Advances in protein chemistry and structural biology最新文献

Protein structure modeling from the prediction algorithm has become a valuable tool in biology and medicine with computational advances. Accurate protein structure prediction is critical in druglike compound discovery, disease mechanism understanding, and protein engineering because it provides molecular level insights into protein folding and its effects on molecular and cellular function. This chapter covers the evolution of protein structure prediction, from traditional methods like homology modeling, threading, and ab initio procedures and the new emerging AlphaFold's influence. AlphaFold's highly recognized precision level and open-access data democratized structural biology research, and that lead to inspiring new prediction models like RoseTTAFold and OmegaFold tools. Alpha Folds design, methodology, and highly accurate performance are thoroughly examined, and comparisons are performed with similar tools. We also highlight limitations, such as protein complex and dynamics forecasting, post-AlphaFold developments in structural databases, computer resources, and multi-scale modeling. Protein structure modeling and predictions have a wide range of applications in biomedical research, including drug discovery, functional annotation, and synthetic biology. Future directions include the integration of protein structure prediction with systems biology and genomics, as well as the use of next-generation AI and quantum computing to boost prediction accuracy. This research emphasizes AI's importance in structural biology and envisions a future in which predictive tools will provide comprehensive insights into protein function, dynamics, and therapeutic potential.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease associated with dementia and neuronal impairments in brain. AD is characterized histopathologically by two hallmark lesions: abnormally phosphorylated Tau inside neurons as intracellular NFTs and extracellular accumulation of amyloid β peptide (Aβ). Furthermore, it is unable to clarify the distinction between the brief association between the development and build-up of Aβ and the commencement of illness. Additionally, a number of experimental findings suggest that symptoms related to Aβ may only manifest within the framework of anabatic Tauopathies. Tau, a natively unfolded protein, essentially involved in microtubule binding and assembly. Tau protein consists of truncated segment and the purpose of this truncated fragment is to initiate and promote the conversion of soluble Tau into aggregates. The most common aberrant posttranslational change found in Neuro Fibrillary Tangles is hyperphosphorylation, which is essentially composed of aggregated Tau. Tau phosphorylation and acetylation of Tau protein at the locations controlled by histone deacetylase 6 compete, which modulates Tau function. Considering the potential benefits of targeting HDAC6 in AD, we propose focusing on the role of HDAC6 in regulating Tau functions and the other targets are the therapeutic understanding of AD.

The neuronal cytoskeleton has remained a less explored area of research in establishing neuroprotection. HDAC6 has been studied with respect to many neurodegenerative diseases, especially AD. It exhibits the ability to interact with various cytoskeletal proteins and to promote migration in cells. Podosomes are actin microstructures that help cells to migrate in the extracellular environment. The aim of this review is to bring into focus the significance of studies on the involvement of podosomes in Alzheimer's disease. We have suggested that Histone Deacetylase 6 plays a vital role in AD, through its interactions with the various signalling processes in the cell, most importantly the cytoskeletal remodelling machinery within the podosomes.

Proteins misfolding in neurodegenerative disorders pose a significant challenge to human health and this necessitates a deeper understanding of the fundamental molecular mechanisms. Molecular chaperones are a diverse group of specialized proteins, which are extensively involved in maintaining cellular protein homeostasis and thus preventing aggregation of misfolded proteins. Pathological advancement in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) is characterized by the rampant accretion of misfolded proteins due to chaperonic failure, leading to progressive neuronal dysfunctioning and eventually cell death. Such as in AD, Hsp70 and Hsp90 chaperones are known to interact with β-amyloid and tau proteins, thus preventing their subsequent aggregation with concomitant refolding into native conformations. In PD, chaperones are involved in assisting mitigation of α-Syn misfolding and aggregation, thereby maintaining the normal neuronal functions and their viability. Similarly in HD, chaperones modulate aberrant misfolding of huntingtin protein and its aggregation, thus highlighting prospective therapeutic targets for disease intervention. Nevertheless, further investigating and understanding the explicit roles of chaperones in modulating several protein misfolding diseases holds potential for the development of novel therapeutic approaches. Moreover, targeting such specialized chaperone machinery in restoring protein homeostasis and alleviating subsequent protein aggregation could be considered as a promising approach in managing neurodegenerative disorders.

