Showing papers in "Biochemistry in 2020"
TL;DR: The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19, and showed how the interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding.
Abstract: Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.
171 citations
TL;DR: Basic mechanisms of NETosis, as well as its role in the pathogenesis of some diseases including COVID-19 are discussed.
Abstract: NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. Various pathogens, antibodies and immune complexes, cytokines, microcrystals, and other physiological stimuli can cause NETosis. Induction of NETosis depends on reactive oxygen species (ROS), the main source of which is NADPH oxidase. Activation of NADPH oxidase depends on increase in the concentration of Ca2+ in the cytoplasm and in some cases on the generation of ROS in mitochondria. NETosis includes release of the granule components into the cytosol, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope, as well as formation of pores in the plasma membrane. In this review, basic mechanisms of NETosis, as well as its role in the pathogenesis of some diseases including COVID-19 are discussed.
157 citations
TL;DR: In this article, a review analyzes information on the oxidative stress associated with the infections caused by SARS-CoV-2 and other respiratory viruses and focuses on involvement of the vascular endothelium in the COVID-19 pathogenesis.
Abstract: Pathogenesis of the novel coronavirus infection COVID-19 is the subject of active research around the world. COVID-19 caused by the SARS-CoV-2 is a complex disease in which interaction of the virus with target cells, action of the immune system and the body’s systemic response to these events are closely intertwined. Many respiratory viral infections, including COVID-19, cause death of the infected cells, activation of innate immune response, and secretion of inflammatory cytokines. All these processes are associated with the development of oxidative stress, which makes an important contribution to pathogenesis of the viral infections. This review analyzes information on the oxidative stress associated with the infections caused by SARS-CoV-2 and other respiratory viruses. The review also focuses on involvement of the vascular endothelium in the COVID-19 pathogenesis.
154 citations
TL;DR: Examination of one of the proteins encoded by SARS-CoV-2 that is most different, a macrodomain of nonstructural protein 3 (nsp3), reveals that the protein retains the ability to bind ADP-ribose, which is an important characteristic of beta coronaviruses and a potential therapeutic target.
Abstract: The virus that causes COVID-19, SARS-CoV-2, has a large RNA genome that encodes numerous proteins that might be targets for antiviral drugs Some of these proteins, such as the RNA-dependent RNA polymerase, helicase, and main protease, are well conserved between SARS-CoV-2 and the original SARS virus, but several others are not This study examines one of the proteins encoded by SARS-CoV-2 that is most different, a macrodomain of nonstructural protein 3 (nsp3) Although 26% of the amino acids in this SARS-CoV-2 macrodomain differ from those observed in other coronaviruses, biochemical and structural data reveal that the protein retains the ability to bind ADP-ribose, which is an important characteristic of beta coronaviruses and a potential therapeutic target
83 citations
TL;DR: The principles of isothermal amplification techniques are described and their high efficiency in designing new highly sensitive detection methods of nucleic acids and enzymes involved in their modifications are demonstrated.
Abstract: Recently, there has been a rapid progress in the development of techniques for isothermal amplification of nucleic acids as an alternative to polymerase chain reaction (PCR). The advantage of these methods is that the nucleic acids amplification can be carried out at constant temperature, unlike PCR, which requires cyclic temperature changes. Moreover, isothermal amplification can be conducted directly in living cells. This review describes the principles of isothermal amplification techniques and demonstrates their high efficiency in designing new highly sensitive detection methods of nucleic acids and enzymes involved in their modifications. The data on successful application of isothermal amplification methods for the analysis of cells and biomolecules with the use of DNA/RNA aptamers are presented.
74 citations
TL;DR: Modern concepts and basic hypotheses on the mechanisms of exosome biogenesis and secretion are presented and current data on the involvement of lipid rafts and their constituent molecules in these processes are summarized.
