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1.
Yakugaku Zasshi ; 141(1): 1-13, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390437

RESUMEN

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.


Asunto(s)
Antineoplásicos , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Factores Inmunológicos , Química Orgánica , Diseño de Fármacos , Técnicas de Silenciamiento del Gen , Humanos , Ligandos , Chaperonas Moleculares/uso terapéutico , Ácido Poliglutámico , Pliegue de Proteína , Deficiencias en la Proteostasis/tratamiento farmacológico , Talidomida/química , Factores de Tiempo , Tokio , Universidades
2.
Genes Genomics ; 43(1): 55-67, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33428154

RESUMEN

BACKGROUND: Since the outbreak of coronavirus disease 2019 (COVID-19) in China, numerous research institutions have invested in the development of anti-COVID-19 vaccines and screening for efficacious drugs to manage the virus. OBJECTIVE: To explore the potential targets and therapeutic drugs for the prevention and treatment of COVID-19 through data mining and bioinformatics. METHODS: We integrated and profoundly analyzed 10 drugs previously assessed to have promising therapeutic potential in COVID-19 management, and have been recommended for clinical trials. To explore the mechanisms by which these drugs may be involved in the treatment of COVID-19, gene-drug interactions were identified using the DGIdb database after which functional enrichment analysis, protein-protein interaction (PPI) network, and miRNA-gene network construction were performed. We adopted the DGIdb database to explore the candidate drugs for COVID-19. RESULTS: A total of 43 genes associated with the 10 potential COVID-19 drugs were identified. Function enrichment analysis revealed that these genes were mainly enriched in response to other invasions, toll-like receptor pathways, and they play positive roles in the production of cytokines such as IL-6, IL-8, and INF-ß. TNF, TLR3, TLR7, TLR9, and CXCL10 were identified as crucial genes in COVID-19. Through the DGIdb database, we predicted 87 molecules as promising druggable molecules for managing COVID-19. CONCLUSIONS: Findings from this work may provide new insights into COVID-19 mechanisms and treatments. Further, the already identified candidate drugs may improve the efficiency of pharmaceutical treatment in this rapidly evolving global situation.


Asunto(s)
Antivirales/farmacología , /genética , /metabolismo , Biología Computacional/métodos , Desarrollo de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Redes Reguladoras de Genes , Humanos , MicroARNs/genética , Mapas de Interacción de Proteínas , /genética
3.
Nat Commun ; 12(1): 708, 2021 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-33514724

RESUMEN

We report the development of a platform of dual targeting Fab (DutaFab) molecules, which comprise two spatially separated and independent binding sites within the human antibody CDR loops: the so-called H-side paratope encompassing HCDR1, HCDR3 and LCDR2, and the L-side paratope encompassing LCDR1, LCDR3 and HCDR2. Both paratopes can be independently selected and combined into the desired bispecific DutaFabs in a modular manner. X-ray crystal structures illustrate that DutaFabs are able to bind two target molecules simultaneously at the same Fv region comprising a VH-VL heterodimer. In the present study, this platform is applied to generate DutaFabs specific for VEGFA and PDGF-BB, which show high affinities, physico-chemical stability and solubility, as well as superior efficacy over anti-VEGF monotherapy in vivo. These molecules exemplify the usefulness of DutaFabs as a distinct class of antibody therapeutics, which is currently being evaluated in patients.


