Biomolecules最新文献

{"title":"Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions.","authors":"Denys Bondar, Yevgen Karpichev","doi":"10.3390/biom14101269","DOIUrl":"10.3390/biom14101269","url":null,"abstract":"<p><p>Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is the most abundant enzyme, with approximately 1-2 million molecules per cell, acting primarily as a DNA damage sensor. It has become a promising biological target for anticancer drug studies. Enhanced PARP expression is present in several types of tumors, such as melanomas, lung cancers, and breast tumors, correlating with low survival outcomes and resistance to treatment. PARP inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy as anticancer agents both as single drugs and as sensitizers for chemo- and radiotherapy. This review explores the properties, characteristics, and challenges of PARP inhibitors, discussing their development from first-generation to third-generation compounds, more sustainable synthesis methods for discovery of new anti-cancer agents, their mechanisms of therapeutic action, and their potential for targeting additional biological targets beyond the catalytic active site of PARP proteins. Perspectives on green chemistry methods in the synthesis of new anticancer agents are also discussed.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"History and Perspective of LAMP-2 Deficiency (Danon Disease).","authors":"Kazuma Sugie, Ichizo Nishino","doi":"10.3390/biom14101272","DOIUrl":"https://doi.org/10.3390/biom14101272","url":null,"abstract":"<p><p>Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). This disease is one of the autophagy-related muscle diseases. Male patients present with the triad of cardiomyopathy, myopathy, and intellectual disability, while female patients present with cardiomyopathy. The disease's leading cause of death is heart failure, and its prognostic factor is cardiomyopathy. Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs). Twenty-six families have been found to have this disease in Japan. It has been over 40 years since the first report of this disease by Danon et al. and over 20 years since the identification of the causative gene, <i>LAMP2</i>, by Nishino et al. Although the pathogenetic mechanism of Danon disease remains unestablished, the first clinical trials using AAV vectors have finally begun in recent years. The development of novel therapies is expected in the future.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pioglitazone as a Possible Treatment for <i>Ataxia-Telangiectasia</i>.","authors":"Rodney Shackelford","doi":"10.3390/biom14101264","DOIUrl":"https://doi.org/10.3390/biom14101264","url":null,"abstract":"<p><p><i>Ataxia-telangiectasia</i> (AT) is a rare autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, and an increased malignancy risk. Cells derived from individuals with AT show multiple defects, including high oxidant and ionizing radiation sensitivities, poor DNA repair, low iron-sulfur cluster levels, and low reduced glutathione. The clinical course of AT is progressive and unrelenting, with most individuals having a survival time of approximately twenty-five years. Presently, AT has no effective treatments, and most patients receive supportive care only. Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT. Here, I will discuss the possible molecular mechanisms of pioglitazone's favorable effects on the AT phenotype and why it may have utility in treating some aspects of AT.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidant Therapies in the Treatment of Multiple Sclerosis.","authors":"Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Paula Salgado-Cámara, Elena García-Martín, José A G Agúndez","doi":"10.3390/biom14101266","DOIUrl":"https://doi.org/10.3390/biom14101266","url":null,"abstract":"<p><p>Several studies have proposed a potential role for oxidative stress in the development of multiple sclerosis (MS). For this reason, it seems tentative to think that treatment with antioxidant substances could be useful in the treatment of this disease. In this narrative review, we provide a summary of the current findings on antioxidant treatments, both in experimental models of MS, especially in experimental autoimmune encephalomyelitis (EAE) and in the cuprizone-induced demyelination model, and clinical trials in patients diagnosed with MS. Practically all the antioxidants tested in experimental models of MS have shown improvement in clinical parameters, in delaying the evolution of the disease, and in improving histological and biochemical parameters, including decreased levels of markers of inflammation and oxidative stress in the central nervous system and other tissues. Only a few clinical trials have been carried out to investigate the potential efficacy of antioxidant substances in patients with MS, most of them in the short term and involving a short series of patients, so the results of these should be considered inconclusive. In this regard, it would be desirable to design long-term, randomized, multicenter clinical trials with a long series of patients, assessing several antioxidants that have demonstrated efficacy in experimental models of MS.