Abstract: Exosomes (secreted extracellular vesicles formed in the intracellular vesicular transport system) play a crucial role in distant cell-cell communication. Exosomes transfer active forms of various biomolecules; the molecular composition of the exosomal cargo is a result of targeted selection and depends on the type of producer cells. The mechanisms underlying exosome formation and cargo selection are poorly understood. It is believed that there are several pathways for exosome biogenesis, although the questions about their independence and simultaneous coexistence in the cell still remain open. The least studied topic is the recently discovered mechanism of exosome formation associated with lipid rafts, or membrane lipid microdomains. Here, we present modern concepts and basic hypotheses on the mechanisms of exosome biogenesis and secretion and summarize current data on the involvement of lipid rafts and their constituent molecules in these processes. Special attention is paid to the analysis of possible role in the exosome formation of raft-forming proteins of the SPFH family, components of planar rafts, and caveolin, the main component of caveolae.
55 citations
TL;DR: In this article, the authors suggest rationale for the use of Nrf2 inducers to prevent development of an excessive inflammatory response in COVID-19 patients, who often present signs of high oxidative stress and systemic inflammation.
Abstract: Nrf2 is a key transcription factor responsible for antioxidant defense in many tissues and cells, including alveolar epithelium, endothelium, and macrophages. Furthermore, Nrf2 functions as a transcriptional repressor that inhibits expression of the inflammatory cytokines in macrophages. Critically ill patients with COVID-19 infection often present signs of high oxidative stress and systemic inflammation - the leading causes of mortality. This article suggests rationale for the use of Nrf2 inducers to prevent development of an excessive inflammatory response in COVID-19 patients.
50 citations
TL;DR: Though PROTACs have achieved some significant advances in settling the drug resistance, more cases are needed to prove the efficiency of PROTACs in addressing resistance hurdle in near future.
Abstract: Cancer drug resistance has become the major problem facing current clinical treatment via different kinds of therapies. Proteolysis targeting chimeras (PROTACs) as a novel and powerful strategy have attracted a great deal of attention both from academia and from industry for their sensitivity to drug-resistant targets relying on their unique characteristics compared to those of traditional inhibitors. PROTACs exert their function by degrading the target protein instead of inhibiting targets. Thus, different kinds of resistance could be conquered by PROTACs such as target mutation or overexpression. Various resistant targets have been overcome by PROTACs, including AR, ER, BTK, BET, and BCR-ABL. Though PROTACs have achieved some significant advances in combating drug resistance, more cases are needed to prove the efficiency of PROTACs in addressing the hurdle of resistance in the near future.
43 citations
TL;DR: This review focuses on the latest advances in drugs targeting the lipid metabolism and leading to promising outcome in preclinical studies and some ongoing clinical trials.
Abstract: Cancer cells are highly dependent on different metabolic pathways for sustaining their survival, growth, and proliferation. Lipid metabolism not only provides the energetic needs of the cells but also provides the raw material for cellular growth and the signaling molecules for many oncogenic pathways. Mainly processed in the liver, lipids play an essential role in the physiology of this organ and in the pathological progression of many diseases such as metabolic syndrome and hepatocellular carcinoma (HCC). The progression of HCC is associated with inflammation and complex metabolic reprogramming, and its prognosis remains poor because of the lack of effective therapies despite many years of dedicated research. Defects in hepatic lipid metabolism induce abnormal gene expression and rewire many cellular pathways involved in oncogenesis and metastasis, implying that interfering with lipid metabolism within the tumor and the surrounding microenvironment may be a novel therapeutic approach for treating liver cancer patients. Therefore, this review focuses on the latest advances in drugs targeting lipid metabolism and leading to promising outcomes in preclinical studies and some ongoing clinical trials.
42 citations
TL;DR: This work develops a reliable and practical protocol for evaluating the binding free energy of covalent inhibitors, and indicates that in the choice of an effective warhead it is crucial to focus on the exothermicity of the point on the free energy surface of a peptide cleavage that connects the acylation and deacylation steps.
