a critical analysis of the approaches used to advance hit compounds into viable lead candidates as well as the possible influence of new targets on drug development in the near future. Finally, we concluded with the present challenges that are faced in TB drug development.</p></div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 4","pages":"1077-1125"},"PeriodicalIF":10.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unleashing the Power of Covalent Drugs for Protein Degradation","authors":"Meng-Jie Fu,&nbsp;Hang Jin,&nbsp;Shao-Peng Wang,&nbsp;Liang Shen,&nbsp;Hong-Min Liu,&nbsp;Ying Liu,&nbsp;Yi-Chao Zheng,&nbsp;Xing-Jie Dai","doi":"10.1002/med.22101","DOIUrl":"10.1002/med.22101","url":null,"abstract":"<div>\u0000 \u0000 <p>Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome-dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions. Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. Traditional PROTACs are encountering obstacles such as limited binding affinity and a restricted range of E3 ligase ligands for facilitating the protein of interest (POI) degradation. Covalent medicines offer the potential to enhance PROTAC efficacy by enabling the targeting of previously considered “undruggable” shallow binding sites. Strategic alterations allow PROTAC to establish covalent connections with particular target proteins, including Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), as well as E3 ligases such as DDB1 and CUL4 associated factor 16 (DCAF16) and Kelch-like ECH-associated protein 1 (Keap1). The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.</p>\u0000 </div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 4","pages":"1045-1076"},"PeriodicalIF":10.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomics: An In-Depth Review on Recent Technical Advances and Their Applications in Biomedicine","authors":"Jing Liang,&nbsp;Jundan Tian,&nbsp;Huadong Zhang,&nbsp;Hua Li,&nbsp;Lixia Chen","doi":"10.1002/med.22098","DOIUrl":"10.1002/med.22098","url":null,"abstract":"<div>\u0000 \u0000 <p>Proteins hold pivotal importance since many diseases manifest changes in protein activity. Proteomics techniques provide a comprehensive exploration of protein structure, abundance, and function in biological samples, enabling the holistic characterization of overall changes in organisms. Nowadays, the breadth of emerging methodologies in proteomics is unprecedentedly vast, with constant optimization of technologies in sample processing, data collection, data analysis, and its scope of application is steadily transitioning from the bench to the clinic. Here, we offer an insightful review of the technical developments in proteomics and its applications in biomedicine over the past 5 years. We focus on its profound contributions in profiling disease spectra, discovering new biomarkers, identifying promising drug targets, deciphering alterations in protein conformation, and unearthing protein–protein interactions. Moreover, we summarize the cutting-edge technologies and potential breakthroughs in the proteomics pipeline and provide the principal challenges in proteomics. Based on these, we aspire to broaden the applicability of proteomics and inspire researchers to enhance our understanding of complex biological systems by utilizing such techniques.</p>\u0000 </div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 4","pages":"1021-1044"},"PeriodicalIF":10.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G9a an Epigenetic Therapeutic Strategy for Neurodegenerative Conditions: From Target Discovery to Clinical Trials","authors":"Aina Bellver-Sanchis,&nbsp;Marta Ribalta-Vilella,&nbsp;Alba Irisarri,&nbsp;Pinky Gehlot,&nbsp;Bhanwar Singh Choudhary,&nbsp;Abhisek Jana,&nbsp;Vivek Kumar Vyas,&nbsp;Deb Ranjan Banerjee,&nbsp;Mercè Pallàs,&nbsp;Ana Guerrero,&nbsp;Christian Griñán-Ferré","doi":"10.1002/med.22096","DOIUrl":"https://doi.org/10.1002/med.22096","url":null,"abstract":"<p>This review provides a comprehensive overview of the role of G9a/EHMT2, focusing on its structure and exploring the impact of its pharmacological and/or gene inhibition in various neurological diseases. In addition, we delve into the advancements in the design and synthesis of G9a/EHMT2 inhibitors, which hold promise not only as a treatment for neurodegeneration diseases but also for other conditions, such as cancer and malaria. Besides, we presented the discovery of dual therapeutic approaches based on G9a inhibition and different epigenetic enzymes like histone deacetylases, DNA methyltransferases, and other lysine methyltransferases. Hence, findings offer valuable insights into developing novel and promising therapeutic strategies targeting G9a/EHMT2 for managing these neurological conditions.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 3","pages":"985-1015"},"PeriodicalIF":10.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/med.22096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Current Progress in the Quest for Vaccines Against the Semliki Forest Virus Complex","authors":"Dorothy Hui Juan Cheong,&nbsp;Bowen Yi,&nbsp;Yi Hao Wong,&nbsp;Justin Jang Hann Chu","doi":"10.1002/med.22097","DOIUrl":"10.1002/med.22097","url":null,"abstract":"<div>\u0000 \u0000 <p>The Semliki Forest virus (SFV) complex comprises of arboviruses that are transmitted by arthropod vectors and cause acute febrile illness in humans. In the last seven decades, re-emergence of these viruses has resulted in numerous outbreaks globally, affecting regions including Africa, Americas, Asia, Europe and the Caribbean. These viruses are transmitted to humans by the bite of infected mosquitoes. Symptoms of infection include high fever, severe joint pain, skin rash, muscle pain and headache. Fatal cases were reported, and mortality rate increased during the epidemic of these viruses. There is therefore a need to control the spread of these emerging arboviruses. Given that vaccination is one of the most effective ways to protect populations against viral outbreaks, efforts have been made to develop and test potential vaccine candidates. However, there are still no licensed vaccines available against the medically important viruses in the SFV complex. This review first summarizes the current knowledge of the SFV complex disease pathogenesis. Next, seven strategies that have been applied in vaccine development against these viruses are reviewed, indicating the immune response and efficacies of these vaccine candidates in in vivo models of infection. Finally, the more promising candidates that have entered clinical trials are discussed and insights into the future development of vaccines for viruses of the SFV complex are given.