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1.
Int J Immunopathol Pharmacol ; 38: 3946320241274255, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39122243

RESUMO

OBJECTIVES: Human endogenous retroviruses (HERVs) are integral components of the human genome, and their reactivation has been implicated in the pathogenesis of some malignancies. External viral co-infections are suspected to play a role in HERV transactivation. This study aimed to investigate the expression of HERV-K np9 elements and HERV-R env gene in pediatric acute lymphoblastic leukemia (ALL) patients. Additionally, we explored potential correlations between HERV expression and common viral infections prevalent in this group of patients. METHODS: Blood samples were collected from 43 pediatric ALL patients and 48 age- and sex-matched healthy controls. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of HERV-K np9 and HERV-R env, along with herpes simplex virus (HSV), parvovirus B19, and polyomavirus BK. RESULTS: HERV-K np9 and HERV-R env showed significantly higher expression in the peripheral blood of ALL patients compared to healthy controls (p < .001 and p = .003, respectively). HSV positivity was associated with significantly increased HERV-K np9 expression. No significant correlations were observed between other investigated viruses and HERV gene expression. CONCLUSION: The overexpression of HERV-K np9 and HERV-R env in pediatric ALL patients suggest their potential role in leukemogenesis. Our findings also suggest a possible link between HSV infection and HERV reactivation in this population. Future investigations are needed to understand the precise roles of these genes and viral infections in the development of ALL.


Assuntos
Retrovirus Endógenos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Retrovirus Endógenos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Masculino , Feminino , Criança , Pré-Escolar , Produtos do Gene env/genética , Produtos do Gene env/metabolismo , Adolescente , Estudos de Casos e Controles
2.
Curr Opin Virol ; 60: 101325, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37075577

RESUMO

Cytomegalovirus (CMV) is a ubiquitous herpesvirus that has a profound impact on the host immune system. Congenital cytomegalovirus (cCMV) infection modulates neonatal immune cell compartments, yet the full impact of in utero exposure on developing fetal immune cells remains poorly characterized. A series of recent studies have identified a potential link between cCMV infection and the development of acute lymphoblastic leukemia (ALL) in childhood. Here, we review the emerging evidence linking CMV and ALL risk, discuss what is known about the causes of childhood ALL, and propose how CMV infection in early life may confer increased ALL risk.


Assuntos
Infecções por Citomegalovirus , Leucemia-Linfoma Linfoblástico de Células Precursoras , Infecções por Citomegalovirus/congênito , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Humanos , Criança , Fatores de Risco , Recém-Nascido , Imunomodulação
4.
J Pediatr Hematol Oncol ; 44(2): e537-e538, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33885040

RESUMO

Patients with hemato-oncologic diseases are particularly vulnerable to severe infections. Adult patients with blood cancers infected with SARS-CoV-2 had poorer treatment outcomes and higher mortality than patients with COVID-19 without burden. However, in pediatric patients with hemato-oncologic diseases the course of COVID-19 is milder than in adults in the same group of patients. In this report, we describe the case of our patient with acute lymphoblastic leukemia infected with SARS-CoV-2 and treated with remdesivir. We also review the existing literature of pediatric patients who have been diagnosed with both hemato-oncologic diseases and COVID-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , SARS-CoV-2/isolamento & purificação , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , COVID-19/complicações , COVID-19/virologia , Criança , Feminino , Humanos , Recidiva Local de Neoplasia/virologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Prognóstico
5.
J Pediatr Hematol Oncol ; 44(2): e543-e545, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34133380

RESUMO

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus-2. Patients with hematologic malignancies have been shown to have higher risk of mortality due to COVID-19 than reported in the general adult population. Reports on acute lymphoblastic leukemia and COVID in children are scarce. We present a case of an 11-year-old male patient undergoing treatment for B-cell acute lymphoblastic leukemia with an atypical course of COVID-19. The patient received a positive result of the syndrome coronavirus-2 polymerase chain reaction test performed due to epidemiologic reasons. The chemotherapy was continued since the patient had no clinical signs of COVID-19. The disease started with intensive gastrointestinal bleeding, followed by severe respiratory tract infection over 2 weeks later.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , COVID-19/complicações , Hemorragia Gastrointestinal/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , SARS-CoV-2/isolamento & purificação , COVID-19/transmissão , COVID-19/virologia , Criança , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Prognóstico
6.
J Clin Invest ; 131(23)2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34609969

RESUMO

The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN's receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host-cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long-term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.