Abstract: The development of reliable ways of predicting the binding free energies of covalent inhibitors is a challenge for computer-aided drug design. Such development is important, for example, in the fight against the SARS-CoV-2 virus, in which covalent inhibitors can provide a promising tool for blocking Mpro, the main protease of the virus. This work develops a reliable and practical protocol for evaluating the binding free energy of covalent inhibitors. Our protocol presents a major advance over other approaches that do not consider the chemical contribution of the binding free energy. Our strategy combines the empirical valence bond method for evaluating the reaction energy profile and the PDLD/S-LRA/s method for evaluating the noncovalent part of the binding process. This protocol has been used in the calculations of the binding free energy of an α-ketoamide inhibitor of Mpro. Encouragingly, our approach reproduces the observed binding free energy. Our study of covalent inhibitors of cysteine proteases indicates that in the choice of an effective warhead it is crucial to focus on the exothermicity of the point on the free energy surface of a peptide cleavage that connects the acylation and deacylation steps. Overall, we believe that our approach should provide a powerful and effective method for in silico design of covalent drugs.
41 citations
TL;DR: Free energy landscapes of β2 adrenergic receptor activation are calculated using atomistic molecular dynamics simulations in an optimized string of swarms framework, which shed new light on how microswitches govern the equilibrium between conformational states.
Abstract: Agonist binding to G protein-coupled receptors (GPCRs) leads to conformational changes in the transmembrane region that activate cytosolic signaling pathways. Although high-resolution structures of different receptor states are available, atomistic details of allosteric signaling across the membrane remain elusive. We calculated free energy landscapes of β2 adrenergic receptor activation using atomistic molecular dynamics simulations in an optimized string of swarms framework, which shed new light on how microswitches govern the equilibrium between conformational states. Contraction of the extracellular binding site in the presence of the agonist BI-167107 is obligatorily coupled to conformational changes in a connector motif located in the core of the transmembrane region. The connector is probabilistically coupled to the conformation of the intracellular region. An active connector promotes desolvation of a buried cavity, a twist of the conserved NPxxY motif, and an interaction between two conserved tyrosines in transmembrane helices 5 and 7 (Y-Y motif), which lead to a larger population of active-like states at the G protein binding site. This coupling is augmented by protonation of the strongly conserved Asp792.50. The agonist binding site hence communicates with the intracellular region via a cascade of locally connected microswitches. Characterization of these can be used to understand how ligands stabilize distinct receptor states and contribute to development drugs with specific signaling properties. The developed simulation protocol can likely be transferred to other class A GPCRs.
TL;DR: This review presents the data on the natural occurrence of chitin and its partially or fully deacetylated derivative chitosan, as well as their properties, methods of modification, and potential applications of derivatives with bactericidal, fungicidal, and antioxidant activities.
Abstract: In this review, we present the data on the natural occurrence of chitin and its partially or fully deacetylated derivative chitosan, as well as their properties, methods of modification, and potential applications of derivatives with bactericidal, fungicidal, and antioxidant activities. The structure and physicochemical characteristics of the polymers, their functions, and features of chitin microbial synthesis and degradation, including the processes occurring in nature, are described. New data on the hydrolytic microorganisms capable of chitin degradation under extreme conditions are presented. Special attention is focused on the effect of physicochemical characteristics of chitosan, including molecular weight, degree of deacetylation, polydispersity index, and number of amino group derivatives (quaternized, succinyl, etc.) on the antimicrobial and antioxidant properties of modified polymers that can be of particular interest for biotechnology, medicine, and agriculture. Analysis of the available literature data confirms the importance of fundamental research to broaden our knowledge on the occurrence of chitin and chitosan in nature, their role in global biosphere cycles, and prospects of applied research aimed at using chitin, chitosan, and their derivatives in various aspects of human activity.
TL;DR: An insight into understanding p53 as a prion-like protein is provided and cancer to be recognized as amyloid or prions-like disease is proposed.
Abstract: The global transcription factor, p53, is a master regulator of gene expression in cells. Mutations in the TP53 gene promote unregulated cell growth through the inactivation of downstream effectors of the p53 pathway. In fact, mutant p53 is highly prone to misfolding and frequently resides inside the cell as large aggregates, causing loss of physiological function of the tumor-suppressor protein. Here, we review the plausible reasons for functional loss of p53, including amyloid formation leading to unhindered cancer progression. We discuss previous as well as recent findings regarding the amyloid formation of p53 in vitro and in vivo. We elaborate on prion-like properties of p53 amyloids and their possible involvement in cancer progression. Because the p53 pathway is historically most targeted for the development of anticancer therapeutics, we have also summarized some of the recent approaches and advances in reviving the antiproliferative activities of wild-type p53. In this Perspective, we provide insight into understanding p53 as a prion-like protein and propose cancer to be recognized as an amyloid or prion-like disease.