Asunto(s)
Anticuerpos Biespecíficos/farmacología , Neovascularización Coroidal/tratamiento farmacológico , Desarrollo de Medicamentos/métodos , Fragmentos Fab de Inmunoglobulinas/farmacología , Ingeniería de Proteínas , Secuencia de Aminoácidos/genética , Animales , Anticuerpos Biespecíficos/genética , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/ultraestructura , Becaplermina/antagonistas & inhibidores , Sitios de Unión de Anticuerpos/genética , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Fragmentos Fab de Inmunoglobulinas/genética , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Fragmentos Fab de Inmunoglobulinas/ultraestructura , Concentración 50 Inhibidora , Inyecciones Intravítreas , Masculino , Modelos Moleculares , Prueba de Estudio Conceptual , Conformación Proteica , Ratas , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
4.
Chin J Integr Med ; 27(1): 3-6, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33420601

RESUMEN

Covid-19 pandemic has caused hundreds of thousands deaths and millions of infections and continued spreading violently. Although researchers are racing to find or develop effective drugs or vaccines, no drugs from modern medical system have been proven effective and the high mutant rates of the virus may lead it resistant to whatever drugs or vaccines developed following modern drug development procedure. Current evidence has demonstrated impressive healing effects of several Chinese medicines (CMs) for Covid-19, which urges us to reflect on the role of CM in the era of modern medicine. Undoubtedly, CM could be promising resources for developing drug candidates for the treatment of Covid-19 in a way similar to the development of artemisinin. But the theory that builds CM, like the emphasis of driving away exogenous pathogen (virus, etc.) by restoring self-healing capacity rather than killing the pathogen directly from the inside and the 'black-box' mode of diagnosing and treating patients, is as important, yet often ignored, an treasure as CM herbs and should be incorporated into modern medicine for future advancement and innovation of medical science.


Asunto(s)
/terapia , Medicamentos Herbarios Chinos/uso terapéutico , Medicina China Tradicional , Antivirales/farmacología , Antivirales/uso terapéutico , Brotes de Enfermedades , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/normas , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Humanos , Medicina China Tradicional/métodos , Medicina China Tradicional/tendencias , Tasa de Mutación , Pandemias , Fitoterapia/métodos , /fisiología
5.
J Pharmacol Exp Ther ; 376(1): 12-20, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33115823

RESUMEN

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.


Asunto(s)
Antivirales/uso terapéutico , Defensa Civil/tendencias , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/tendencias , Animales , Biomarcadores/análisis , /genética , Defensa Civil/métodos , Desarrollo de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Marcadores Genéticos/genética , Humanos , Pandemias
6.
Adv Drug Deliv Rev ; 169: 168-189, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33316346

RESUMEN

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented effort toward the development of an effective and safe vaccine. Aided by extensive research efforts into characterizing and developing countermeasures towards prior coronavirus epidemics, as well as recent developments of diverse vaccine platform technologies, hundreds of vaccine candidates using dozens of delivery vehicles and routes have been proposed and evaluated preclinically. A high demand coupled with massive effort from researchers has led to the advancement of at least 31 candidate vaccines in clinical trials, many using platforms that have never before been approved for use in humans. This review will address the approach and requirements for a successful vaccine against SARS-CoV-2, the background of the myriad of vaccine platforms currently in clinical trials for COVID-19 prevention, and a summary of the present results of those trials. It concludes with a perspective on formulation problems which remain to be addressed in COVID-19 vaccine development and antigens or adjuvants which may be worth further investigation.


Asunto(s)
Adyuvantes Inmunológicos/síntesis química , /prevención & control , Desarrollo de Medicamentos/métodos , /efectos de los fármacos , Adyuvantes Inmunológicos/uso terapéutico , Animales , /uso terapéutico , Composición de Medicamentos/métodos , Composición de Medicamentos/tendencias , Desarrollo de Medicamentos/tendencias , Humanos , Proteínas Recombinantes/síntesis química , Proteínas Recombinantes/uso terapéutico , /inmunología
8.
Nat Commun ; 11(1): 5485, 2020 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-33127883

