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[PMID]:29480838
[Au] Autor:Cheng Y; Nickman NA; Jamjian C; Stevens V; Zhang Y; Sauer B; LaFleur J
[Ad] Endereço:Biomedical Informatics Center, George Washington University, Washington, DC.
[Ti] Título:Predicting poor adherence to antiretroviral therapy among treatment-naïve veterans infected with human immunodeficiency virus.
[So] Source:Medicine (Baltimore);97(2):e9495, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies suggested that human immunodeficiency virus (HIV) infected patients at risk of poor adherence were not distinguishable only based on the baseline characteristics. This study is to identify patient characteristics that would be consistently associated with poor adherence across regimens and to understand the associations between initial and long-term adherence. HIV treatment-naïve patients initiated on protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or integrase strand transfer inhibitors were identified from the Veteran Health Administration system. Initial adherence measured as initial coverage ratio (ICR) and long-term adherence measured as thereafter 1-year proportion days covered (PDC) of base agent and complete regimen were estimated for each patient. The patients most likely to exhibit poor adherence were African-American, with lower socioeconomic status, and healthier. The initial coverage ratio of base agent and complete regimen were highly correlated, but the correlations between ICR and thereafter 1-year PDC were low. However, including initial adherence as a predictor in predictive model would substantially increase predictive accuracy of future adherence.
[Mh] Termos MeSH primário: Infecções por HIV/tratamento farmacológico
Inibidores de Integrase de HIV/uso terapêutico
Adesão à Medicação
Inibidores de Proteases/uso terapêutico
Inibidores da Transcriptase Reversa/uso terapêutico
[Mh] Termos MeSH secundário: Análise de Variância
Feminino
Infecções por HIV/diagnóstico
Infecções por HIV/epidemiologia
Integrase de HIV
Nível de Saúde
Seres Humanos
Modelos Logísticos
Masculino
Meia-Idade
Prognóstico
Estudos Retrospectivos
Fatores de Risco
Fatores Socioeconômicos
Estados Unidos
United States Department of Veterans Affairs
Veteranos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Protease Inhibitors); 0 (Reverse Transcriptase Inhibitors); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180227
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009495


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[PMID]:29199485
[Au] Autor:de Miguel R; Montejano R; Stella-Ascariz N; Arribas JR
[Ad] Endereço:a HIV Unit, Internal Medicine Service , Hospital Universitario La Paz-IdiPAZ , Madrid , Spain.
[Ti] Título:A safety evaluation of raltegravir for the treatment of HIV.
[So] Source:Expert Opin Drug Saf;17(2):217-223, 2018 Feb.
[Is] ISSN:1744-764X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Raltegravir (RAL) was the first commercialized agent from a new drug class with an innovative target, the integrase. Since its introduction in clinical practice RAL has become widely used for the treatment of HIV-1 infected patients. A decade after its approval, this article reviews key evidence from RAL with a special interest on safety outcomes. Areas covered: Pharmacologic, safety and efficacy data of RAL from clinical trials and post-commercialization published reports are hereby summarized after a literature review including PubMed search, relating proceedings and abstracts from relevant international HIV conferences, assessment reports from European and United States regulatory agencies and treatment guidelines (World Health Organization, United States Department of Health and Human Services and European AIDS Clinical Society), up to October 2017. Most frequent search terms were 'raltegravir', 'safety', 'adverse events', 'efficacy' and 'integrase-inhibitors'. Expert opinion: Despite the arrival of new integrase strand transfer inhibitors (INSTIs) with advantages in terms of dosing convenience (elvitegravir, ELV) and higher genetic barrier (dolutegravir, DTG), RAL has stood the test of time and its overall favourable safety profile, without significant appearance of unexpected adverse events, vouch for its relevance in the antiretroviral armamentarium.
[Mh] Termos MeSH primário: Infecções por HIV/tratamento farmacológico
Inibidores de Integrase de HIV/administração & dosagem
Raltegravir Potássico/administração & dosagem
[Mh] Termos MeSH secundário: Integrase de HIV/efeitos dos fármacos
Inibidores de Integrase de HIV/efeitos adversos
Seres Humanos
Raltegravir Potássico/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 43Y000U234 (Raltegravir Potassium); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1080/14740338.2018.1411903


