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1.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925625

RESUMO

The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Doenças do Sistema Nervoso/terapia , Esclerose Amiotrófica Lateral/terapia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Biológicos , Doenças Neurodegenerativas/terapia , Doença de Parkinson/terapia , Preparações Farmacêuticas , Transplante de Células-Tronco/métodos , Transplante de Células-Tronco/tendências
3.
Mol Pharmacol ; 99(4): 256-265, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33547249

RESUMO

The high failure rate of drugs in the clinical pipeline is likely in part the result of inadequate preclinical models, particularly those for neurologic disorders and neurodegenerative disease. Such preclinical animal models often suffer from fundamental species differences and rarely recapitulate all facets of neurologic conditions, whereas conventional two-dimensional (2D) in vitro models fail to capture the three-dimensional spatial organization and cell-to-cell interactions of brain tissue that are presumed to be critical to the function of the central nervous system. Recent studies have suggested that stem cell-derived neuronal organoids are more physiologically relevant than 2D neuronal cultures because of their cytoarchitecture, electrophysiological properties, human origin, and gene expression. Hence there is interest in incorporating such physiologically relevant models into compound screening and lead optimization efforts within drug discovery. However, despite their perceived relevance, compared with previously used preclinical models, little is known regarding their predictive value. In fact, some have been wary to broadly adopt organoid technology for drug discovery because of the low-throughput and tedious generation protocols, inherent variability, and lack of compatible moderate-to-high-throughput screening assays. Consequently, microfluidic platforms, specialized bioreactors, and automated assays have been and are being developed to address these deficits. This mini review provides an overview of the gaps to broader implementation of neuronal organoids in a drug discovery setting as well as emerging technologies that may better enable their utilization. SIGNIFICANCE STATEMENT: Neuronal organoid models offer the potential for a more physiological system in which to study neurological diseases, and efforts are being made to employ them not only in mechanistic studies but also in profiling/screening purposes within drug discovery. In addition to exploring the utility of neuronal organoid models within this context, efforts in the field aim to standardize such models for consistency and adaptation to screening platforms for throughput evaluation. This review covers potential impact of and hurdles to implementation.


Assuntos
Descoberta de Drogas/métodos , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Organoides/efeitos dos fármacos , Organoides/fisiologia , Animais , Descoberta de Drogas/tendências , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Doenças Neurodegenerativas/fisiopatologia
4.
MAbs ; 13(1): 1860476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33459118

RESUMO

In this 12th annual installment of the Antibodies to Watch article series, we discuss key events in antibody therapeutics development that occurred in 2020 and forecast events that might occur in 2021. The coronavirus disease 2019 (COVID-19) pandemic posed an array of challenges and opportunities to the healthcare system in 2020, and it will continue to do so in 2021. Remarkably, by late November 2020, two anti-SARS-CoV antibody products, bamlanivimab and the casirivimab and imdevimab cocktail, were authorized for emergency use by the US Food and Drug Administration (FDA) and the repurposed antibodies levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 in Russia and India, respectively. Despite the pandemic, 10 antibody therapeutics had been granted the first approval in the US or EU in 2020, as of November, and 2 more (tanezumab and margetuximab) may be granted approvals in December 2020.* In addition, prolgolimab and olokizumab had been granted first approvals in Russia and cetuximab saratolacan sodium was first approved in Japan. The number of approvals in 2021 may set a record, as marketing applications for 16 investigational antibody therapeutics are already undergoing regulatory review by either the FDA or the European Medicines Agency. Of these 16 mAbs, 11 are possible treatments for non-cancer indications and 5 are potential treatments for cancer. Based on the information publicly available as of November 2020, 44 antibody therapeutics are in late-stage clinical studies for non-cancer indications, including 6 for COVID-19, and marketing applications for at least 6 (leronlimab, tezepelumab, faricimab, ligelizumab, garetosmab, and fasinumab) are planned in 2021. In addition, 44 antibody therapeutics are in late-stage clinical studies for cancer indications. Of these 44, marketing application submissions for 13 may be submitted by the end of 2021. *Note added in proof on key events announced during December 1-21, 2020: margetuximab-cmkb and ansuvimab-zykl were approved by FDA on December 16 and 21, 2020, respectively; biologics license applications were submitted for ublituximab and amivantamab.