RESUMEN

Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. However, current machine-learning-based predictions of drug response often fail to identify robust translational biomarkers from preclinical models. Here, we present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data derived from three-dimensional organoid culture models. The biomarkers identified by our approach accurately predict the drug responses of 114 colorectal cancer patients treated with 5-fluorouracil and 77 bladder cancer patients treated with cisplatin. We further confirm our biomarkers using external transcriptomic datasets of drug-sensitive and -resistant isogenic cancer cell lines. Finally, concordance analysis between the transcriptomic biomarkers and independent somatic mutation-based biomarkers further validate our method. This work presents a method to predict cancer patient drug responses using pharmacogenomic data derived from organoid models by combining the application of gene modules and network-based approaches.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Aprendizaje Automático , Organoides/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Cisplatino/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Desarrollo de Medicamentos/métodos , Fluorouracilo/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Organoides/efectos de los fármacos , Mapas de Interacción de Proteínas/efectos de los fármacos , Transcriptoma , Vejiga Urinaria/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo
11.
J Proteome Res ; 19(11): 4355-4363, 2020 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-33006287

RESUMEN

A model that predicts levels of coronavirus (CoV) respiratory and fecal-oral transmission potentials based on the shell disorder has been built using neural network (artificial intelligence, AI) analysis of the percentage of disorder (PID) in the nucleocapsid, N, and membrane, M, proteins of the inner and outer viral shells, respectively. Using primarily the PID of N, SARS-CoV-2 is grouped as having intermediate levels of both respiratory and fecal-oral transmission potentials. Related studies, using similar methodologies, have found strong positive correlations between virulence and inner shell disorder among numerous viruses, including Nipah, Ebola, and Dengue viruses. There is some evidence that this is also true for SARS-CoV-2 and SARS-CoV, which have N PIDs of 48% and 50%, and case-fatality rates of 0.5-5% and 10.9%, respectively. The underlying relationship between virulence and respiratory potentials has to do with the viral loads of vital organs and body fluids, respectively. Viruses can spread by respiratory means only if the viral loads in saliva and mucus exceed certain minima. Similarly, a patient is likelier to die when the viral load overwhelms vital organs. Greater disorder in inner shell proteins has been known to play important roles in the rapid replication of viruses by enhancing the efficiency pertaining to protein-protein/DNA/RNA/lipid bindings. This paper suggests a novel strategy in attenuating viruses involving comparison of disorder patterns of inner shells (N) of related viruses to identify residues and regions that could be ideal for mutation. The M protein of SARS-CoV-2 has one of the lowest M PID values (6%) in its family, and therefore, this virus has one of the hardest outer shells, which makes it resistant to antimicrobial enzymes in body fluid. While this is likely responsible for its greater contagiousness, the risks of creating an attenuated virus with a more disordered M are discussed.


Asunto(s)
Inteligencia Artificial , Betacoronavirus , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Vacunas Virales , Betacoronavirus/química , Betacoronavirus/genética , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Desarrollo de Medicamentos/métodos , Humanos , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/genética , Proteínas Intrínsecamente Desordenadas/metabolismo , Pandemias/prevención & control , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/prevención & control , Neumonía Viral/transmisión , Neumonía Viral/virología , Carga Viral , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/metabolismo
12.
Yakugaku Zasshi ; 140(10): 1225-1233, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32999201

RESUMEN

This article describes our stereoselective and site-selective chemical methods for exploiting cationic heterocycles as electron-withdrawing groups (EWGs). We envisioned that the phosphoramide N-H proton of a pyridyl phosphoramide 3 would be activated by the cationic pyridinium moiety that is formed upon protonation. The resulting imide-like N-H proton and the acidic pyridinium proton of the pyridinium phosphoramide 3⋅HX cooperate together, making 3⋅HX a highly acidic dual Brønsted acid. The catalytic ability of 3⋅HX was demonstrated in the development of the first asymmetric Diels-Alder reaction between 1-amide dienes and maleimides. Focusing on the activation of N-bromosuccinimide (NBS) because of its structural similarity to maleimides, the enantioselective bromolactonization of trisubstituted olefinic acids was accomplished utilizing pyridyl phosphoramide 3f as a Brønsted base catalyst bearing an acidic N-H proton. Lastly, our strategy for the site-selective acylation of polyol compounds is described. In our system, a pyridine aldoxime ester 10, used as a mild acylating reagent, was activated by a catalytic amount of Lewis acid via the inductive effect of the cationic pyridinium moiety. The resulting metal complex preferentially attracted the alcohol with a Lewis basic site, thereby facilitating selective acylation via a template effect. This metal-template-driven strategy allowed for the site-selective acylation of diverse α-hydroxyamides, including unprotected N-glycolyl aminosugars.