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MGACL: Prediction Drug-Protein Interaction Based on Meta-Graph Association-Aware Contrastive Learning.","authors":"Pinglu Zhang, Peng Lin, Dehai Li, Wanchun Wang, Xin Qi, Jing Li, Jianshe Xiong","doi":"10.3390/biom14101267","DOIUrl":"https://doi.org/10.3390/biom14101267","url":null,"abstract":"<p><p>The identification of drug-target interaction (DTI) is crucial for drug discovery. However, how to reduce the graph neural network's false positives due to its bias and negative transfer in the original bipartite graph remains to be clarified. Considering that the impact of heterogeneous auxiliary information on DTI varies depending on the drug and target, we established an adaptive enhanced personalized meta-knowledge transfer network named <b>M</b>eta <b>G</b>raph <b>A</b>ssociation-Aware <b>C</b>ontrastive <b>L</b>earning (MGACL), which can transfer personalized heterogeneous auxiliary information from different nodes and reduce data bias. Meanwhile, we propose a novel DTI association-aware contrastive learning strategy that aligns high-frequency drug representations with learned auxiliary graph representations to prevent negative transfer. Our study improves the DTI prediction performance by about 3%, evaluated by analyzing the area under the curve (AUC) and area under the precision-recall curve (AUPRC) compared with existing methods, which is more conducive to accurately identifying drug targets for the development of new drugs.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycosphingolipids in Cardiovascular Disease: Insights from Molecular Mechanisms and Heart Failure Models.","authors":"Sarah Huang, Karima Abutaleb, Sumita Mishra","doi":"10.3390/biom14101265","DOIUrl":"https://doi.org/10.3390/biom14101265","url":null,"abstract":"<p><p>This review explores the crucial role of glycosphingolipids (GSLs) in the context of cardiovascular diseases (CVDs), focusing on their biosynthesis, metabolic pathways, and implications for clinical outcomes. GSLs are pivotal in regulating a myriad of cellular functions that are essential for heart health and disease progression. Highlighting findings from both human cohorts and animal models, this review emphasizes the potential of GSLs as biomarkers and therapeutic targets. We advocate for more detailed mechanistic studies to deepen our understanding of GSL functions in cardiovascular health, which could lead to innovative strategies for diagnosis, treatment, and personalized medicine in cardiovascular care.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Many Faces of Autophagy: Balancing Survival and Cell Death.","authors":"Barbara Canonico","doi":"10.3390/biom14101268","DOIUrl":"https://doi.org/10.3390/biom14101268","url":null,"abstract":"<p><p>Autophagy and apoptosis are two fundamental biological mechanisms that may cooperate or be antagonistic, and both are involved in deciding the fate of cells in physiological or pathological conditions [...].</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights into Clinically Relevant Ribosome-Targeting Antibiotics.","authors":"Szymon J Krawczyk, Marta Leśniczak-Staszak, Ewelina Gowin, Witold Szaflarski","doi":"10.3390/biom14101263","DOIUrl":"https://doi.org/10.3390/biom14101263","url":null,"abstract":"<p><p>Antibiotics targeting the bacterial ribosome are essential to combating bacterial infections. These antibiotics bind to various sites on the ribosome, inhibiting different stages of protein synthesis. This review provides a comprehensive overview of the mechanisms of action of clinically relevant antibiotics that target the bacterial ribosome, including macrolides, lincosamides, oxazolidinones, aminoglycosides, tetracyclines, and chloramphenicol. The structural and functional details of antibiotic interactions with ribosomal RNA, including specific binding sites, interactions with rRNA nucleotides, and their effects on translation processes, are discussed. Focus is placed on the diversity of these mechanisms and their clinical implications in treating bacterial infections, particularly in the context of emerging resistance. Understanding these mechanisms is crucial for developing novel therapeutic agents capable of overcoming bacterial resistance.