RESUMEN
Alzheimer's disease (AD) manifests as a progressive decline in cognitive function and mental behavior. Targeting two crucial enzymes associated with AD, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), in combination, holds promise for therapeutic breakthroughs. In this study, 40 derivatives of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide were designed based on prior research. These derivatives underwent synthesis and assessment for their inhibitory potential against AChE and BACE 1. ADME predictions indicated favorable physicochemical properties for these compounds. The findings offer novel avenues for exploring the dual inhibition of AChE and BACE 1 as a promising therapeutic strategy for AD.
RESUMEN
Considering the failure of many enzyme inhibitors for Alzheimer's disease (AD), research is now focused on multi-target directed drug discovery. In this paper, inhibition of two essential enzymes implicated in AD pathologies, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), has been explored. Taking clues from our previous work, 41 novel indol-3-yl phenyl allylidene hydrazine carboximidamide derivatives were synthesized. The results indicated that compounds inhibited both enzymes in micromolar concentrations. Compound 1l is proposed as the most active. In silico, it was seen to occupy the binding pocket of AChE and BACE 1. The ADME predictions showed that these compounds have acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and BACE 1 dual inhibition as a promising strategy for AD treatment.
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Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively treat respiratory conditions by targeting cysteinyl leukotriene receptors, CysLT1 and CysLT2 subtypes. This review explores the multifaceted effects of LTs, extending beyond bronchoconstriction. CysLT receptors are not only present in the respiratory system but are also crucial in neuronal signaling pathways. LTRAs modulate these receptors, influencing downstream signaling, calcium levels, inflammation, and oxidative stress (OS) within neurons hinting at broader implications. Recent studies identify novel molecular targets, sparking interest in repurposing LTRAs for therapeutic use. Clinical trials are investigating their potential in neuroinflammation control, particularly in Alzheimer's disease (AD) and Parkinson's diseases (PD). However, montelukast, a long-standing LTRA since 1998, raises concerns due to neuropsychiatric adverse drug reactions (ADRs). Despite widespread use, understanding montelukast's metabolism and underlying ADR mechanisms remains limited. This review comprehensively examines LTRAs' diverse biological effects, emphasizing non-bronchoconstrictive activities. It also analyses plausible mechanisms behind LTRAs' neuronal effects, offering insights into their potential as neurodegenerative disease modulators. The aim is to inform clinicians, researchers, and pharmaceutical developers about LTRAs' expanding roles, particularly in neuroinflammation control and their promising repurposing for neurodegenerative disease management.
Asunto(s)
Antagonistas de Leucotrieno , Receptores de Leucotrienos , Humanos , Antagonistas de Leucotrieno/uso terapéutico , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/efectos adversos , Animales , Receptores de Leucotrienos/metabolismo , Sulfuros/uso terapéutico , Sulfuros/farmacología , Sulfuros/efectos adversos , Acetatos/uso terapéutico , Acetatos/farmacología , Acetatos/efectos adversos , Neurotransmisores/metabolismo , Transducción de Señal/efectos de los fármacos , Ciclopropanos , QuinolinasRESUMEN
Siglec-1, also known as Sialoadhesin (Sn) and CD169 is highly conserved among vertebrates and with 17 immunoglobulin-like domains is Siglec-1 the largest member of the Siglec family. Expression of Siglec-1 is found primarily on dendritic cells (DCs), macrophages and interferon induced monocyte. The structure of Siglec-1 is unique among siglecs and its function as a receptor is also different compared to other receptors in this class as it contains the most extracellular domains out of all the siglecs. However, the ability of Siglec-1 to internalize antigens and to pass them on to lymphocytes by allowing dendritic cells and macrophages to act as antigen presenting cells, is the main reason that has granted Siglec-1's key role in multiple human disease states including atherosclerosis, coronary artery disease, autoimmune diseases, cell-cell signaling, immunology, and more importantly bacterial and viral infections. Enveloped viruses for example have been shown to manipulate Siglec-1 to increase their virulence by binding to sialic acids present on the virus glycoproteins allowing them to spread or evade immune response. Siglec-1 mediates dissemination of HIV-1 in activated tissues enhancing viral spread via infection of DC/T-cell synapses. Overall, the ability of Siglec-1 to bind a variety of target cells within the immune system such as erythrocytes, B-cells, CD8+ granulocytes and NK cells, highlights that Siglec-1 is a unique player in these essential processes.