Asunto(s)
Cationes/química , Cationes/síntesis química , Química Orgánica/métodos , Desarrollo de Medicamentos/métodos , Electrones , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Acilación , Amidas/química , Catálisis , Complejos de Coordinación/química , Reacción de Cicloadición , Ésteres/química , Compuestos de Pralidoxima/química , Estereoisomerismo
13.
Yakugaku Zasshi ; 140(10): 1243-1249, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32999203

RESUMEN

Here the author describes the tumor-selective delivery of a fluorescence photosensitizing agent and an antitumor agent, based on the polymer effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) based copolymer, by utilizing the enhanced permeability and retention (EPR) effect seen in solid tumors. Firstly, the tumor distribution of the photosensitizer, zinc-protoporphyrin IX (ZnPP), was significantly increased by conjugation with the HPMA polymer (P-ZnPP). The P-ZnPP suppressed tumor growth by local generation of cytotoxic singlet oxygen, and the tumor tissue was visualized by fluorescence upon light irradiation. Subsequently, a two-step mechanism for tumor selectivity was observed for the cytotoxic anthracycline, pirarubicin (THP), which conjugated the HPMA-based copolymer via a hydrazone bond (P-THP). The EPR-dependent accumulation of P-THP and the tumor-selective release of THP in the tumor tissues led to highly tumor-selective toxicity. Rapid cell uptake of THP compared to other anthracyclines, and deeper P-THP penetration of the tumor cell spheroid were attributed to the superior antitumor activity of P-THP. The molecular weight of P-THP affected its antitumor activity; oligomeric P-THP derivatives with higher molecular weights, DP-THP and SP-THP, showed even higher antitumor activity. P-THP was effective for both implanted tumor and autochthonous tumor models. These results indicate that nano-sized anticancer drugs based on polymer effect are promising clinical therapeutics.


Asunto(s)
Antineoplásicos , Sistemas de Liberación de Medicamentos , Desarrollo de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fármacos Fotosensibilizantes , Polímeros , Protoporfirinas , Animales , Antraciclinas/química , Antraciclinas/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Metacrilatos/química , Terapia Molecular Dirigida , Peso Molecular , Neoplasias/patología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo
14.
Yakugaku Zasshi ; 140(10): 1259-1268, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32999205

RESUMEN

RNA interference (RNAi) is the standard method of suppressing gene expression because of its target specificity, potency, and ability to silence the expression of virtually any gene. Using 21-mer small interfering RNA (siRNA) is the general approach for inducing RNAi, as siRNA can be easily prepared using a DNA/RNA synthesizer. Synthetic siRNA can be chemically modified to increase the potency of RNAi activity and abrogate innate immune stimulation. However, designing chemically modified siRNA requires substantial experimentation. A practical method for understanding the interaction of siRNA and RNAi-related proteins and how modifications affect RNA-protein interactions is therefore needed. Plasmid DNA (pDNA) expressing short hairpin RNA (shRNA) can also be used to induce RNAi. pDNA produces numerous shRNAs that induce RNAi with potent and longterm RNAi activity, even if only one pDNA molecule is delivered to the nucleus. However, this approach has some drawbacks with regard to its therapeutic application, such as a low pDNA transfection efficiency due to its huge molecular size and innate immune responses induced by extra genes, such as CpG motifs. To overcome these issues with RNAi inducers (siRNA and pDNA), our group developed some chemical approaches using chemically modified oligonucleotides. This article focuses on our two original approaches. The first involves the groove modification of siRNA duplexes to understand siRNA-protein interactions using 7-bromo-7-deazaadenosine and 3-bromo-3-deazaadenosine as chemical probes, while the second involves the generation of RNAi medicine using chemically modified DNA, known as an intelligent shRNA expression device (iRed).