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Gonadal Steroid Hormones in the Eye: Therapeutic Implications.","authors":"Javier Valero-Ochando, Antolin Cantó, Rosa López-Pedrajas, Inmaculada Almansa, María Miranda","doi":"10.3390/biom14101262","DOIUrl":"https://doi.org/10.3390/biom14101262","url":null,"abstract":"<p><p>Gonadal steroid hormones are critical regulatory substances involved in various developmental and physiological processes from fetal development through adulthood. These hormones, derived from cholesterol, are synthesized primarily by the gonads, adrenal cortex, and placenta. The synthesis of these hormones involves a series of enzymatic steps starting in the mitochondria and includes enzymes such as cytochrome P450 and aromatase. Beyond their genomic actions, which involve altering gene transcription over hours, gonadal steroids also exhibit rapid, nongenomic effects through receptors located on the cell membrane. Additionally, recent research has highlighted the role of these hormones in the central nervous system (CNS). However, the interactions between gonadal steroid hormones and the retina have received limited attention, though it has been suggested that they may play a protective role in retinal diseases. This review explores the synthesis of gonadal hormones, their mechanisms of action, and their potential implications in various retinal and optic nerve diseases, such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), or retinitis pigmentosa (RP), discussing both protective and risk factors associated with hormone levels and their therapeutic potential.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Structural Investigation of the Interaction between a GC-376-Based Peptidomimetic PROTAC and Its Precursor with the Viral Main Protease of Coxsackievirus B3.","authors":"Alessia De Santis, Deborah Grifagni, Andrea Orsetti, Elena Lenci, Antonio Rosato, Mariapina D'Onofrio, Andrea Trabocchi, Simone Ciofi-Baffoni, Francesca Cantini, Vito Calderone","doi":"10.3390/biom14101260","DOIUrl":"https://doi.org/10.3390/biom14101260","url":null,"abstract":"<p><p>The conservation of the main protease in viral genomes, combined with the absence of a homologous protease in humans, makes this enzyme family an ideal target for developing broad-spectrum antiviral drugs with minimized host toxicity. GC-376, a peptidomimetic 3CL protease inhibitor, has shown significant efficacy against coronaviruses. Recently, a GC-376-based PROTAC was developed to target and induce the proteasome-mediated degradation of the dimeric SARS-CoV-2 3CL^Pro protein. Extending this approach, the current study investigates the application of the GC-376 PROTAC to the 3C^Pro protease of enteroviruses, specifically characterizing its interaction with CVB3 3C^Pro through X-ray crystallography, NMR (Nuclear Magnetic Resonance) and biochemical techniques. The crystal structure of CVB3 3C^Pro bound to the GC-376 PROTAC precursor was obtained at 1.9 Å resolution. The crystallographic data show that there are some changes between the binding of CVB3 3C^Pro and SARS-CoV-2 3CL^Pro, but the overall similarity is strong (RMSD on C-alpha 0.3 Å). The most notable variation is the orientation of the benzyloxycarbonyl group of GC-376 with the S4 subsite of the proteases. NMR backbone assignment of CVB3 3C^Pro bound and unbound to the GC-376 PROTAC precursor (80% and 97%, respectively) was obtained. This information complemented the investigation, by NMR, of the interaction of CVB3 3C^Pro with the GC-376 PROTAC, and its precursor allows us to define that the GC-376 PROTAC binds to CVB3 3C^Pro in a mode very similar to that of the precursor. The NMR relaxation data indicate that a quench of dynamics of a large part of the protein backbone involving the substrate-binding site and surrounding regions occurs upon GC-376 PROTAC precursor binding. This suggests that the substrate cavity, by sampling different backbone conformations in the absence of the substrate, is able to select the suitable one necessary to covalently bind the substrate, this being the latter reaction, which is the fundamental step required to functionally activate the enzymatic reaction. The inhibition activity assay showed inhibition potency in the micromolar range for GC-376 PROTAC and its precursor. Overall, we can conclude that the GC-376 PROTAC fits well within the binding sites of both proteases, demonstrating its potential as a broad-spectrum antiviral agent.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}