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Enfermedades Transmisibles , Lectina 1 Similar a Ig de Unión al Ácido Siálico , Animales , Humanos , Lectina 1 Similar a Ig de Unión al Ácido Siálico/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Ácidos Siálicos , InmunoglobulinasRESUMEN
The covalent fusion of immunostimulatory adjuvants to immunogenic antigens is a promising strategy for the development of effective synthetic vaccines for infectious diseases. Herein, we describe the conjugation of a mycobacterial peptide antigen from the 6 kDa early secretory antigenic target (ESAT6) to a suitably functionalised trehalose dibehenate (TDB), a potent glycolipid adjuvant targeting macrophage inducible C-type lectin (Mincle).
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Lectinas Tipo C , Trehalosa , Adyuvantes Inmunológicos/farmacología , Antígenos , Glucolípidos/farmacología , Trehalosa/farmacología , Vacunas SintéticasRESUMEN
Hexosamine biosynthetic (HBP) and PI3K/AKT/mTOR pathways are found to predominate the proliferation and survival of prostate cancer cells. Both these pathways have their own specific intermediates to propagate the secondary signals in down-stream cascades and besides having their own structured network, also have shared interconnecting branches. These interconnections are either competitive or co-operative in nature depending on the microenvironmental conditions. Specifically, in prostate cancer HBP and mTOR pathways increases the expression and protein level of androgen receptor in order to support cancer cell proliferation, advancement and metastasis. Pharmacological inhibition of a single pathway is therefore insufficient to stop disease progression as the cancer cells manage to alter the signalling channel. This is one of the primary reasons for the therapeutic failure in prostate cancer and emergence of chemoresistance. Inhibition of these multiple pathways at their common junctures might prove to be of benefit in men suffering from an advanced disease state. Hence, a thorough understanding of these cellular intersecting points and their significance with respect to signal transduction mechanisms might assist in the rational designing of combinations for effective management of prostate cancer.
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Acetilglucosamina/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/patología , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Humanos , Masculino , Fosfatidilinositol 3-Quinasas/química , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/química , Transducción de Señal , Serina-Treonina Quinasas TOR/químicaRESUMEN
Protein O-linked ß-D-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), an essential post-translational as well as cotranslational modification, is the attachment of ß-D-N-acetylglucosamine to serine and threonine residues of nucleocytoplasmic proteins. An aberrant O-GlcNAc profile on certain proteins has been implicated in metabolic diseases such as diabetes and cancer. Inhibitors of O-GlcNAc transferase (OGT) are valuable tools to study the cell biology of protein O-GlcNAc modification. In this study we report novel uridine-peptide conjugate molecules composed of an acceptor peptide covalently linked to a catalytically inactive donor substrate analogue that bears a pyrophosphate bioisostere and explore their inhibitory activities against OGT by a radioactive hOGT assay. Further, we investigate the structural basis of their activities via molecular modelling, explaining their lack of potency towards OGT inhibition.
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Difosfatos/química , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , Péptidos/síntesis química , Péptidos/farmacología , Diseño de Fármacos , Humanos , Modelos Moleculares , Estructura Molecular , Conformación ProteicaRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant burden both clinically and economically worldwide. Increasing resistance to current antibiotics requires an urgent investigation into novel classes of antimicrobial agents. This study presents a structure-activity relationship (SAR) rationale for pyrazole linked phenylthiazole analogues as new antibacterial agents. A library of 23 novel pyrazole linked phenylthiazole compounds were synthesised, followed by screening for antimicrobial activity against five bacterial species and two fungi. The most active compound 14b has shown promising antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) strain (MIC 4 µg/mL). Furthermore, the active pyrazole linked phenylthiazole compound exhibited a better toxicity profile than standard antibiotics. In summary, these results demonstrate that a pyrazole linked phenylthiazole scaffold has potential as a lead for further investigation to afford novel antibacterial agents.
