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1.
Cancer Discov ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615656

RESUMO

Glioblastoma (GBM) is the most lethal primary brain cancer characterized by therapeutic resistance, which is promoted by GBM stem cells (GSCs). Here, we interrogated gene expression and whole genome CRISPR/Cas9 screening in a large panel of patient-derived GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs) to identify master regulators of GSC stemness, revealing an essential transcription state with increased RNA polymerase II-mediated transcription. The YY1 and transcriptional CDK9 complex was essential for GSC survival and maintenance in vitro and in vivo. YY1 interacted with CDK9 to regulate transcription elongation in GSCs. Genetic or pharmacological targeting of YY1-CDK9 complex elicited RNA m6A modification-dependent interferon responses, reduced regulatory T cell infiltration, and augmented efficacy of immune checkpoint therapy in glioblastoma. Collectively, these results suggest that YY1-CDK9 transcription elongation complex defines a targetable cell state with active transcription, suppressed interferon responses, and immunotherapy resistance in glioblastoma.

2.
J Chem Inf Model ; 61(9): 4224-4235, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34387990

RESUMO

With the rapidly evolving SARS-CoV-2 variants of concern, there is an urgent need for the discovery of further treatments for the coronavirus disease (COVID-19). Drug repurposing is one of the most rapid strategies for addressing this need, and numerous compounds have already been selected for in vitro testing by several groups. These have led to a growing database of molecules with in vitro activity against the virus. Machine learning models can assist drug discovery through prediction of the best compounds based on previously published data. Herein, we have implemented several machine learning methods to develop predictive models from recent SARS-CoV-2 in vitro inhibition data and used them to prioritize additional FDA-approved compounds for in vitro testing selected from our in-house compound library. From the compounds predicted with a Bayesian machine learning model, lumefantrine, an antimalarial was selected for testing and showed limited antiviral activity in cell-based assays while demonstrating binding (Kd 259 nM) to the spike protein using microscale thermophoresis. Several other compounds which we prioritized have since been tested by others and were also found to be active in vitro. This combined machine learning and in vitro testing approach can be expanded to virtually screen available molecules with predicted activity against SARS-CoV-2 reference WIV04 strain and circulating variants of concern. In the process of this work, we have created multiple iterations of machine learning models that can be used as a prioritization tool for SARS-CoV-2 antiviral drug discovery programs. The very latest model for SARS-CoV-2 with over 500 compounds is now freely available at www.assaycentral.org.


Assuntos
COVID-19 , SARS-CoV-2 , Teorema de Bayes , Humanos , Aprendizado de Máquina , Simulação de Acoplamento Molecular
3.
J Med Chem ; 64(15): 11267-11287, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34288674

RESUMO

Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease-Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki* = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.


Assuntos
Aldeídos/química , COVID-19/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Inibidores de Cisteína Proteinase/uso terapêutico , SARS-CoV-2/enzimologia , Trypanosoma cruzi/enzimologia , Aldeídos/metabolismo , Aldeídos/farmacologia , Catepsina L/antagonistas & inibidores , Catepsina L/metabolismo , Cisteína Endopeptidases/metabolismo , Cisteína Proteases/metabolismo , Inibidores de Cisteína Proteinase/química , Desenho de Fármacos , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , SARS-CoV-2/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
4.
Cancer Discov ; 10(11): 1722-1741, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32703768

RESUMO

Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo. Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies. SIGNIFICANCE: Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas.This article is highlighted in the In This Issue feature, p. 1611.

6.
Microorganisms ; 8(4)2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32224991

RESUMO

Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened 7680 compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified seven compounds of interest with potent in vitro activity against the parasite with a therapeutic index of 10 or greater, including the previously unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of new T. cruzi leads that can potentially move quickly to the clinic.

7.
J Med Chem ; 63(6): 3298-3316, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32125159

RESUMO

Cruzain, an essential cysteine protease of the parasitic protozoan, Trypanosoma cruzi, is an important drug target for Chagas disease. We describe here a new series of reversible but time-dependent inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl heterocycles meant to provide replacements for the irreversible reactive "warheads" of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine, and vinyl-2-(N-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (Ki* = 0.1-0.4 µM). These cruzain inhibitors exhibited moderate to excellent selectivity versus human cathepsins B, L, and S and showed no apparent toxicity to human cells but were effective in cell cultures of Trypanosoma brucei brucei (EC50 = 1-15 µM) and eliminated T. cruzi in infected murine cardiomyoblasts (EC50 = 5-8 µM). PVHIs represent a new class of cruzain inhibitors that could progress to viable candidate compounds to treat Chagas disease and human sleeping sickness.


Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Peptidomiméticos/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/farmacologia , Compostos de Vinila/farmacologia , Animais , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/metabolismo , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Cinética , Camundongos , Simulação de Acoplamento Molecular , Mioblastos Cardíacos/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Ligação Proteica , Proteínas de Protozoários/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Compostos de Vinila/síntese química , Compostos de Vinila/metabolismo
8.
Metabolites ; 10(3)2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32121389

RESUMO

Soil covers most of Earth's continental surface and is fundamental to life-sustaining processes such as agriculture. Given its rich biodiversity, soil is also a major source for natural product drug discovery from soil microorganisms. However, the study of the soil small molecule profile has been challenging due to the complexity and heterogeneity of this matrix. In this study, we implemented high-resolution liquid chromatography-tandem mass spectrometry and large-scale data analysis tools such as molecular networking to characterize the relative contributions of city, state and regional processes on backyard soil metabolite composition, in 188 soil samples collected from 14 USA States, representing five USA climate regions. We observed that region, state and city of collection all influence the overall soil metabolite profile. However, many metabolites were only detected in unique sites, indicating that uniquely local phenomena also influence the backyard soil environment, with both human-derived and naturally-produced (plant-derived, microbially-derived) metabolites identified. Overall, these findings are helping to define the processes that shape the backyard soil metabolite composition, while also highlighting the need for expanded metabolomic studies of this complex environment.

9.
ACS Med Chem Lett ; 11(3): 249-257, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32184953

RESUMO

Utilizing a target repurposing and parasite-hopping approach, we tested a previously reported library of compounds that were active against Trypanosoma brucei, plus 31 new compounds, against a variety of protozoan parasites including Trypanosoma cruzi, Leishmania major, Leishmania donovani, and Plasmodium falciparum. This led to the discovery of several compounds with submicromolar activities and improved physicochemical properties that are early leads toward the development of chemotherapeutic agents against kinetoplastid diseases and malaria.

10.
Cell Stem Cell ; 26(2): 187-204.e10, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31956038

RESUMO

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvß5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvß5 inhibition. Collectively, our studies identify integrin αvß5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.


Assuntos
Glioblastoma , Células-Tronco Neurais , Infecção por Zika virus , Zika virus , Humanos , Receptores de Vitronectina , Fatores de Transcrição SOXB1/genética
11.
J Med Chem ; 63(2): 470-489, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31549836

RESUMO

Zika virus is an emerging flavivirus that causes the neurodevelopmental congenital Zika syndrome and that has been linked to the neuroinflammatory Guillain-Barré syndrome. The absence of a vaccine or a clinically approved drug to treat the disease combined with the likelihood that another outbreak will occur in the future defines an unmet medical need. Several promising drug candidate molecules have been reported via repurposing studies, high-throughput compound library screening, and de novo design in the short span of a few years. Intense research activity in this area has occurred in response to the World Health Organization declaration of a Public Health Emergency of International Concern on February 1, 2016. In this Perspective, the authors review the emergence of Zika virus, the biology of its replication, targets for therapeutic intervention, target product profile, and current drug development initiatives.


Assuntos
Antivirais/uso terapêutico , Infecção por Zika virus/tratamento farmacológico , Zika virus/efeitos dos fármacos , Animais , Desenvolvimento de Medicamentos , Descoberta de Drogas , Humanos , Vacinas Virais , Infecção por Zika virus/patologia , Infecção por Zika virus/prevenção & controle
12.
Viruses ; 11(4)2019 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010044

RESUMO

Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a small library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2'-C-methyluridine and 2'-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate for the aryloxyl phosphoramidate ProTide group of 2'-C-methyluridine completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2'-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound's triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.


Assuntos
Antivirais/farmacologia , Células-Tronco Neurais/virologia , Nucleosídeos/análogos & derivados , Nucleosídeos/farmacologia , Zika virus/efeitos dos fármacos , Descoberta de Drogas , Humanos , Pró-Fármacos/farmacologia , Bibliotecas de Moléculas Pequenas
13.
J Exp Med ; 216(5): 1071-1090, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30948495

RESUMO

Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)-associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches.