Assuntos
Anticorpos/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Desenvolvimento de Medicamentos/tendências , Descoberta de Drogas/tendências , Reposicionamento de Medicamentos/tendências , SARS-CoV-2/efeitos dos fármacos , Animais , Anticorpos/efeitos adversos , Antivirais/efeitos adversos , COVID-19/diagnóstico , COVID-19/virologia , Difusão de Inovações , Aprovação de Drogas , Previsões , Interações Hospedeiro-Patógeno , Humanos , SARS-CoV-2/imunologia
5.
Yakugaku Zasshi ; 141(1): 1-13, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390437

RESUMO

Chemical biology and structural development studies performed at The University of Tokyo during 1977-2020 are outlined chronologically. The studies are divided into three parts, i.e., (i) chemical biology of chemical carcinogenesis and molecular design of anti-tumor agents, (ii) structural development studies on biological response modifiers, and (iii) studies on so-called dramatype drug discovery focusing on pharmacological chaperones and protein knockdown-inducers. The first part describes analysis of DNA modification by Glu-P-1, which is a typical carcinogenic heterocyclic amine found in cooked foods, as well as molecular design of DNA-cleaving agents with anti-tumor properties. The second part deals with structural development studies of nuclear receptor ligands and various biological response modifiers derived from thalidomide, including the ligand superfamily concept and the multi-template strategy. The third part describes pharmacological chaperones that should be useful for the treatment of protein misfolding diseases, including Niemann-Pick type C disease and retinitis pigmentosa, and a protein knockdown strategy aimed at degradation of neurodegenerative-disease-causing polyglutamic aggregative proteins.


Assuntos
Antineoplásicos , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/tendências , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Fatores Imunológicos , Química Orgânica , Desenho de Fármacos , Técnicas de Silenciamento de Genes , Humanos , Ligantes , Chaperonas Moleculares/uso terapêutico , Ácido Poliglutâmico , Dobramento de Proteína , Deficiências na Proteostase/tratamento farmacológico , Talidomida/química , Fatores de Tempo , Tóquio , Universidades
6.
Yakugaku Zasshi ; 141(1): 61-66, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390449

RESUMO

Glaucoma, the leading cause of blindness in adults, is a progressive neurodegenerative disease characterized by retinal ganglion cell (RGC) death. Currently, many intraocular pressure (IOP)-lowering drugs known to affect this disease progression have been developed as therapeutic agents. However, there are many cases of disease progression, even with sufficient IOP reduction. Therefore, newer therapeutic approaches other than IOP-lowering drugs are needed. To elucidate the pathogenesis of glaucoma and to develop therapeutic agents, the evaluation of RGCs is imperative, as their degeneration is the main cause of this disease. However, it is difficult to obtain RGCs from healthy individuals, let alone glaucoma patients. Therefore, research on the pathophysiology of glaucoma and drug discovery has not progressed sufficiently. Recent developments have made it possible to generate induced pluripotent stem (iPS) cells from the blood or skin of glaucoma patients and induce them to differentiate into RGCs to study the pathogenesis of glaucoma. In addition, drug repositioning for ophthalmological diseases such as glaucoma is one of the most active fields. Many of these repositioned drugs have found therapeutic applications in ophthalmology. Here, we introduce the current status of the pharmacological treatment of glaucoma and its prospects.


Assuntos
Descoberta de Drogas/tendências , Reposicionamento de Medicamentos/tendências , Glaucoma/terapia , Diferenciação Celular , Progressão da Doença , Glaucoma/etiologia , Glaucoma/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Pressão Intraocular , Células Ganglionares da Retina/patologia
8.
J Pharmacol Exp Ther ; 376(1): 12-20, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33115823

RESUMO

Faced with the health and economic consequences of the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the biomedical community came together to identify, diagnose, prevent, and treat the novel disease at breathtaking speeds. The field advanced from a publicly available viral genome to a commercialized globally scalable diagnostic biomarker test in less than 2 months, and first-in-human dosing with vaccines and repurposed antivirals followed shortly thereafter. This unprecedented efficiency was driven by three key factors: 1) international multistakeholder collaborations, 2) widespread data sharing, and 3) flexible regulatory standards tailored to meet the urgency of the situation. Learning from the remarkable success achieved during this public health crisis, we are proposing a biomarker-centric approach throughout the drug development pipeline. Although all therapeutic areas would benefit from end-to-end biomarker science, efforts should be prioritized to areas with the greatest unmet medical needs, including neurodegenerative diseases, chronic lower respiratory diseases, metabolic disorders, and malignant neoplasms. SIGNIFICANCE STATEMENT: Faced with the unprecedented threat of the severe acute respiratory syndrome coronavirus 2 pandemic, the biomedical community collaborated to develop a globally scalable diagnostic biomarker (viral DNA) that catalyzed therapeutic development at breathtaking speeds. Learning from this remarkable efficiency, we propose a multistakeholder biomarker-centric approach to drug development across therapeutic areas with unmet medical needs.