TL;DR: This work overviews most recently developed mitochondria-targeting peptides and peptidomimetics to outline the key aspects of structural requirement and design principle and discusses successful and potential applications of mitochondrial delivery to assess opportunities and challenges in mitochondria -targeting.
Abstract: Mitochondria are multifunctional subcellular organelles whose operations encompass energy production, signal transduction, and metabolic regulation. Given their wide range of roles, they have been studied extensively as a potential therapeutic target for the treatment of various diseases, including cancer, diabetes, and neurodegenerative diseases. Mitochondrion-mediated pathways have been identified as promising targets in the context of these diseases. However, the delivery of specific probes and drugs to the mitochondria is one of the major problems that remains to be solved. Over the past decade, much effort has been devoted to developing mitochondrion-targeted delivery methods based on the membrane characteristics and the protein import machinery of mitochondria. While various methods utilizing small molecules to polymeric particles have been introduced, it is notable that many of these compounds share common structural elements and physicochemical properties for optimal selectivity and efficiency. In this Perspective, we will review the most recently developed mitochondrion-targeting peptides and peptidomimetics to outline the key aspects of structural requirements and design principles. We will also discuss successful and potential applications of mitochondrial delivery to assess opportunities and challenges in the targeting of mitochondria.
TL;DR: Insight is provided into small molecules that stabilize small amyloid species in the presence of membranes for the development of tool compounds for deeper investigations of these transient species.
Abstract: Aggregation and the formation of oligomeric intermediates of amyloid-β (Aβ) at the membrane interface of neuronal cells are implicated in the cellular toxicity and pathology of Alzheimer's disease. Small molecule compounds have been shown to suppress amyloid aggregation and cellular toxicity, but often the presence of a lipid membrane negates their activity. A high-throughput screen of 1800 small molecules was performed to search for membrane active inhibitors, and 21 primary hits were discovered. Through the use of fluorescence-based assays, transmission electron microscopy, and dot blot assays, the initial 21 primary hits were narrowed down to five lead compounds. Nuclear magnetic resonance and circular dichroism experiments were used for further confirmation of amyloid inhibition at the membrane interface and to obtain insights into the secondary structure of amyloid-β, while size exclusion chromatography was used to characterize the size of Aβ species. Lastly, dye-leakage assays allowed us to understand how the addition of the five lead compounds affected amyloid-β's ability to permeate the lipid bilayer. These results provide insights into small molecules that stabilize small amyloid species in the presence of membranes for the development of tool compounds for deeper investigations of these transient species.
TL;DR: This review describes similarities and differences in the structure of cold shock proteins of prokaryotes and CSD proteins of eukaryotes with special emphasis on the functions related to the RNA/DNA-binding ability of these proteins.
Abstract: This review summarizes the features of cold shock domain (CSD) proteins in the context of their interactions with nucleic acids and describes similarities and differences in the structure of cold shock proteins of prokaryotes and CSD proteins of eukaryotes with special emphasis on the functions related to the RNA/DNA-binding ability of these proteins. The mechanisms and specificity of their interaction with nucleic acids in relation to the growing complexity of protein domain structure are described, as well as various complexes of the mammalian Y-box binding protein 1 (YB-1) with nucleic acids (filaments, globules, toroids). The role of particular amino acid residues in the binding of nitrogenous bases and the sugar-phosphate backbone of nucleic acids is emphasized. The data on the nucleic acid sequences recognized by the Y-box binding proteins are systematized. Post-translational modifications of YB-1, especially its phosphorylation, affect the recognition of specific sequences in the promoter regions of various groups of genes by YB-1 protein. The data on the interaction of Lin28 protein with let-7 miRNAs are summarized. The features of the domain structure of plant CSD proteins and their effect on the interaction with nucleic acids are discussed.