</p></div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 3","pages":"947-967"},"PeriodicalIF":10.9,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal Control Over Circadian Rhythms With Light","authors":"Dušan Kolarski,&nbsp;Wiktor Szymanski,&nbsp;Ben L. Feringa","doi":"10.1002/med.22099","DOIUrl":"10.1002/med.22099","url":null,"abstract":"<p>Circadian rhythms are endogenous biological oscillators that synchronize internal physiological processes and behaviors with external environmental changes, sustaining homeostasis and health. Disruption of circadian rhythms leads to numerous diseases, including cardiovascular and metabolic diseases, cancer, diabetes, and neurological disorders. Despite the potential to restore healthy rhythms in the organism, pharmacological chronotherapy lacks spatial and temporal resolution. Addressing this challenge, chrono-photopharmacology, the approach that employs small molecules with light-controlled activity, enables the modulation of circadian rhythms when and where needed. Two approaches—relying on irreversible and reversible drug activation—have been proposed for this purpose. These methodologies are based on photoremovable protecting groups and photoswitches, respectively. Designing photoresponsive bioactive molecules requires meticulous structural optimization to obtain the desired chemical and photophysical properties, and the design principles, detailed guidelines and challenges are summarized here. In this review, we also analyze all the known circadian modulators responsive to light and dissect the rationale following their construction and application to control circadian biology from the protein level to living organisms. Finally, we present the strength of a reversible approach in allowing the modulation of the circadian period and the phase.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 3","pages":"968-984"},"PeriodicalIF":10.9,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/med.22099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Synuclein in Parkinson's Disease: From Bench to Bedside","authors":"Gabriele Bellini,&nbsp;Vanessa D'Antongiovanni,&nbsp;Giovanni Palermo,&nbsp;Luca Antonioli,&nbsp;Matteo Fornai,&nbsp;Roberto Ceravolo,&nbsp;Nunzia Bernardini,&nbsp;Pascal Derkinderen,&nbsp;Carolina Pellegrini","doi":"10.1002/med.22091","DOIUrl":"10.1002/med.22091","url":null,"abstract":"<p>α-Synuclein (α-syn), a pathological hallmark of PD, is emerging as a bridging element at the crossroads between neuro/immune-inflammatory responses and neurodegeneration in PD. Several evidence show that pathological α-syn accumulates in neuronal and non-neuronal cells (i.e., neurons, microglia, macrophages, skin cells, and intestinal cells) in central and peripheral tissues since the prodromal phase of the disease, contributing to brain pathology. Indeed, pathological α-syn deposition can promote neurogenic/immune-inflammatory responses that contribute to systemic and central neuroinflammation associated with PD. After providing an overview of the structure and functions of physiological α-syn as well as its pathological forms, we review current studies about the role of neuronal and non-neuronal α-syn at the crossroads between neuroinflammation and neurodegeneration in PD. In addition, we provide an overview of the correlation between the accumulation of α-syn in central and peripheral tissues and PD, related symptoms, and neuroinflammation. Special attention was paid to discussing whether targeting α-syn can represent a suitable therapeutical approach for PD.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 3","pages":"909-946"},"PeriodicalIF":10.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/med.22091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the Delivery, Activation and Therapeutics Applications of Bioorthogonal Prodrugs","authors":"Zhou Zhou,&nbsp;Yuanjun Sun,&nbsp;Jing Pang,&nbsp;Ya-Qiu Long","doi":"10.1002/med.22095","DOIUrl":"10.1002/med.22095","url":null,"abstract":"<div>\u0000 \u0000 <p>Traditional prodrug strategies have been leveraged to overcome many inherent drawbacks of active native drugs in the drug research and development. However, endogenous stimuli such as specific microenvironment or enzymes are relied on to achieve the prodrug activation, resulting in unintended drug release and systemic toxicity. Alternatively, bioorthogonal cleavage reaction-enabled bioorthogonal prodrugs activation via exogenous triggers has emerged as a valuable approach, featuring spatiotemporally controlled drug release. Such bioorthogonal prodrug strategies would ensure targeted drug delivery and/or in situ generation, further circumventing systemic toxicity or premature elimination of active drugs. In recent years, metal-free bioorthogonal cleavage reactions with fast kinetics have boomed in the bioorthogonal prodrug design. Meanwhile, transition-metal-catalyzed and photocatalytic deprotection reactions have also been developed to trigger prodrug activation in biological systems. Besides traditional small molecule prodrugs, gasotransmitters have been successfully delivered to specific organelles or cells via bioorthogonal reactions, and nanosystems have been devised into bioorthogonal triggers as well. Herein, we present an overview of the latest advances in these bioorthogonally-uncaged prodrugs, focused on the delivery, activation and therapeutics applications.</p></div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"45 3","pages":"887-908"},"PeriodicalIF":10.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}