Assuntos
Antivirais/uso terapêutico , COVID-19/epidemiologia , Defesa Civil/tendências , Desenvolvimento de Medicamentos/tendências , Descoberta de Drogas/tendências , Animais , Biomarcadores/análise , COVID-19/tratamento farmacológico , COVID-19/genética , Defesa Civil/métodos , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Marcadores Genéticos/genética , Humanos , Pandemias
9.
Nat Rev Drug Discov ; 20(2): 145-159, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33353986

RESUMO

Image-based profiling is a maturing strategy by which the rich information present in biological images is reduced to a multidimensional profile, a collection of extracted image-based features. These profiles can be mined for relevant patterns, revealing unexpected biological activity that is useful for many steps in the drug discovery process. Such applications include identifying disease-associated screenable phenotypes, understanding disease mechanisms and predicting a drug's activity, toxicity or mechanism of action. Several of these applications have been recently validated and have moved into production mode within academia and the pharmaceutical industry. Some of these have yielded disappointing results in practice but are now of renewed interest due to improved machine-learning strategies that better leverage image-based information. Although challenges remain, novel computational technologies such as deep learning and single-cell methods that better capture the biological information in images hold promise for accelerating drug discovery.


Assuntos
Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Processamento de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Animais , Biologia Computacional/métodos , Biologia Computacional/tendências , Descoberta de Drogas/tendências , Indústria Farmacêutica/tendências , Ensaios de Triagem em Larga Escala/métodos , Ensaios de Triagem em Larga Escala/tendências , Humanos , Processamento de Imagem Assistida por Computador/tendências , Aprendizado de Máquina/tendências
10.
Molecules ; 26(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375159

RESUMO

It is known that enzymes are involved in many pathological conditions, such as inflammation, diabetes, microbial infections, HIV, neoplastic, neglected diseases and others [...].


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Humanos
11.
Ned Tijdschr Geneeskd ; 1642020 12 03.
Artigo em Holandês | MEDLINE | ID: mdl-33332053

RESUMO

Over twenty different antipsychotics are available in the treatment of schizophrenia. All antipsychotics are generally effective, although differences exist in terms of efficacy but also in side effect profile. So far, all antipsychotics block the dopamine-2 (D2) receptor in the brain, including recently available antipsychotics such as lurasidone, cariprazine and brexpiprazole. However large differences exist in binding strength to the D2 receptor that influence dosage ranges. Thus, there seems to be a rock-solid law of antipsychotics: D2 receptor blockade is necessary for an antipsychotic to be effective. Hitherto, the effects of molecules that do not block the D2 receptor for the treatment of psychotic disorders are either disappointing or equivocal, e.g. glutamate system modulators as the metabotropic mGLu2/3 agonist LY2140023. This is disappointing because there is a great need for antipsychotics with novel mechanisms of action. This is pivotal as a proportion of patients with schizophrenia do not sufficiently benefit from currently available dopamine-blocking antipsychotics with limited effects on negative and cognitive symptoms of schizophrenia. In addition, side effects of antipsychotics sometimes prevent its long-term use. Recently, a randomized controlled trial evaluated SEP-363856 for the treatment of acute schizophrenia, a molecule that does not bind to the D2 receptor but binds to trace amine-associated (TAAR) receptors and 5-HT1A receptors. SEP-363856 was more effective compared to placebo after 4 weeks of treatment (effect size 0.45). This is encouraging, although the duration of the RCT and relatively selected group of patients preclude firm conclusions on its efficacy. We may be hopeful that antipsychotics with a novel mechanism of action are investigated, but only the future will learn whether SEP-363856 will have true added value to improve the life of patients suffering from psychotic disorders.


Assuntos
Antipsicóticos/farmacologia , Descoberta de Drogas/tendências , Transtornos Psicóticos/tratamento farmacológico , Piranos/farmacologia , Esquizofrenia/tratamento farmacológico , Doença Aguda , Antagonistas de Dopamina/farmacologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
12.
Int J Immunopathol Pharmacol ; 34: 2058738420966078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33045858

RESUMO

Given the sharp spreading of COVID-19 pandemic all around the world, our attention was brought to consider that that many cationic drugs (i.e. those characterized by the presence, at physiological pH value, of one or more cationic groups, both primary, secondary, tertiary and guanidinic aminic groups) could have any effect in impairing SARS-CoV2 entry in the host cell. This could open to new therapeutic chances against COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , Inibidores Enzimáticos/farmacologia , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Humanos , Pandemias , Pneumonia Viral/epidemiologia
13.
J Transl Med ; 18(1): 390, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059719

RESUMO

While the COVID-19 pandemic has spurred intense research and collaborative discovery worldwide, the development of a safe, effective, and targeted antiviral from the ground up is time intensive. Therefore, most antiviral discovery efforts are focused on the re-purposing of clinical stage or approved drugs. While emerging data on drugs undergoing COVID-19 repurpose are intriguing, there is an undeniable need to develop broad-spectrum antivirals to prevent future viral pandemics of unknown origin. The ideal drug to curtail rapid viral spread would be a broad-acting agent with activity against a wide range of viruses. Such a drug would work by modulating host-proteins that are often shared by multiple virus families thereby enabling preemptive drug development and therefore rapid deployment at the onset of an outbreak. Targeting host-pathways and cellular proteins that are hijacked by viruses can potentially offer broad-spectrum targets for the development of future antiviral drugs. Such host-directed antivirals are also likely to offer a higher barrier to the development and selection of drug resistant mutations. Given that most approved antivirals do not target host-proteins, we reinforce the need for the development of such antivirals that can be used in pre- and post-exposure populations.