TL;DR: This review provides an insight into the structure, functional properties, and biotechnological application of phospholipase A2 andospholipases in general.
Abstract: Enzymes of the phospholipase superfamily are involved in lipid metabolism, as well as regulation of membrane composition, cell signaling, and inflammation. This review provides an insight into the structure, functional properties, and biotechnological application of phospholipase A2 and phospholipases in general.
TL;DR: Results of experimental studies are analyzed demonstrating that liquid–liquid phase separation not only governs functional compartmentalization of the cell nucleus but also contributes to the formation of the 3D genomic architecture.
Abstract: Functional compartmentalization of the cell nucleus plays an important role in the regulation of genome activity by providing accumulation of enzymes and auxiliary factors in the reaction centers, such as transcription factories, Cajal bodies, speckles, etc. The mechanisms behind the nucleus functional compartmentalization are still poorly understood. There are reasons to believe that the key role in the nucleus compartmentalization belongs to the process of liquid-liquid phase separation. In this brief review, we analyze results of experimental studies demonstrating that liquid-liquid phase separation not only governs functional compartmentalization of the cell nucleus but also contributes to the formation of the 3D genomic architecture.
TL;DR: A detailed description of the reaction catalyzed by E. coli type II L-asparaginase (EcAII) is provided, providing strong evidence that EcAII catalyzes the reaction according to the double-displacement (ping-pong) mechanism, with formation of a covalent intermediate.
Abstract: Two bacterial type II l-asparaginases, from Escherichia coli and Dickeya chrysanthemi, have played a critical role for more than 40 years as therapeutic agents against juvenile leukemias and lympho...
TL;DR: It is found that buffer pKa and sterics have significant effects on activity, evaluated through cyclic voltammetry (CV), and buffer acidity and structure are important considerations when optimizing and evaluating systems for proton-dependent catalysis in water.
Abstract: Cobalt-mimochrome VI*a (CoMC6*a) is a synthetic mini-protein that catalyzes aqueous proton reduction to hydrogen (H2). In buffered water, there are multiple possible proton donors, complicating the...
TL;DR: Lauryl maltose neopentylglycol (LMNG) detergents have been found to have significant advantages for purifying GPCRs in a native state as they impart more stability to the receptor than DDM, and these results provide a rational foundation to develop detergent variants for stabilizing membrane proteins.
Abstract: The structural and functional properties of G protein-coupled receptors (GPCRs) are often studied in a detergent micellar environment, but many GPCRs tend to denature or aggregate in short alkyl chain detergents. In our previous work [Lee, S., et al. (2016) J. Am. Chem. Soc. 138, 15425-15433], we showed that GPCRs in alkyl glucosides were highly dynamic, resulting in the penetration of detergent molecules between transmembrane α-helices, which is the initial step in receptor denaturation. Although this was not observed for GPCRs in dodecyl maltoside (DDM, also known as lauryl maltoside), even this detergent is not mild enough to preserve the integrity of many GPCRs during purification. Lauryl maltose neopentylglycol (LMNG) detergents have been found to have significant advantages for purifying GPCRs in a native state as they impart more stability to the receptor than DDM. To gain insights into how they stabilize GPCRs, we used atomistic molecular dynamics simulations of wild type adenosine A2A receptor (WT-A2AR), thermostabilized A2AR (tA2AR), and wild type β2-adrenoceptor (β2AR) in a variety of detergents (LMNG, DMNG, OGNG, and DDM). Analysis of molecular dynamics simulations of tA2AR in LMNG, DMNG, and OGNG showed that this series of detergents exhibited behavior very similar to that of an analogous series of detergents DDM, DM, and OG in our previous study. However, there was a striking difference upon comparison of the behavior of LMNG to that of DDM. LMNG showed considerably less motion than DDM, which resulted in the enhanced density of the aliphatic chains around the hydrophobic regions of the receptor and considerably more hydrogen bond formation between the head groups. This contributed to enhanced interaction energies between both detergent molecules and between the receptor and detergent, explaining the enhanced stability of GPCRs purified in this detergent. Branched detergents occlude between transmembrane helices and reduce their flexibility. Our results provide a rational foundation to develop detergent variants for stabilizing membrane proteins.
