RESUMO
Tauopathies are a group of neurodegenerative disorders characterized by the aggregation of the microtubule-associated protein tau. Aggregates of misfolded tau protein are believed to be implicated in neuronal death, which leads to a range of symptoms including cognitive decline, behavioral change, dementia, and motor deficits. Currently, there are no effective treatments for tauopathies. There are four clinical candidates in phase III trials and 16 in phase II trials. While no effective treatments are currently approved, there is increasing evidence to suggest that various therapeutic approaches may slow the progression of tauopathies or improve symptoms. This review outlines the landscape of therapeutic drugs (indexed through February 28, 2023) that target tau pathology and describes drug candidates in clinical development as well as those in the discovery and preclinical phases. The review also contains information on notable therapeutic programs that are inactive or that have been discontinued from development.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Tauopatias , Humanos , Encéfalo/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Proteínas tau/metabolismo , Disfunção Cognitiva/metabolismo , Doença de Alzheimer/patologiaRESUMO
Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Biomarcadores , Descoberta de Drogas , Humanos , Proteínas tauRESUMO
We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
Assuntos
Inibidores Enzimáticos/farmacologia , Doença de Huntington/tratamento farmacológico , Quinurenina 3-Mono-Oxigenase/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Doença de Huntington/metabolismo , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Kynurenine monooxygenase (KMO) catalyzes the conversion of kynurenine to 3-hydroxykynurenine. Modulation of KMO activity has been implicated in several neurodegenerative diseases, including Huntington disease. Our goal is to develop potent and selective small-molecule KMO inhibitors with suitable pharmacokinetic characteristics for in vivo proof-of-concept studies and subsequent clinical development. We developed a comprehensive panel of biochemical and cell-based assays that use liquid chromatography/tandem mass spectrometry to quantify unlabeled kynurenine and 3-hydroxykynurenine. We describe assays to measure KMO inhibition in cell and tissue extracts, as well as cellular assays including heterologous cell lines and primary rat microglia and human peripheral blood mononuclear cells.
Assuntos
Ensaios Enzimáticos/métodos , Quinurenina 3-Mono-Oxigenase/antagonistas & inibidores , Quinurenina 3-Mono-Oxigenase/metabolismo , Animais , Células CHO , Linhagem Celular , Cromatografia Líquida/métodos , Cricetulus , Cães , Descoberta de Drogas , Células HEK293 , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Cinurenina/análogos & derivados , Cinurenina/biossíntese , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/química , Leucócitos Mononucleares/efeitos dos fármacos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem/métodosRESUMO
Magnetic supports are tested for use in batch affinity capture of proteins. Two types of magnetic polymer composites were used for solid phase synthesis and for the batch affinity chromatography of folate binding protein from a protein mixture. Gly-Gly-L-Methotrexate as well as other analogs were synthesized on magnetic supports consisting of either polyoxyalkyleneamine grafted onto polystyrene beads or a copolymer of polyethylene glycol dimethylacrylamide (PEGA). Both supports incorporated within their matrix sub-micron particles of paramagnetic magnetite. The peptide-methotrexate analogs were attached to the magnetic supports via a photocleavable linker. The bound methotrexate-peptide analogs were equilibrated with a protein mixture consisting of bovine albumin, chicken albumin, folate binding protein, lysozyme, lactoferrin and lactoperoxidase precursor in phosphate buffered saline (PBS) and then after magnetically separating and washing the supports of any unbound components the bound protein was removed either through the photocleavage of the tethered methotrexate-peptide ligand or via exchange with soluble methotrexate. In all cases, the photocleavage or exchange with soluble methotrexate released folate binding protein as the major affinity captured protein. Of the two magnetic supports tested, the PEGA based support was found to be superior to the polyoxyalkyleneamine grafted polystyrene support and comparable to beaded agarose in releasing bound folate binding protein. Of the two methods for removing bound protein, photocleavage of the covalently attached ligand was found to release exclusively folate binding protein as opposed to exchange with soluble methotrexate which released residual amounts of the non-specifically bound proteins bovine and chicken albumin, in addition to folate binding protein. Thus, use of the PEGA based magnetic support in conjunction with a photocleavable linker should help facilitate the automation of multiple parallel affinity chromatography for proteomics applications.
Assuntos
Proteínas de Transporte/isolamento & purificação , Cromatografia de Afinidade/métodos , Ferro/química , Metotrexato/análogos & derivados , Óxidos/química , Proteômica/métodos , Receptores de Superfície Celular/isolamento & purificação , Acrilamidas/química , Ligação Competitiva , Proteínas de Transporte/química , Óxido Ferroso-Férrico , Receptores de Folato com Âncoras de GPI , Magnetismo , Metotrexato/química , Estrutura Molecular , Fotólise , Polietilenoglicóis/química , Poliestirenos/química , Proteínas/química , Proteínas/isolamento & purificação , Receptores de Superfície Celular/químicaRESUMO
With the influx of targets generated by genomics and proteomics initiatives, a new drug discovery paradigm is emerging. Many companies are setting up target family platforms that tackle multiple targets and therapeutic areas simultaneously. Virtual screening (VS) techniques are a fundamental component of such platforms for in silico filtering of compound collections and prioritization of chemistry and screening efforts. At the heart of these, structure-based docking and scoring methods are especially effective in identifying bioactive molecules if the structure of a target is available. As structural genomics maps the structural space of the proteome, these techniques are expected to become commonplace. In light of this, an overview of the latest developments in VS methodology is given here. In particular, emphasis is placed on those techniques adaptable to high-throughput VS in parallel drug discovery platforms. The first examples of docking across multiple targets have already appeared in the literature and will be reviewed here.