Asunto(s)
Desarrollo de Medicamentos/métodos , Interferencia de ARN , ARN Interferente Pequeño/síntesis química , ADN , Inmunidad Innata , Oligonucleótidos/química , Dominios y Motivos de Interacción de Proteínas , ARN Interferente Pequeño/química , Tratamiento con ARN de Interferencia , Tubercidina/química
16.
J Proteome Res ; 19(11): 4242-4258, 2020 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-32957788

RESUMEN

Viruses remain a major challenge in the fierce fight against diseases. There have been many pandemics caused by various viruses throughout the world over the years. Recently, the global outbreak of COVID-19 has had a catastrophic impact on human health and the world economy. Antiviral drug treatment has become another essential means to overcome pandemics in addition to vaccine development. How to quickly find effective drugs that can control the development of a pandemic is a hot issue that still needs to be resolved in medical research today. To accelerate the development of drugs, it is necessary to target the key target proteins in the development of the pandemic, screen active molecules, and develop reliable methods for the identification and characterization of target proteins based on the active ingredients of drugs. This article discusses key target proteins and their biological mechanisms in the progression of COVID-19 and other major epidemics. We propose a model based on these foundations, which includes identifying potential core targets, screening potential active molecules of core targets, and verifying active molecules. This article summarizes the related innovative technologies and methods. We hope to provide a reference for the screening of drugs related to pandemics and the development of new drugs.


Asunto(s)
Desarrollo de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Pandemias , Proteómica/métodos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Técnicas de Química Analítica , Infecciones por Coronavirus/tratamiento farmacológico , Bases de Datos de Proteínas , Humanos , Peste/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico
17.
BMC Bioinformatics ; 21(Suppl 13): 394, 2020 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-32938374

RESUMEN

BACKGROUND: Drug-target interaction prediction is of great significance for narrowing down the scope of candidate medications, and thus is a vital step in drug discovery. Because of the particularity of biochemical experiments, the development of new drugs is not only costly, but also time-consuming. Therefore, the computational prediction of drug target interactions has become an essential way in the process of drug discovery, aiming to greatly reducing the experimental cost and time. RESULTS: We propose a learning-based method based on feature representation learning and deep neural network named DTI-CNN to predict the drug-target interactions. We first extract the relevant features of drugs and proteins from heterogeneous networks by using the Jaccard similarity coefficient and restart random walk model. Then, we adopt a denoising autoencoder model to reduce the dimension and identify the essential features. Third, based on the features obtained from last step, we constructed a convolutional neural network model to predict the interaction between drugs and proteins. The evaluation results show that the average AUROC score and AUPR score of DTI-CNN were 0.9416 and 0.9499, which obtains better performance than the other three existing state-of-the-art methods. CONCLUSIONS: All the experimental results show that the performance of DTI-CNN is better than that of the three existing methods and the proposed method is appropriately designed.


Asunto(s)
Desarrollo de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Redes Neurales de la Computación , Humanos
18.
PLoS One ; 15(9): e0237809, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32915792