TL;DR: The SARS-CoV-2 main protease (Mpro) is essential to viral replication and cleaves highly specific substrate sequences, making it an obvious target for inhibitor design as discussed by the authors.
Abstract: The SARS-CoV-2 main protease (Mpro) is essential to viral replication and cleaves highly specific substrate sequences, making it an obvious target for inhibitor design. However, as for any virus, SARS-CoV-2 is subject to constant neutral drift and selection pressure, with new Mpro mutations arising over time. Identification and structural characterization of Mpro variants is thus critical for robust inhibitor design. Here we report sequence analysis, structure predictions, and molecular modeling for seventy-nine Mpro variants, constituting all clinically observed mutations in this protein as of April 29, 2020. Residue substitution is widely distributed, with some tendency toward larger and more hydrophobic residues. Modeling and protein structure network analysis suggest differences in cohesion and active site flexibility, revealing patterns in viral evolution that have relevance for drug discovery.
TL;DR: This work engineered the hOGG1 enzyme, a primary 8-oxoguanine DNA glycosylase, into a guanine oxidation-profiling tool, and successfully identified more than 1,400 guanines oxidation sites in the mouse embryonic fibroblast genome.
Abstract: The occurrence of 8-oxo-7,8-dihydroguanine (OG) in the genome, as one of the major DNA oxidative damages, has been implicated in an array of biological processes, ranging from mutagenesis to transcriptional regulation. Genome-wide mapping of oxidative damages could shed light on the underlying cellular mechanism. In the present study, we engineered the hOGG1 enzyme, a primary 8-oxoguanine DNA glycosylase, into a guanine oxidation-profiling tool. Our method, called enTRAP-seq, successfully identified more than 1400 guanine oxidation sites in the mouse embryonic fibroblast genome. These OG peaks were enriched in open chromatin regions and regulatory elements, including promoters, 5' untranslated regions, and CpG islands. Collectively, we present a simple and generalizable approach for the genome-wide profiling of DNA damages with high sensitivity and specificity.
TL;DR: KLF2-mediated inhibition of NF-KB signaling leads to the suppression of cell response to the pro-inflammatory cytokines IL-ip and TNFa and results in the attenuation of inflammatory processes.
Abstract: KLF2 is a member of the Kruppel-like transcription factor family of proteins containing highly conserved DNA-binding zinc finger domains. KLF2 participates in the differentiation and regulation of the functional activity of monocytes, T lymphocytes, adipocytes, and vascular endothelial cells. The activity of KLF2 is controlled by several regulatory systems, including the MEKK2,3/MEK5/ERK5/MEF2 MAP kinase cascade, Rho family G-proteins, histone acetyltransferases CBP and p300, and histone deacetylases HDAC4 and HDAC5. Activation of KLF2 in endothelial cells induces eNOS expression and provides vasodilatory effect. Many KLF2-dependent genes participate in the suppression of blood coagulation and aggregation of T cells and macrophages with the vascular endothelium, thereby preventing atherosclerosis progression. KLF2 can have a dual effect on the gene transcription. Thus, it induces expression of multiple genes, but suppresses transcription of NF-κB-dependent genes. Transcription factors KLF2 and NF-κB are reciprocal antagonists. KLF2 inhibits induction of NF-κB-dependent genes, whereas NF-κB downregulates KLF2 expression. KLF2-mediated inhibition of NF-κB signaling leads to the suppression of cell response to the pro-inflammatory cytokines IL-1β and TNFα and results in the attenuation of inflammatory processes.
TL;DR: Approaches to the targeted delivery of various chemotherapeutic agents, radionuclides, immunotoxins, photosensitizers, as well as the prospects for gene therapy aimed at cancer cells with EGFR overexpression are reviewed in detail.