Assuntos
Neoplasias Encefálicas/genética , Cromatina/genética , Glioblastoma/genética , Transcrição Genética/genética , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Carcinogênese/genética , Linhagem Celular Tumoral , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/cirurgia , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neurais/metabolismo , Fatores de Transcrição/genética , Transcriptoma
14.
Viruses ; 11(4)2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974762

RESUMO

Zika virus (ZIKV), which is associated with microcephaly in infants and Guillain-Barré syndrome, reemerged as a serious public health threat in Latin America in recent years. Previous high-throughput screening (HTS) campaigns have revealed several potential hit molecules against ZIKV, including methotrexate (MTX), which is clinically used as an anti-cancer chemotherapy and anti-rheumatoid agent. We studied the mechanism of action of MTX against ZIKV in relation to its inhibition of dihydrofolate reductase (DHFR) in vitro using Vero and human neural stem cells (hNSCs). As expected, an antiviral effect for MTX against ZIKV was observed, showing up to 10-fold decrease in virus titer during MTX treatment. We also observed that addition of leucovorin (a downstream metabolite of DHFR pathway) rescued the ZIKV replication impaired by MTX treatment in ZIKV-infected cells, explaining the antiviral effect of MTX through inhibition of DHFR. We also found that addition of adenosine to ZIKV-infected cells was able to rescue ZIKV replication inhibited by MTX, suggesting that restriction of de novo synthesis adenosine triphosphate (ATP) pools suppresses viral replication. These results confirm that the DHFR pathway can be targeted to inhibit replication of ZIKV, similar to other published results showing this effect in related flaviviruses.


Assuntos
Antivirais/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Metotrexato/farmacologia , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Zika virus/crescimento & desenvolvimento , Adenosina/metabolismo , Animais , Células Cultivadas , Humanos , Leucovorina/metabolismo , Células-Tronco Neurais , Carga Viral
15.
J Med Chem ; 62(7): 3171-3183, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30418766

RESUMO

Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDAC inhibitor. In this perspective, the authors review the majority of reported kinase/HDAC hybrid inhibitors.


Assuntos
Histona Desacetilases/química , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Sítios de Ligação , Domínio Catalítico , Desenho de Fármacos , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/metabolismo , Cloridrato de Erlotinib/uso terapêutico , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-30061280

RESUMO

Zika virus (ZIKV) has been linked to the development of microcephaly in newborns, as well as Guillain-Barré syndrome. There are currently no drugs available to treat ZIKV infection, and accordingly, there is an unmet medical need for the discovery of new therapies. High-throughput drug screening efforts focusing on indirect readouts of cell viability are prone to a higher frequency of false positives in cases where the virus is viable in the cell but the cytopathic effect (CPE) is reduced or delayed. Here, we describe a fast and label-free phenotypic high-content imaging assay to detect cells affected by the virus-induced CPE using automated imaging and analysis. Protection from the CPE correlates with a decrease in viral antigen production, as observed by immunofluorescence. We trained our assay using a collection of nucleoside analogues with activity against ZIKV; the previously reported antiviral activities of 2'-C-methylribonucleosides and ribavirin against the Zika virus in Vero cells were confirmed using our developed method. To validate the ability of our assay to reveal new anti-ZIKV compounds, we profiled a novel library of 24 natural product derivatives and found compound 1 to be an inhibitor of the ZIKV-induced cytopathic effect; the activity of the compound was confirmed in human fetal neural stem cells (NSCs). The described technique can be easily leveraged as a primary screening assay for profiling of the activities of large compound libraries against ZIKV and can be expanded to other ZIKV strains and other cell lines displaying morphological changes upon ZIKV infection.


Assuntos
Antivirais/farmacologia , Zika virus/efeitos dos fármacos , Animais , Antivirais/química , Chlorocebus aethiops , Espectroscopia de Ressonância Magnética , Células Vero , Infecção por Zika virus/virologia
17.
PLoS Negl Trop Dis ; 12(8): e0006512, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30138453

RESUMO

Cysteine proteases (CPs) play key roles in the pathogenesis of protozoan parasites, including cell/tissue penetration, hydrolysis of host or parasite proteins, autophagy, and evasion or modulation of the host immune response, making them attractive chemotherapeutic and vaccine targets. This review highlights current knowledge on clan CA cysteine proteases, the best-characterized group of cysteine proteases, from 7 protozoan organisms causing human diseases with significant impact: Entamoeba histolytica, Leishmania species (sp.), Trypanosoma brucei, T. cruzi, Cryptosporidium sp., Plasmodium sp., and Toxoplasma gondii. Clan CA proteases from three organisms (T. brucei, T. cruzi, and Plasmodium sp.) are well characterized as druggable targets based on in vitro and in vivo models. A number of candidate inhibitors are under development. CPs from these organisms and from other protozoan parasites should be further characterized to improve our understanding of their biological functions and identify novel targets for chemotherapy.


