Advances in protein chemistry and structural biology最新文献

There are two hallmarks for the Alzheimer's disease that are currently used to identify the disease- the presence of the proteins Amyloid-β and Tau. Amyloid PET has been studied for a long time and many effective probes have been introduced, some approved by the FDA, including [¹⁸F]-florbetaben (Neuraceq), [¹⁸F]-florbetapir (Amyvid), [¹⁸F]-flutemetamol (Vizamyl). However, it was found that imaging of NFTs could give more accurate results as the accumulation of Tau could directly be correlated with neurodegeneration, which isn't the case for Amyloid-β. Amyloid PET is thereby a diagnostic tool, which can rather be used for confirming the absence of Alzheimer's Disease. Tau PET, which was found to be a potentially useful diagnostic tool was explored further as it can directly be associated with the extent of spread of the disease. This led to the discovery of many probes for Tau PET. The initial ones were non-selective for Tau over Aβ. Further exploration suggested two generations of Tau probes, both with higher selectivity for Tau over Aβ. A second generation was introduced to overcome the shortcomings of the first generation which are examined in this review. Much research on effective Tau PET probes has led to an FDA-approved Tau probe, ¹⁸F-flortaucipir. This systematic review discusses the characteristics and effectiveness of the first-generation probes, second-generation probes and other newer probes. It discusses the structural changes made in the probes over time that led to the enhancement of their properties as a Tau probe, that is, increased affinity and selectivity for Tau. It also discusses the shortcomings of probes developed so far and the ideal characteristics for Tau probes.

The prognosis for mixed-lineage leukemia (MLL), particularly in young children, remains a significant health concern due to the limited therapeutic options available. MLL refers to KMT2A chromosomal translocations that produce MLL fusion proteins. The protein menin, which is essential for the malignant potential of these MLL fusion proteins, offers novel targets for acute leukemia treatment. This study reports the identification of potential new inhibitors of MLL-mediated leukemia targeting menin through the screening of two distinct drug libraries and existing inhibitors. The 3D structure of the protein was retrieved from the Protein Data Bank (ID: 8IG0). The drug libraries, sourced from public repositories such as the 'Epigenetic Drug Library' and 'The FDA-anticancer Drug Library,' yielded top candidates like Tozaseritib and Panobinostat, which exhibited the highest binding energy scores in the Glide virtual screening module. Additionally, 31 known menin-MLL1 inhibitors were identified through PDB screening and subsequently docked with the menin protein. The top three inhibitors (M-525, M-808, and MI-89) were selected for further analysis. Five menin-ligand complexes were validated using molecular dynamics analysis and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations to verify the stability and binding mechanisms.These findings provide insights into the molecular mechanisms of these drugs and lay the groundwork for future clinical development aimed at improving outcomes for acute myeloid leukemia (AML) patients.

Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.

Cholesterol, produced by astrocytes, is vital for the formation and maintenance of synapse, highlighting the significance of lipid metabolism in neuronal health. Neural stem cells (NSCs) are versatile, self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes, playing a pivotal role in both embryonic development and adult neurogenesis. In the central nervous system (CNS), NSCs primarily reside in the subventricular zone (SVZ) and the sub-granular layer of the dentate gyrus, where they give rise to neural progenitors and subsequently to neurons and glial cells. Oligodendrocytes play a crucial role in the CNS function and myelin sheath formation, which is essential for rapid neuronal signal transmission. Astrocytes contribute to brain homeostasis by regulating lipid metabolism and providing metabolic support to neurons. Sphingolipids and phospholipids are integral to neural cell membrane structure and function, influencing processes such as neurogenesis, cell signaling, and synaptic plasticity. Furthermore, the ApoE4 allele impacts lipid metabolism, affecting the risk of neurodegenerative diseases. This paper explores the role of various cell types and lipids in the CNS, emphasizing the importance of lipid metabolism in maintaining neural function and the implications for neurodegenerative conditions.

Tau is a microtubule-binding, hydrophilic protein and appears randomly coiled in circular dichroism spectra. Tau can have many post-translational modifications such as phosphorylation, acetylation, SUMOylation, glycation, ubiquitinylation, etc. The abnormal phosphorylation of Tau lowers its affinity to bind the microtubules, causing to neuronal instability. Hyperphosphorylated Tau can get detach from the microtubules and get aggregate in neuronal cell body to form a neurofibrillary tangle, which leads to weaken axonal transport and cause synaptic dysfunction. Tau itself is a SUMO-1 target protein and the modified lysine has been identified as the K340 located within 4R-Tau. The interaction between Tau and SUMO-1 was confirmed by an independent study, by showing that the SUMO-1 immunoreactivity is co-localized with phosphorylated Tau. In addition to this, Tau can also be ubiquitinated and degraded by the proteasome through both ubiquitin-dependent and ubiquitin-independent pathways. Our study shows that SUMOylation at lysine K340 stimulates Tau phosphorylation and inhibits ubiquitination-mediated Tau degradation, thus favouring its aggregation.