Over the past century, the development of advancements in hemophilia therapy has experienced unprecedented success, starting with virally contaminated blood product infusions and progressing to safe plasma-derived and recombinant factor replacements, non-factor based rebalancing agents, long-lasting gene therapies, and moving forward into an era of potentially curative gene editing. Hemophilia A (FVIII deficiency) and B (FIX deficiency) are rare, monogenic, congenital bleeding disorders caused by mutations in the F8 and F9 genes, respectively. These mutations, along with environmental and cellular stressors, result in the translation of misfolded FVIII or FIX proteins, leaving patients with hemophilia susceptible to spontaneous bleeding and hemophilic arthropathy. Misfolded FVIII or FIX proteins show reduced clotting activity, are more vulnerable to degradation, and contribute to cellular stress and immune activation. Hemophilia is diagnosed using a combination of functional and immunological assays to detect Factor VIII or FIX activity and protein levels, which are proportional to phenotype severity. Newer approaches to clinical management of hemophilia include intravenous half-life extended clotting factor preparations, subcutaneous non-factor treatments and three gene therapies approved by the U.S. Food and Drug Administration. Gene therapy provides longer-term, therapeutic factor levels without the need for clotting factor replacement prophylaxis. Ongoing research to further improve therapeutic options is focused on small molecule therapies such as molecular chaperones and protein stabilizers, as well as CRISPR/Cas9 gene editing tools with curative potential. In combination with innovative therapeutic strategies, it will remain critical to bolster patient adherence to treatments by advocating for patients to play an active role in making decisions about their health care.

Parkinson's disease (PD), a progressive neurodegenerative disorder, is primarily characterized by the accumulation of alpha-synuclein (α-syn) aggregates in the brain, leading to the neuronal dysfunction and degeneration. As a result, targeting α-syn aggregation is emerging as a promising therapeutic strategy for delaying or stopping disease progression. The present chapter tried to explore the progress made in the development of small molecule inhibitors in preventing or reversing the aggregation of α-syn. Overall, the chapter provides an overview of the mechanisms underlying α-syn misfolding and aggregation, and highlights potential small molecules inhibitors of α-syn aggregation with an update about their clinical trial studies. The chapter also provides current status of clinical trials of these inhibitors. Furthermore, emerging strategies including combination therapies, multi-target approaches, and small molecule-based chaperone therapeutics that might enhance the efficacy of these small molecule inhibitors are discussed. Future directions are also highlighted, emphasizing the emerging potential of small molecule inhibitors in disease-modifying treatments for PD.

Alzheimer's disease (AD), among the diseases associated with dementia, is the most prevalent. It has been estimated that over 55 million people older than 65 years-old are living with dementia worldwide. Two-thirds of the AD population are women. It is estimated that by 2050 there will be 139 million people with dementia. AD is a neurodegenerative, progressive and irreversible process, affecting the patient's daily life activities. The pathological neurodegenerative process of AD begins 15-20 years before the appearance of the first clinical symptoms. The histopathological analysis reveals the presence of neurofibrillary tangles (NFTs) and neuritic plaques [1] the main hallmarks of AD. In this work, we are describing the NFTs that are made up of paired helical filaments of tau protein, which undergo post-translational modifications such as hyperphosphorylation and truncation, favoring conformational changes of the molecule. The most relevant information about the pathological processing of the tau protein is presented, focusing on the truncation at Glu391 (minimal filament nucleus, PHF-core) as a pathological inducing event of the tau protein and as an early biomarker of AD. Based on reports and our evidence, we suggest that the hyperphosphorylated tau protein participates as the neuroprotective event against this highly toxic PHF-core.