Assuntos
Cisteína Proteases/metabolismo , Eucariotos/enzimologia , Parasitos/metabolismo , Animais , Humanos , Proteínas de Protozoários/metabolismo
18.
Bioorg Med Chem ; 26(8): 1713-1726, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29478802

RESUMO

Reverse transcriptase (RT) is responsible for replicating the HIV-1 genome and is a validated therapeutic target for the treatment of HIV infections. During each cycle of the RT-catalyzed DNA polymerization process, inorganic pyrophosphate is released as the by-product of nucleotide incorporation. Small molecules were identified that act as bioisosteres of pyrophosphate and can selectively freeze the catalytic cycle of HIV-1 RT at the pre-translocated stage of the DNA- or RNA-template-primer-enzyme complex.


Assuntos
Difosfatos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Biocatálise , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Difosfatos/síntese química , Difosfatos/química , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
19.
Anal Chem ; 89(19): 10414-10421, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28892370

RESUMO

Trypanosoma cruzi parasites are the causative agents of Chagas disease, a leading infectious form of heart failure whose pathogenesis is still not fully characterized. In this work, we applied untargeted liquid chromatography-tandem mass spectrometry to heart sections from T. cruzi-infected and uninfected mice. We combined molecular networking and three-dimensional modeling to generate chemical cartographical heart models. This approach revealed for the first time preferential parasite localization to the base of the heart and regiospecific distributions of nucleoside derivatives and eicosanoids, which we correlated to tissue-damaging immune responses. We further detected novel cardiac chemical signatures related to the severity and ultimate outcome of the infection. These signatures included differential representation of higher- vs lower-molecular-weight carnitine and phosphatidylcholine family members in specific cardiac regions of mice infected with lethal or nonlethal T. cruzi strains and doses. Overall, this work provides new insights into Chagas disease pathogenesis and presents an analytical chemistry approach that can be broadly applied to the study of host-microbe interactions.


Assuntos
Coração/parasitologia , Miocárdio/química , Espectrometria de Massas em Tandem , Trypanosoma cruzi/patogenicidade , Animais , Área Sob a Curva , Carnitina/química , Carnitina/metabolismo , Doença de Chagas/diagnóstico , Doença de Chagas/parasitologia , Doença de Chagas/veterinária , Cromatografia Líquida de Alta Pressão , Eicosanoides/química , Eicosanoides/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Miocárdio/patologia , Nucleosídeos/análogos & derivados , Nucleosídeos/metabolismo , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Análise de Componente Principal , Curva ROC
20.
AIDS ; 31(11): 1519-1528, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28657962

RESUMO

BACKGROUND: Cytomegalovirus (CMV) is a common HIV-1 copathogen. Since CMV infection is an important contributor to immune activation, the driving force of HIV disease, an anti-CMV strategy might be beneficial to HIV-infected patients. Shin et al. (J Acquir Immune Defic Syndr 2014; 65:251-258) reported that anti-CMV therapy with valganciclovir in coinfected individuals results in a decrease of HIV viral load that is not accompanied by a decrease of immune activation. This suggests an alternative mechanism for HIV inhibition other than suppression of CMV-mediated inflammation. METHOD: We evaluated the anti-HIV activity of ganciclovir (GCV), the active form of valganciclovir, on HIV replication in human tissues ex vivo. RESULTS: We show that GCV has a direct suppressive activity on HIV replication in human tissues ex vivo, including laboratory strains, drug-resistant and primate HIV-1 isolates. We deciphered the mechanism of this inhibition and showed that GCV-TP is incorporated in the nascent DNA chain and acts as a delayed chain terminator. CONCLUSION: Our results suggest that anti-CMV strategy using valganciclovir in HIV-1-infected individuals may reduce HIV-1 viral load not only indirectly by decreasing CMV-mediated immune activation but also directly by inhibiting HIV-1 reverse transcriptase.


Assuntos
Antivirais/farmacologia , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/efeitos dos fármacos , Ganciclovir/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Área Sob a Curva , Linfócitos T CD4-Positivos , Colo do Útero/patologia , Colo do Útero/virologia , Coinfecção , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Feminino , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Técnicas In Vitro , Ativação Linfocitária/efeitos dos fármacos , Tonsila Palatina/patologia , Tonsila Palatina/virologia , Vagina/patologia , Vagina/virologia , Carga Viral
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