The structure of proteins holds the key to their optimum functioning. Misfolding of proteins often renders them useless and the resulting aggregates are implicated in endoplasmic reticulum stress and the onset of several human diseases. Therefore, a robust system, spearheaded by unfolded protein response (UPR) is in place as a quality check. The unfolded proteins are cleared and marked for degradation. UPR pathway consists of multiple factors, such as the chaperone GRP78, and is often deregulated in cancers, thus presenting as an attractive target for therapy. Emerging evidence indicates epigenetic regulation of UPR with the involvement of non-coding RNAs, such as, microRNAs and long non-coding RNAs, as well as DNA methylation and histone modifications. Here, we provide an overview of UPR in tumorigenesis with a focus on mutual inter-regulatory relationship between UPR and non-coding RNAs. We also discuss the novel findings on transport of misfolded proteins in exosomes and the promising role of epigenetic drugs in modulation of UPR.

The field of cancer therapeutics has witnessed significant advancements over the past decades, particularly with the emergence of immunotherapy. This chapter traces the transformative journey from traditional antibody-based therapies to the innovative use of nanobodies in the treatment and diagnosis of solid tumors. Nanobodies are the smallest fragments of antibodies derived from camelid immunoglobulins and have redefined the possibilities in cancer theranostics due to their unique structural and functional properties. We provide an overview of the biochemical characteristics of nanobodies that make them particularly suitable for theranostic applications, such as their small size, high stability, enhanced infiltration into the complex tumor microenvironment (TME) and ability to bind with high affinity to epitopes that are inaccessible to conventional antibodies. Further, their ease of modification and functionalization has enabled the development of nanobody-based drug conjugates/toxins and radiolabeled compounds for precise imaging and targeted radiotherapy. We elucidate how nanobodies are being served as valuable tools for prognostic assessment, enabling clinicians to predict disease aggressiveness, monitor treatment response, and stratify patients for personalized therapeutic interventions.

Hepatocyte nuclear factor 4-alpha (HNF4α), a well-preserved member of the nuclear receptor superfamily of transcription factors, is found in the liver. It is recognized as a central controller of gene expression specific to the liver and plays a key role in preserving the liver's homeostasis. Irregular expression of HNF4α is increasingly recognized as a crucial factor in the proliferation, cell death, invasiveness, loss of specialized functions, and metastasis of cancer cells. An increasing number of studies are pointing to abnormal HNF4α expression as a key component of cancer cell invasion, apoptosis, proliferation, dedifferentiation, and metastasis. Understanding HNF4α's intricate involvement in liver carcinogenesis provides a promising avenue for therapeutic intervention. This chapter attempts to shed light on the diverse aspects of HNF4's role in liver carcinogenesis and demonstrate how this knowledge can be harnessed for approaches to prevent and treat liver cancer. This comprehensive chapter will offer an elaborate perspective on HNF4's function in liver cancer, delineating its molecular mechanisms that aid in the emergence of liver cancer. Furthermore, it will highlight the potential to help create more effective and precisely targeted therapeutic strategies, rekindling fresh optimism in the fight against this formidable condition.

Neurodegeneration is marked by the altered proteostasis and protein degradation mechanism. This is caused due to the accumulation of aberrant proteins. Alzheimer's disease is one of the leading causes of neurodegeneration characterized by the aggregation of Tau and Amyloid-β proteins intracellularly and extracellularly, respectively. The intracellular aggregation of Tau triggers accumulation of oxidative stress, loss of ER and mitochondrial function, leading to the aggravation of aggregates formation. Thus, increasing the load of aberrant proteins on chaperones and degradative mechanism, such as autophagy and ubiquitin-proteasome system. Although several small molecules are known to target and prevent Tau aggregation, the detrimental effects in the cell due to aggregates accumulation shall not be overlooked. In such instance, small molecules that effectively target Tau aggregates and the cellular aberrations would be of great importance. Here we have discussed the efficacy of natural molecule, Limonoid, isolated from Azadirachta indica that prevents Tau aggregation and also activates the heat shock protein system. The activated heat shock protein system elevates the levels of Hsp70 that is known to interact with aberrantly folded Tau. Further, the role of Hsp70 in directing Tau clearance by macroautophagy or chaperone-mediated autophagy elucidates the effect of limonoids in overcoming AD pathology due to Tau aggregation.

In the quest to develop effective therapeutic strategies for diseases associated with protein misfolding and aggregation, molecular chaperones have emerged as pivotal players. This chapter explores the role of chaperones, such as Hsp40, Hsp70, and Hsp90, in mediating the disaggregation of misfolded proteins and facilitating proper folding under stress conditions. Despite their lack of sequence specificity, these proteins adeptly recognize exposed hydrophobic regions in partially folded states, thereby preventing aggregation and promoting functional conformations. The intricate network of chaperone interactions is crucial for maintaining cellular homeostasis and mitigating the pathological consequences of protein misfolding, particularly in conditions like Alzheimer's disease and various cancers. Innovative therapeutic approaches, including the use of pharmacological and chemical chaperones, aim to restore functionality to mutated or misfolded proteins, exemplified by interventions targeting the ΔF508 mutation in CFTR. While promising, the modulation of chaperone activity must be carefully calibrated to avoid disrupting cellular functions. This chapter highlights the potential of chaperone-mediated disaggregation as a therapeutic strategy, addressing both the current advancements and the challenges that lie ahead in harnessing these proteins for clinical benefit.