Abstract: Epidermal growth factor receptor (EGFR) is an integral surface protein mediating cellular response to a number of growth factors. Its overexpression and increased activation due to mutations is one of the most common traits of many types of cancer. Development and clinical use of the agents, which block EGFR activation, became a prime example of the personalized targeted medicine. However, despite the obvious success in this area, cancer cure remains unattainable in most cases. Because of that, as well as the result of the search for possible ways to overcome the difficulties of treatment, a huge number of new treatment methods relying on the use of EGFR overexpression and its changes to destroy cancer cells. Modern data on the structure, functioning, and intracellular transport of EGFR, its natural ligands, as well as signaling cascades triggered by the EGFR activation, peculiarities of the EGFR expression and activation in oncological disorders, as well as applied therapeutic approaches aimed at blocking EGFR signaling pathway are summarized and analyzed in this review. Approaches to the targeted delivery of various chemotherapeutic agents, radionuclides, immunotoxins, photosensitizers, as well as the prospects for gene therapy aimed at cancer cells with EGFR overexpression are reviewed in detail. It should be noted that increasing attention is being paid nowadays to the development of multifunctional systems, either carrying several different active agents, or possessing several environment-dependent transport functions. Potentials of the systems based on receptor-mediated endocytosis of EGFR and their possible advantages and limitations are discussed.
TL;DR: In this article, solid state nuclear magnetic resonance (ssNMR) measurements were performed on 2H,15N,13C-labeled FUS-LC fibrils, which provided new information about the interactions of hydroxyl-bearing residues with one another and with water.
Abstract: In aqueous solutions, the 214-residue low-complexity domain of the FUS protein (FUS-LC) is known to undergo liquid-liquid phase separation and also to self-assemble into amyloid-like fibrils. In previous work based on solid state nuclear magnetic resonance (ssNMR) methods, a structural model for the FUS-LC fibril core was developed, showing that residues 39-95 form the fibril core. Unlike fibrils formed by amyloid-β peptides, α-synuclein, and other amyloid-forming proteins, the FUS-LC core is largely devoid of purely hydrophobic amino acid side chains. Instead, the core-forming segment contains numerous hydroxyl-bearing residues, including 18 serines, six threonines, and eight tyrosines, suggesting that the FUS-LC fibril structure may be stabilized in part by inter-residue hydrogen bonds among side chain hydroxyl groups. Here we describe ssNMR measurements, performed on 2H,15N,13C-labeled FUS-LC fibrils, that provide new information about the interactions of hydroxyl-bearing residues with one another and with water. The ssNMR data support the involvement of specific serine, threonine, and tyrosine residues in hydrogen-bonding interactions. The data also reveal differences in hydrogen exchange rates with water for different side chain hydroxyl groups, providing information about solvent exposure and penetration of water into the FUS-LC fibril core.
TL;DR: The results indicate that acidic conditions compromise the ability CP to sequester Mn(II) and thereby starve microbial pathogens of this nutrient, and highlights the importance of considering the chemical complexity of biological sites when describing the interplay between CP and microbes in host-pathogen interactions.
Abstract: Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth o...
TL;DR: This review critically considers the possible mechanisms of the therapeutic effect of “mitochondrial transplantation” and suggests that exogenous mitochondria penetrate into cardiomyocytes, retaining functional activity, and compensate for impaired energy output of endogenous mitochondria.
Abstract: "Mitochondrial transplantation" refers to a procedure for introducing isolated mitochondria into a damaged area of a heart or other organ. A considerable amount of data has been accumulated on the therapeutic effects of "mitochondrial transplantation" in animals with ischemic heart damage. In 2017, the first attempts were made to apply this procedure in a clinic. The authors of the method suggest that exogenous mitochondria penetrate into cardiomyocytes, retaining functional activity, and compensate for impaired energy output of endogenous mitochondria. This hypothesis contradicts the well-known fact of loss of mitochondrial functions in the presence of high concentrations of Ca2+, which are characteristic of the extracellular medium. This review critically considers the possible mechanisms of the therapeutic effect of "mitochondrial transplantation".
TL;DR: The data suggest that targeting the common epitope could be a more effective treatment strategy rather than targeting only Aβ or only tau, and have an important clinical significance for AD and related tauopathies.
Abstract: The deposition of amyloid-β (Aβ) plaques and tau-based neurofibrillary tangles is a neuropathological feature of Alzheimer’s disease (AD). While studies have shown that the Aβ and tau interaction r...