Assuntos
Hospedeiro Imunocomprometido , Pneumopatias/virologia , Pulmão/virologia , Vírus da Parainfluenza 3 Humana/metabolismo , Infecções por Paramyxoviridae/virologia , Adulto , Sítios de Ligação , Análise Mutacional de DNA , Feminino , Frequência do Gene , Doença Enxerto-Hospedeiro/tratamento farmacológico , Células HEK293 , Humanos , Leucemia Mieloide Aguda , Mutação , Ácido Micofenólico/administração & dosagem , Ácido N-Acetilneuramínico/química , Vírus da Parainfluenza 3 Humana/genética , Infecções por Paramyxoviridae/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Receptores Virais/metabolismo , Sirolimo/administração & dosagem , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/metabolismo , Internalização do Vírus , Adulto Jovem
7.
Pediatr Blood Cancer ; 68(10): e29194, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34251092

RESUMO

Acute lymphoblastic leukaemia (ALL) is the most common type of leukaemia diagnosed in children. The prevailing hypothesis regarding pathogenesis of childhood ALL was developed by Greaves, and states that ALL is caused by an abnormal immune response to a common infection. The response arises either due to naivety of the immune system caused by a lack of common childhood infections, or genetic susceptibility due to specific alleles. The former explanation is known as the delayed infection hypothesis. COVID-19 is a new infection that no children in the UK were exposed to prior to 2020. Furthermore, the lockdown measures designed to prevent spread of this virus have also greatly reduced spread of other common infections. It is therefore important to examine the evidence for this hypothesis, and to consider it in the context of the pandemic to determine what effect lockdown measures may have on incidence of ALL in children.


Assuntos
COVID-19/complicações , Controle de Doenças Transmissíveis/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , SARS-CoV-2/isolamento & purificação , COVID-19/transmissão , COVID-19/virologia , Criança , Humanos , Incidência , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Fatores de Risco , Reino Unido/epidemiologia
8.
EBioMedicine ; 67: 103355, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33915337

RESUMO

BACKGROUND: There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses. METHODS: We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape. FINDINGS: We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape. INTERPRETATION: Our results highlight the potential need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered.


Assuntos
COVID-19/imunologia , Evasão da Resposta Imune , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , SARS-CoV-2/genética , COVID-19/virologia , Pré-Escolar , Evolução Molecular , Feminino , Genoma Viral , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunidade Humoral , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/imunologia , Análise de Sequência de RNA , Sequenciamento Completo do Genoma , Adulto Jovem
10.
PLoS Pathog ; 17(1): e1009190, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476323

RESUMO

Gag polymerization with viral RNA at the plasma membrane initiates HIV-1 assembly. Assembly processes are inefficient in vitro but are stimulated by inositol (1,3,4,5,6) pentakisphosphate (IP5) and inositol hexakisphosphate (IP6) metabolites. Previous studies have shown that depletion of these inositol phosphate species from HEK293T cells reduced HIV-1 particle production but did not alter the infectivity of the resulting progeny virions. Moreover, HIV-1 substitutions bearing Gag/CA mutations ablating IP6 binding are noninfectious with destabilized viral cores. In this study, we analyzed the effects of cellular depletion of IP5 and IP6 on HIV-1 replication in T cells in which we disrupted the genes encoding the kinases required for IP6 generation, IP5 2-kinase (IPPK) and Inositol Polyphosphate Multikinase (IPMK). Knockout (KO) of IPPK from CEM and MT-4 cells depleted cellular IP6 in both T cell lines, and IPMK disruption reduced the levels of both IP5 and IP6. In the KO lines, HIV-1 spread was delayed relative to parental wild-type (WT) cells and was rescued by complementation. Virus release was decreased in all IPPK or IPMK KO lines relative to WT cells. Infected IPMK KO cells exhibited elevated levels of intracellular Gag protein, indicative of impaired particle assembly. IPMK KO compromised virus production to a greater extent than IPPK KO suggesting that IP5 promotes HIV-1 particle assembly in IPPK KO cells. HIV-1 particles released from infected IPPK or IPMK KO cells were less infectious than those from WT cells. These viruses exhibited partially cleaved Gag proteins, decreased virion-associated p24, and higher frequencies of aberrant particles, indicative of a maturation defect. Our data demonstrate that IP6 enhances the quantity and quality of virions produced from T cells, thereby preventing defects in HIV-1 replication.


Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/virologia , HIV-1/fisiologia , Fosfatos de Inositol/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Montagem de Vírus , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Produtos do Gene gag/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Tumorais Cultivadas , Vírion/fisiologia
11.
Pediatr Transplant ; 25(5): e13875, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32949079

RESUMO

Respiratory viral infections are known causes of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we report a unique case of a child with viral pneumonia caused by coinfection with human metapneumovirus (MPV), respiratory syncytial virus (RSV), and SARS-CoV-2 after HSCT. A 9-year-old girl with acute lymphoblastic leukemia underwent allogeneic HSCT from a matched, unrelated donor. During the post-transplant period, in profound leukopenia (below 10 leukocytes/µL), she was diagnosed with SARS-CoV-2, MPV, and RSV pneumonia and was treated with ribavirin and chloroquine. Before leukocyte recovery, the girl became asymptomatic, and SARS-CoV-2 and RSV clearance was achieved. The shedding of SARS-CoV-2 stopped before immune system recovery, and one may hypothesize that the lack of an inflammatory response might have been a contributing factor to the mild clinical course. Post-transplant care in HSCT recipients with COVID-19 infection is feasible in regular transplant units, provided the patient does not present with respiratory failure. Early and repeated testing for SARS-CoV-2 in post-transplant patients with concomitant infection mitigation strategies should be considered in children after HSCT who develop fever, respiratory symptoms, and perhaps gastrointestinal symptoms to control the spread of COVID-19 both in patients and in healthcare workers in hospital environments. Training of staff and the availability of personal protective equipment are crucial for containing SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , SARS-CoV-2 , Anemia Aplástica/patologia , Medula Óssea/patologia , COVID-19/complicações , Criança , Feminino , Humanos , Metapneumovirus , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Período Pós-Operatório , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/terapia , Vírus Sinciciais Respiratórios , Ribavirina/uso terapêutico , Transplante Homólogo , Tratamento Farmacológico da COVID-19
12.
Med Microbiol Immunol ; 209(6): 693-703, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32995957

RESUMO

Microbial translocation (MT) and altered gut microbiota have been described in acute leukemic patients and contribute to immune activation and inflammation. However, phage translocation has not been investigated in leukemia patients yet. We recruited 44 leukemic patients and 52 healthy adults and quantified the levels of 3 phages in peripheral blood, which were the most positive phages screened from fecal samples. The content of 16S rRNA in plasma was detected by qPCR to assess the intestinal mucosa of these patients. Spearman's rank correlation was used to analyze the relationship between phage load and the relevant clinical data. We found the most prevalent phages in fecal samples were λ phage, Wphi phage, and P22 phage, and λ phage had the highest detection rate in plasma (68%). Phage content was affected by chemotherapy and course of disease and correlated with the levels of CRP (r = 0.43, p = 0.003), sCD14 (r = 0.37, p = 0.014), and sCD163 (r = 0.44, p = 0.003). Our data indicate that plasma phage load is a promising marker for gut barrier damage and that gut phage translocation correlates with monocyte/macrophage activation and systemic inflammatory response in leukemic patients.


Assuntos
Translocação Bacteriana , Bacteriófagos/isolamento & purificação , Microbioma Gastrointestinal , Mucosa Intestinal/efeitos dos fármacos , Leucemia Mieloide Aguda/sangue , RNA Bacteriano/sangue , RNA Ribossômico 16S/sangue , Viremia/diagnóstico , Adulto , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Proteína C-Reativa/análise , Feminino , Humanos , Mucosa Intestinal/microbiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/microbiologia , Leucemia Mieloide Aguda/virologia , Receptores de Lipopolissacarídeos/sangue , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Permeabilidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Receptores de Superfície Celular/sangue , Viremia/etiologia
13.
PLoS Pathog ; 16(9): e1008813, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925973