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Antibacterianos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pirazoles/farmacología , Tiazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
The O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a master regulator of installing O-GlcNAc onto serine or threonine residues on a multitude of target proteins. Numerous nuclear and cytosolic proteins of varying functional classes, including translational factors, transcription factors, signaling proteins, and kinases are OGT substrates. Aberrant O-GlcNAcylation of proteins is implicated in signaling in metabolic diseases such as diabetes and cancer. Selective and potent OGT inhibitors are valuable tools to study the role of OGT in modulating a wide range of effects on cellular functions. We report linear bisubstrate ether-linked uridine-peptide conjugates as OGT inhibitors with micromolar affinity. In vitro evaluation of the compounds revealed the importance of donor substrate, linker and acceptor substrate in the rational design of bisubstrate analogue inhibitors. Molecular dynamics simulations shed light on the binding of this novel class of inhibitors and rationalized the effect of amino acid truncation of acceptor peptide on OGT inhibition.
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Inhibidores Enzimáticos/farmacología , Éteres/farmacología , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , Péptidos/farmacología , Uridina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Éteres/química , Humanos , Simulación de Dinámica Molecular , Estructura Molecular , N-Acetilglucosaminiltransferasas/metabolismo , Péptidos/química , Relación Estructura-Actividad , Especificidad por Sustrato , Uridina/químicaRESUMEN
Liposomal delivery systems have significantly enhanced the efficacy and safety of chemotherapeutic agents compared to free (non-liposomal) formulations. Liposomes are vesicles made up of lipophilic bilayer and a hydrophilic core which provides perfect opportunity for their application as transport vehicle for various therapeutic and diagnostic agents. Doxorubicin is the most exploited chemotherapeutic agent for evaluation of different liposomal applications, as its physicochemical properties permit high drug entrapment and easy remote loading in pre-formulated liposomes. Pegylated liposomal doxorubicin clinically approved and, on the market, Doxil®, exemplifies the benefits offered upon the surface modification of liposome with polyethylene glycol. This unique formulation prolonged the drug residence time in the circulation and increased accumulation of doxorubicin in tumor tissue via passive targeting (enhanced permeability and retention effect). However, there is ample scope for further improvement in the efficiency of targeting tumors by coupling biological active ligands onto the liposome surface to generate intelligent drug delivery systems. Small biomolecules such as peptides, fraction of antibodies and carbohydrates have the potential to target receptors present on the surface of the malignant cells. Hence, active targeting of malignant cells using functionalised nanocarrier (liposomes encapsulated with doxorubicin) have been attempted which is reviewed in this article.
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Antineoplásicos , Doxorrubicina , Antineoplásicos/uso terapéutico , Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos , Liposomas , PolietilenglicolesRESUMEN
Reduction in sensitivity in terms of cytotoxicity is responsible for therapy failure in patients undergoing chemotherapy with first-line anticancer drug molecules. A plethora of literature evidence points out that increased O-linked ß-N-acetylglucosamine transferase (OGT) enzyme level/hyper-O-GlcNAcylation has direct implications in development of cancer and interferes with clinical outcomes of chemotherapy via interaction with oncogenic factors. The aim of this research was to evaluate the combination approach of anticancer drugs with an OGT inhibitor (OSMI-1) as an alternative way to resolve issues in the treatment of prostate cancer and assess the benefits offered by this approach. Effect of combination of doxorubicin and docetaxel with OSMI-1 on drug-induced cell death and synergism/antagonism was investigated using resazurin assay. Reduction in OGT enzyme level was evaluated using ELISA kit. Caspase-3/7 fluorescence assay was performed to detect apoptosis induction in PC-3 cells after treatment with the combinations of doxorubicin and OGT inhibitor to further understand the mechanism of cell death by concomitant treatment. Studies reveal that combination approach is indeed effective in terms of reducing the half-maximum growth inhibition value of doxorubicin when concomitantly treated with OSMI-1 and has synergistic effect in prostate cancer cells. PC-3 cells exhibited elevated levels of OGT enzyme in comparison to WPMY-1, and OSMI-1 has potential to inhibit OGT enzyme significantly. Data show that OSMI-1 alone and in combination with doxorubicin reduces OGT enzyme level significantly accompanied by increased apoptosis in prostate cancer cells. Combination of doxorubicin with OSMI-1 reduced the elevated OGT level which led to a drastic increase in sensitivity of PC-3 cells toward doxorubicin in comparison to doxorubicin alone. This finding provides important insight regarding alternative treatment strategies for effective management of cancer.