RESUMEN

Chimeric mice with humanized livers are considered a useful animal model for predicting human (h-) drug metabolism and toxicity. In this study, the characteristics of fresh h-hepatocytes (cFHHs, PXB-cells®) isolated from chimeric mice (PXB-mice®) were evaluated in vitro to confirm their utility for drug development. cFHHs cultured at high density (2.13 × 105 cells/cm2) displayed stable production of h-albumin and cytochrome P450 (CYP) 3A activities for at least 21 days. The mRNA expression levels of 10 of 13 CYP, UDP-glucuronosyltransferase (UGT), and transporters were maintained at >10% of the levels of freshly isolated cFHHs after 21 days. From 1 week, many bile canaliculi were observed between cFHHs, and the accumulation of the multidrug resistance-associated protein and bile salt export pump substrates in these bile canaliculi was clearly inhibited by cyclosporin A. Microarray analysis of cFHHs cultured at high density and at low density (0.53 × 105 cells/cm2) revealed that high density culture maintained high expressions of some transcription factors (HNF4α, PXR, and FXR) perhaps involved in the high CYP, UGT and transporter gene expressions of cFHHs. These results strongly suggest that cFHHs could be a novel in vitro tool for drug development studies.


Asunto(s)
Canalículos Biliares/efectos de los fármacos , Desarrollo de Medicamentos/métodos , Hepatocitos/efectos de los fármacos , Cultivo Primario de Células/métodos , Quimera por Trasplante , Animales , Canalículos Biliares/citología , Canalículos Biliares/metabolismo , Células Cultivadas , Niño , Preescolar , Ciclosporina/farmacología , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Femenino , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
19.
PLoS One ; 15(8): e0238150, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32866159

RESUMEN

Immunogenicity is an important concern for therapeutic antibodies during drug development. By analyzing co-crystal structures of idiotypic antibodies and their antibodies, we found that anti-idiotypic antibodies usually bind the Complementarity Determining Regions (CDR) of idiotypic antibodies. Sequence and structural features were identified for distinguishing immunogenic antibodies from non-immunogenic antibodies. For example, non-immunogenic antibodies have a significantly larger cavity volume at the CDR region and a more hydrophobic CDR-H3 loop than immunogenic antibodies. Antibodies containing no Gly at the turn of CDR-H2 loop are often immunogenic. We integrated these features together with a machine learning platform to Predict Immunogenicity for humanized and full human THerapeutic Antibodies (PITHA). This method achieved an accuracy of 83% in leave-one-out experiment for 29 therapeutic antibodies with available crystal structures. The accuracy decreased to 65% for 23 test antibodies with modeled structures, because their crystal structures were not available, and the prediction was made with modeled structures. The server of this method is accessible at http://mabmedicine.com/PITHA.


Asunto(s)
Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/inmunología , Formación de Anticuerpos/inmunología , Cristalografía por Rayos X/métodos , Desarrollo de Medicamentos/métodos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Conformación Proteica
20.
Cancer Treat Rev ; 89: 102061, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32738737

RESUMEN

Renal cell cancer (RCC) is the third most diagnosed genitourinary malignancy in the world. Nearly a half of the diagnoses and 60% of related deaths occur in low-middle income countries (LMs), where prognosis is generally poor. We conducted a systematic research of ClinicalTrials.gov, searching RCC ongoing studies for adult patients. We included 205 trials in the final analysis. The enrolling centers were mainly distributed in high-income settings (88.9%). We estimated 94.6% of the trial population was enrolled in only five countries and none in LMs. Clinical drug development for RCC is driven by early phase studies, mainly assessing small molecule tyrosine kinase inhibitors and immunotherapy or the combination. Sixty percent of the trials were industry sponsored. Only a minority of the trials were in the early setting of care, adjuvant or neoadjuvant therapy. Disparities in drug development in LMs mirror a common underestimation of the value of research among the national priorities in cancer health planning, resulting in poor ethnic diversity and inclusiveness. This commonly results in incomplete knowledge of activity and safety of medicines across different ethnic groups, with consequences on priorities for cancer interventions and estimates of benefit in LMs patients. The use of RCC as a case study for inclusiveness suggests poor inclusion of non- Caucasian populations in the trials, especially trials testing new immunotherapy and targeted agents where RCC drug development is more pronounced, resulting in issues of generalizability in other ethnic groups when these compounds are approved with no ethnic restrictions or specifications.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/estadística & datos numéricos , Desarrollo de Medicamentos/métodos , Humanos , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto
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