Pancreatic cancer remains one of the most lethal malignancies, with a five-year survival rate among the lowest of all cancers. This poor prognosis is largely due to the aggressive nature of the disease and its resistance to conventional treatments such as surgery, chemotherapy, and radiation therapy. Chimeric antigen receptor (CAR) T-cell therapy, a novel immunotherapeutic approach leverages the patient's own immune system to specifically target and eliminate cancer cells by genetically engineering T cells to express CARs that recognize tumor-specific antigens. While CAR-T therapy has demonstrated remarkable success in treating hematologic malignancies, its application to solid tumors like pancreatic cancer presents significant challenges. Recent advancements in CAR-T cell design, like the addition of co-stimulatory domains and dual-targeting CARs, have enhanced their efficacy against solid tumors. Additionally, strategies to modify the tumor microenvironment (TME), such as combining CAR-T therapy with immune checkpoint inhibitors and cytokine modulation, are being investigated to boost CAR-T cell activity against pancreatic cancer. Early-phase clinical trials targeting antigens such as carcinoembryonic antigen (CEA) and mesothelin (MSLN) in pancreatic cancer have yielded encouraging results, though obstacles like antigen escape and limited T-cell persistence remain significant challenges. This chapter outlines the current state of CAR-T therapy for pancreatic cancer, focusing on the emerging approaches to address these obstacles and underscore the potential of CAR-T therapy to transform the future of pancreatic cancer treatment.

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition, marked by memory loss and a steady deterioration in cognitive function. Lipid metabolism, which encompasses different lipid types such sphingolipids, cholesterol, fat-soluble vitamins, and fatty acids, is one of the key components of AD pathogenesis. These lipids are essential for many cellular functions, and the onset and course of AD are greatly influenced by their dysregulation. Sphingolipids, which include gangliosides, sulfatides, ceramides, and sphingomyelins, are essential for signal transduction, myelin sheath development, and the integrity of cell membranes. Sphingolipid metabolism is altered in AD, as seen by changes in ceramide levels and a reduction in sulfatides. These changes are associated with inflammation and neuronal death. Additionally, sphingomyelins and gangliosides are implicated; specific alterations in their concentrations have been reported in brains affected by AD, suggesting their participation in amyloid-β (Aβ) pathology and neurodegeneration.

Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer, associated with high morbidity and mortality rates. Current treatments, including surgical resection, chemotherapy, targeted therapy, and radiation, offer limited improvement in prognosis, with a low five-year survival rate. Thus, innovative therapeutic approaches are critically needed. The study utilized a network pharmacology approach to explore the phytocompounds of P. major and P. lanceolata targeting key genes in NSCLC. It involved collecting compounds of P. major and P. lanceolata using IMPPAT 2.0 and literature, screening drug-likeliness compounds using SWISS ADME, target prediction for bioactive compounds using SWISS targets, screening NSCLC-related targets using Genecards and OMIM, gene function annotation using DAVID GO and KEGG analysis, constructing a "Compounds-Targets-Pathway" network and analyzing protein interaction to identify hub genes using STRING and Cytoscape software, conducting molecular docking using Autodocktools and Autodock Vina, and lastly performing molecular dynamics simulations using GROMACS. Functional enrichment GO analysis and KEGG pathway analysis indicated that the primary mechanism of action of P. major and P. lanceolata phytocompounds in NSCLC treatment involves regulating cellular metabolism, survival, and cell cycle progression through various signaling pathways, including PKB, RA, PTP, hormone-mediated signaling, and PI3K. Molecular docking studies identified eight bioactive compounds with strong affinity for EGFR and three for MET, suggesting potential treatments for NSCLC with EGFR and MET mutations. Molecular dynamics simulations revealed that apigenin-7-O-glucoside is a promising therapeutic option for NSCLC with EGFR mutations, while scutellarein is more effective for MET mutations. The research provides the scientific basis for developing quality control standards and therapeutic applications, particularly for treating EGFR and MET mutations in NSCLC. It also highlights the need for further investigation into using P. major and P. lanceolata phytocompounds in NSCLC treatment.