Assuntos
Antivirais , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Necessidades e Demandas de Serviços de Saúde , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/classificação , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/normas , Descoberta de Drogas/organização & administração , Descoberta de Drogas/normas , Descoberta de Drogas/tendências , Saúde Global , Necessidades e Demandas de Serviços de Saúde/organização & administração , Necessidades e Demandas de Serviços de Saúde/normas , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Mutagênese/efeitos dos fármacos , Determinação de Necessidades de Cuidados de Saúde/organização & administração , Determinação de Necessidades de Cuidados de Saúde/normas , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Internalização do Vírus/efeitos dos fármacos
16.
Theranostics ; 10(16): 7034-7052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32641977

RESUMO

This review provides an update for the international research community on the cell modeling tools that could accelerate the understanding of SARS-CoV-2 infection mechanisms and could thus speed up the development of vaccines and therapeutic agents against COVID-19. Many bioengineering groups are actively developing frontier tools that are capable of providing realistic three-dimensional (3D) models for biological research, including cell culture scaffolds, microfluidic chambers for the culture of tissue equivalents and organoids, and implantable windows for intravital imaging. Here, we review the most innovative study models based on these bioengineering tools in the context of virology and vaccinology. To make it easier for scientists working on SARS-CoV-2 to identify and apply specific tools, we discuss how they could accelerate the discovery and preclinical development of antiviral drugs and vaccines, compared to conventional models.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Vacinas Virais/isolamento & purificação , Vacinas Virais/farmacologia , Betacoronavirus/química , Betacoronavirus/genética , Betacoronavirus/imunologia , Bioengenharia/métodos , Bioengenharia/tendências , Reatores Biológicos , Técnicas de Cultura de Células , Simulação por Computador , Infecções por Coronavirus/imunologia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Avaliação de Medicamentos/métodos , Avaliação de Medicamentos/tendências , Farmacorresistência Viral , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Modelos Biológicos , Organoides/citologia , Organoides/virologia , Pneumonia Viral/imunologia , Nanomedicina Teranóstica
18.
J Med Microbiol ; 69(8): 1040-1048, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32692643

RESUMO

Given the increased reporting of multi-resistant bacteria and the shortage of newly approved medicines, researchers have been looking towards extreme and unusual environments as a new source of antibiotics. Streptomyces currently provides many of the world's clinical antibiotics, so it comes as no surprise that these bacteria have recently been isolated from traditional medicine. Given the wide array of traditional medicines, it is hoped that these discoveries can provide the much sought after core structure diversity that will be required of a new generation of antibiotics. This review discusses the contribution of Streptomyces to antibiotics and the potential of newly discovered species in traditional medicine. We also explore how knowledge of traditional medicines can aid current initiatives in sourcing new and chemically diverse antibiotics.


Assuntos
Antibacterianos/isolamento & purificação , Descoberta de Drogas/tendências , Microbiologia do Solo , Streptomyces/metabolismo , Animais , Antibacterianos/biossíntese , Cavernas/química , Invertebrados/química , Medicina Tradicional , Peptídeo Sintases/metabolismo , Plantas Medicinais/química , Policetídeo Sintases/metabolismo , Poríferos/química , Streptomyces/química , Streptomyces/enzimologia
19.
J Antimicrob Chemother ; 75(9): 2381-2383, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32591771

RESUMO

The development of therapeutic agents against SARS-CoV-2/COVID-19  faces numerous barriers and a multidisciplinary approach to evaluating drug efficacy and toxicity is essential. Experimental and preclinical data should be integrated into a comprehensive analysis, where drug potency, the timing of therapy initiation, drug combinations, variability in systemic and local drug exposure and short- and long-term toxicities represent fundamental factors for the rational identification of candidates and prioritization of clinical investigations. Although the identification of SARS-CoV-2 therapeutics is a priority, rigorous and transparent methodologies are crucial to ensure that accelerated research programmes result in high-quality and reproducible findings.


Assuntos
Anticorpos Antivirais/efeitos dos fármacos , Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas/tendências , Pneumonia Viral/tratamento farmacológico , Animais , Anticorpos Antivirais/sangue , Antivirais/farmacologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Descoberta de Drogas/métodos , Humanos , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico
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