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Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Docetaxel/farmacología , Doxorrubicina/farmacología , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , Apoptosis , Línea Celular Tumoral , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Neoplasias de la PróstataRESUMEN
A series of novel furan-2-yl-1H-pyrazoles and their chemical precursors were synthesized and evaluated for their effectiveness at disrupting α-synuclein (α-syn) aggregation in vitro. The compounds were found to inhibit α-syn aggregation with efficacy comparable to the promising drug candidate anle138b. The results of this study indicate that compounds 8b, 8l, and 9f may qualify as secondary leads for the structure-activity relationship studies aimed to identify the suitable compounds for improving the modulatory activity targeted at α-syn self-assembly related to Parkinson's disease.
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Enfermedad de Parkinson , alfa-Sinucleína , Furanos/farmacología , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
The present status of antibiotic research requires the urgent invention of novel agents that act on multidrug-resistant bacteria. The World Health Organization has classified antibiotic-resistant bacteria into critical, high and medium priority according to the urgency of need for new antibiotics. Naturally occurring uridine-derived "nucleoside antibiotics" have shown promising activity against numerous priority resistant organisms by inhibiting the transmembrane protein MraY (translocase I), which is yet to be explored in a clinical context. The catalytic activity of MraY is an essential process for bacterial cell viability and growth including that of priority organisms. Muraymycins are one subclass of naturally occurring MraY inhibitors. Despite having potent antibiotic properties, the structural complexity of muraymycins advocates for simplified analogues as potential lead structures. Herein, we report a systematic structure-activity relationship (SAR) study of serine template-linked, simplified muraymycin-type analogues. This preliminary SAR lead study of serine template analogues successfully revealed that the complex structure of naturally occurring muraymycins could be easily simplified to afford bioactive scaffolds against resistant priority organisms. This study will pave the way for the development of novel antibacterial lead compounds based on a simplified serine template.
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Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Nucleósidos/farmacología , Transferasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Relación Estructura-Actividad , Transferasas/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)RESUMEN
Montelukast is a cysteinyl leukotriene (CysLT) receptor antagonist with efficacy against a variety of diseases, including asthma and inflammation-related conditions. However, various neuropsychiatric events (NEs) suspected to be related to montelukast have been reported recently, with limited understanding on their association and underlying mechanisms. This study aimed to investigate whether montelukast can induce neuroinflammation and neurotoxicity in microglial HAPI cells and neural SH-SY5Y cells. The present study also compared the effects of montelukast with a 5-lipoxygenase inhibitor (zileuton) and a cyclooxygenase-2 inhibitor (celecoxib) to better understand modulation of related pathways. HAPI or SH-SY5Y cells were treated with the indicated drugs (3.125 µM-100 µM) for 24 h to investigate drug-induced neuroinflammation and neurotoxicity. Montelukast induced cytotoxicity in HAPI cells (50-100 µM), accompanied with caspase-3/7 activation, prostaglandin E2 (PGE2) release, and reactive oxygen species (ROS) production. Whilst both montelukast and zileuton down-regulated CysLT release in HAPI cells, zileuton did not significantly affect cell viability or inflammatory and oxidative factors. Celecoxib decreased HAPI cell viability (6.25-100 µM), accompanied with increasing caspase-3/7 activation and ROS production, but in contrast to montelukast increased CysLT release and decreased PGE2 production. Similar to observations in HAPI cells, both montelukast and celecoxib (50-100 µM) but not zileuton produced toxicity in SH-SY5Y neuroblastoma cells. Similarly, CM from HAPI cells treated with either montelukast or zileuton produced toxicity in SH-SY5Y cells. The results of the current study show the capability of montelukast to directly induce toxicity and inflammation in HAPI cells, possibly through the involvement of PGE2 and ROS, and toxicity in undifferentiated SH-SY5Y neuroblastoma cells. The current study highlights the importance of consideration between benefit and risk of montelukast usage and provides references for future investigation on decreasing montelukast-related NEs.