RESUMO

HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Glicoproteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Polimorfismo Genético , Replicação Viral , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Infecções por HIV/genética , Infecções por HIV/metabolismo , Soropositividade para HIV , Interações Hospedeiro-Patógeno , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Células Tumorais Cultivadas , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
14.
Br J Haematol ; 190(5): e274-e276, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32652563
18.
Int J Mol Sci ; 22(1)2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33396968

RESUMO

Despite the world's combined efforts, human immunodeficiency virus (HIV), the causative agent of AIDS, remains one of the world's most serious public health challenges. High genetic variability of HIV complicates the development of anti-HIV vaccine, and there is an actual clinical need for increasing the efficiency of anti-HIV drugs in terms of targeted delivery and controlled release. Tenofovir (TFV), a nucleotide-analog reverse transcriptase inhibitor, has gained wide acceptance as a drug for pre-exposure prophylaxis or treatment of HIV infection. In our study, we explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) (mPEG-b-PEPA) as candidates for developing a long-acting/controlled-release formulation of TFV. Two types of mPEG-b-PEPA with numbers of ethylene phosphoric acid (EPA) fragments of 13 and 49 were synthesized by catalytic ring-opening polymerization, and used for preparing four types of adducts with TFD. Antiviral activity of [mPEG-b-PEPA]TFD or tenofovir disoproxil fumarate (TDF) was evaluated using the model of experimental HIV infection in vitro (MT-4/HIV-1IIIB). Judging by the values of the selectivity index (SI), TFD exhibited an up to 14-fold higher anti-HIV activity in the form of mPEG-b-PEPA adducts, thus demonstrating significant promise for further development of long-acting/controlled-release injectable TFV formulations.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Polímeros/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tenofovir/administração & dosagem , Fármacos Anti-HIV/farmacologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Ácidos Fosfóricos/química , Polietileno/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Tenofovir/farmacologia , Células Tumorais Cultivadas
19.
J Cell Biochem ; 121(4): 2811-2817, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31696995

RESUMO

Hepatitis C virus (HCV) infection is a major public health problem, having a high prevalence in Egypt. Leukemia and lymphoma have been associated with HCV infection. MicroRNA-155 (miR-155) has been reported to play a regulatory role in cancer, inflammation, and immune response to infection. The expression level of miR-155 in HCV viremic patients is controversial; although high miR-155 levels were demonstrated in HCV genotypes 1,2, and 3, low levels of miR-155 were detected in Egyptian patients with HCV genotype 4. Several studies have investigated the correlation between the levels of miRNA-155 and the replication of HCV, others have evaluated miRNA-155 as a prognostic biomarker in different types of cancer. No studies have investigated the impact of miRNA-155 knockdown on HCV pediatric patients associated with childhood acute lymphoblastic leukemia (ALL). We knocked-out the miR_155a in cultured polymorphonuclear cells (PBMCs) obtained from 60 children with ALL; 30 were associated with HCV-4 infection and 30 were HCV negative. The miR_155a, HCV viral load, and cell proliferation werre assessed in treated and untreated cells using TaqMan assay quantitative polymerase chain reaction. We found that miRNA-155 was significantly upregulated by seven folds in the HCV-4 associated ALL group; while being linked to high HCV viral load and leukemic burden, miR_155a knock-out can improve the disease outcome. We conclude that miR-155 is a critical miRNA that is considered a therapeutic target in pediatric HCV leukemic patients.


Assuntos
Hepatite C/metabolismo , Hepatite C/virologia , MicroRNAs/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Proliferação de Células , Criança , Egito , Perfilação da Expressão Gênica , Genótipo , Hepacivirus , Humanos , Imunofenotipagem , Neutrófilos/metabolismo , Prognóstico , Carga Viral
20.
J Med Chem ; 62(24): 11430-11436, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31714780

RESUMO

A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 exhibited an improved water solubility of 5.6 µg/mL compared with ETR (≪1 µg/mL), better stability in human and rat liver microsomes, and a great oral bioavailability of 44%, making it promising as a drug candidate. In addition, no apparent toxicity was observed in the acute toxicity assay (2 g/kg) and HE staining.


Assuntos
Fármacos Anti-HIV/farmacologia , Apoptose/efeitos dos fármacos , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Microssomos Hepáticos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Feminino , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Ligantes , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Ratos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Replicação Viral/efeitos dos fármacos
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