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Acetatos/farmacología , Supervivencia Celular/efectos de los fármacos , Quinolinas/farmacología , Animales , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular , Línea Celular Tumoral , Ciclopropanos , Dinoprostona/metabolismo , Humanos , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , SulfurosRESUMEN
Numerous post-translational modifications (PTMs) of the Parkinson's disease (PD) associated α-synuclein (α-syn) protein have been recognised to play critical roles in disease aetiology. Indeed, dysregulated phosphorylation and proteolysis are thought to modulate α-syn aggregation and disease progression. Among the PTMs, enzymatic glycosylation with N-acetylglucosamine (GlcNAc) onto the protein's hydroxylated amino acid residues is reported to deliver protective effects against its pathogenic processing. This modification has been reported to alter its pathogenic self-assembly. As such, manipulation of the protein's O-GlcNAcylation status has been proposed to offer a PD therapeutic route. However, targeting upstream cellular processes can lead to mechanism-based toxicity as the enzymes governing O-GlcNAc cycling modify thousands of acceptor substrates. Small glycopeptides that couple the protective effects of O-GlcNAc with the selectivity of recognition sequences may prove useful tools to modulate protein aggregation. Here we discuss efforts to probe the effects of various O-GlcNAc modified peptides on wild-type α-synuclein aggregation.
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Acetilglucosamina/metabolismo , alfa-Sinucleína/metabolismo , Acetilglucosamina/química , Conformación de Carbohidratos , Relación Dosis-Respuesta a Droga , Glicosilación , Humanos , Enfermedad de Parkinson/metabolismo , Agregado de Proteínas/efectos de los fármacos , Relación Estructura-Actividad , alfa-Sinucleína/química , alfa-Sinucleína/genéticaRESUMEN
Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson's disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.
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Flavonoides/farmacología , Colorantes Fluorescentes/farmacología , alfa-Sinucleína/antagonistas & inhibidores , Animales , Flavonoides/química , Colorantes Fluorescentes/química , Humanos , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Tomografía de Emisión de Positrones , Agregado de Proteínas/efectos de los fármacos , Tomografía Computarizada de Emisión de Fotón Único , alfa-Sinucleína/metabolismoRESUMEN
Pathological hyperphosphorylation of tau and subsequent aggregation to form neurofibrillary tangles (NFTs) is closely related to progression of neurodegenerative diseases such as Alzheimer's disease (AD) and progressive supranuclear palsy. A recent study showed that MK-8719 (6) is a selective and potent small molecule inhibitor of human O-GlcNAcase (hOGA). The pharmacological inhibition of OGA, the sole enzyme involved in removal of a sugar moiety (O-GlcNAc residue) from tau, increases global O-GlcNAc levels within the brain and reduces tau phosphorylation. The OGA inhibitor slows neurodegeneration and improves cognitive function in AD and related tauopathies. Here, we discuss the findings of that study and the development of OGA inhibitors as novel therapeutic strategy for treatment of age-related memory impairment in neurodegenerative diseases.
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Enfermedad de Alzheimer , Tauopatías , Encéfalo , Humanos , Ovillos Neurofibrilares , Fosforilación , Azúcares , beta-N-Acetilhexosaminidasas , Proteínas tauRESUMEN
The present status of antibiotic resistant requires an urgent invention of novel agents that act on clinically unexplored antibacterial targets. The enzyme MraY (phospho-MurNAc-pentapeptide translocase), essential for bacterial cell wall synthesis, fulfils this criterion as it has not been explored as a target in a clinical context. Specifically, the enzyme is involved in the lipid-linked cycle of peptidoglycan biosynthesis and is reportedly targeted by naturally-occurring nucleoside antibiotics. The antimicrobial 'caprazamycin' class of nucleoside antibiotics targets Mycobacterium tuberculosis and clinically relevant Gram-negative bacteria such as Pseudomonas aeruginosa besides various drug resistant strains and is therefore an eligible starting point for the development of novel agents. In this review, we aim to summarise the structure-activity relationships of the natural, semi-synthetic as well as synthetic analogues of nucleoside antibiotic caprazamycins. This review highlights caprazamycins as promising lead structures for development of potent and selective antimicrobial agents that target MraY, the bacterial enzyme involved in the first membrane-dependent step in bacterial peptidoglycan assembly.
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Antibacterianos/farmacología , Azepinas/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Productos Biológicos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Transferasas/antagonistas & inhibidores , Uridina/análogos & derivados , Antibacterianos/química , Azepinas/química , Proteínas Bacterianas/metabolismo , Productos Biológicos/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Relación Estructura-Actividad , Transferasas/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos) , Uridina/química , Uridina/farmacologíaRESUMEN
Post-translational modifications (PTMs) of proteins are becoming the focus of intense research due to their implications in a broad spectrum of neurodegenerative diseases. Various PTMs have been identified to alter the toxic profiles of proteins which play critical roles in disease etiology. In Alzheimer's disease (AD), dysregulated phosphorylation is reported to promote pathogenic processing of the microtubule-associated tau protein. Among the PTMs, the enzymatic addition of N-acetyl-d-glucosamine (GlcNAc) residues to Ser/Thr residues is reported to deliver protective effects against the pathogenic processing of both amyloid precursor protein (APP) and tau. Modification of tau with as few as one single O-GlcNAc residue inhibits its toxic self-assembly. This modification also has the same effect on the assembly of the Parkinson's disease (PD) associated α-synuclein (ASyn) protein. In fact, O-GlcNAcylation ( O-linked GlcNAc modification) affects the processing of numerous proteins implicated in AD, PD, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) in a similar manner. As such, manipulation of a protein's O-GlcNAcylation status has been proposed to offer therapeutic routes toward addressing multiple neurodegenerative pathologies. Here we review the various effects that O-GlcNAc modification, and its modulated expression, have on pathogenically significant proteins involved in neurodegenerative disease.
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Acetilglucosamina/metabolismo , Encéfalo/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Agregación Patológica de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional/fisiología , Animales , Encéfalo/patología , Humanos , Enfermedades Neurodegenerativas/patología , Agregación Patológica de Proteínas/patología , Pliegue de ProteínaRESUMEN
A reversible post-translational protein modification which involves addition of N-acetylglucosamine (GlcNAc) onto hydroxyl groups of serine and/or threonine residues which is known as O-GlcNAcylation, has emerged as a potent competitor of phosphorylation. This glycosyltransfer reaction is catalyzed by the enzyme O-linked ß-N-acetylglucosamine transferase (OGT). This enzyme uses uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end product of hexosamine biosynthetic pathway, to modify numerous nuclear and cytosolic proteins. O-GlcNAcylation influences cancer cell metabolism in such a way that hyper-O-GlcNAcylation is considered as a prominent trait of many cancers, and is proposed as a major factor enabling cancer cell proliferation and progression. Growing evidence supports a connection between O-GlcNAcylation and major oncogenic factors, including for example, c-MYC, HIF-1α, and NF-κB. A comprehensive study of the roles of O-GlcNAc modification of oncogenic factors is warranted as a thorough understanding may help drive advances in cancer diagnosis and therapy. The focus of this article is to highlight the interplay between oncogenic factors and O-GlcNAcylation along with OGT in cancer cell proliferation and survival. The prospects for OGT inhibitors will also be discussed.