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[PMID]:29054407
[Au] Autor:Wang Z; Hou X; Wang Y; Xu A; Cao W; Liao M; Zhang R; Tang J
[Ad] Endereço:College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China.
[Ti] Título:Ubiquitination of non-lysine residues in the retroviral integrase.
[So] Source:Biochem Biophys Res Commun;494(1-2):57-62, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Retroviral integrase catalyzes the integration of retroviral genome into host chromosomal DNA, which is a prerequisite of effective viral replication and infection. The human immunodeficiency virus type 1 (HIV-1) integrase has previously been reported to be regulated by the ubiquitination, but the molecular characterization of integrase ubiquitination is still unclear. In this study, we analyzed the ubiquitination of avian leukosis virus (ALV) integrase in detail. The ubiquitination assay showed that, like HIV-1, ALV integrase could also be modified by ubiquitination when expressed in 293 T and DF-1 cells. Domain mapping analysis revealed that the ubiquitination of ALV integrase might mainly occurred in the catalytic core and the N-terminal zinc-binding domains. Both lysine and non-lysine residues within integrase of ALV and HIV-1 were responsible for the ubiquitin conjugation, and the N-terminal HHCC zinc-binding motif might play an important role in mediating integrase ubiquitination. Interestingly, mass spectrometry analysis identified the Thr10 and Cys37 residues in the HHCC zinc-binding motif as the ubiquitination sites, indicating that ubiquitin may be conjugated to ALV integrase through direct interaction with the non-lysine residues. These findings revealed the detailed features of retroviral integrase ubiquitination and found a novel mechanism of ubiquitination mediated by the non-lysine residues within the N-terminal zinc-binding domain of integrase.
[Mh] Termos MeSH primário: Vírus da Leucose Aviária/enzimologia
Integrase de HIV/química
Integrase de HIV/metabolismo
Integrases/química
Integrases/metabolismo
Proteínas dos Retroviridae/química
Proteínas dos Retroviridae/metabolismo
Retroviridae/enzimologia
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Sequência de Aminoácidos
Animais
Vírus da Leucose Aviária/genética
Vírus da Leucose Aviária/fisiologia
Linhagem Celular
Galinhas
Células HEK293
Integrase de HIV/genética
HIV-1/enzimologia
HIV-1/genética
HIV-1/fisiologia
Seres Humanos
Integrases/genética
Lisina/química
Mutagênese Sítio-Dirigida
Retroviridae/genética
Retroviridae/fisiologia
Proteínas dos Retroviridae/genética
Ubiquitinação
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Retroviridae Proteins); 0 (p31 integrase protein, Human immunodeficiency virus 1); EC 2.7.7.- (HIV Integrase); EC 2.7.7.- (Integrases); J41CSQ7QDS (Zinc); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171022
[St] Status:MEDLINE


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[PMID]:28837332
[Au] Autor:Wang Y; Lin HQ; Wang P; Hu JS; Ip TM; Yang LM; Zheng YT; Chi-Cheong Wan D
[Ad] Endereço:School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR, China.
[Ti] Título:Discovery of a Novel HIV-1 Integrase/p75 Interacting Inhibitor by Docking Screening, Biochemical Assay, and in Vitro Studies.
[So] Source:J Chem Inf Model;57(9):2336-2343, 2017 Sep 25.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein-protein interaction between lens epithelium-derived growth factor (LEDGF/p75) and HIV-1 integrase becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. These small molecules are termed as LEDGINs; and several newly identified LEDGINs have been reported to significantly reduce HIV-1 replication. Through this project, we have finished the docking screening of the Maybridge database against the p75 binding site of HIV-1 integrase using both DOCK and Autodock Vina software. Finally, we have successfully identified a novel scaffold LEDGINs inhibitor DW-D-5. Its antiviral activities and anticatalytic activity of HIV-1 integrase are similar to other LEDGINs under development. We demonstrated that the combination of DW-D-5 and FDA approved anti-HIV drugs resulted in additive inhibitory effects on HIV-1 replication, indicating that DW-D-5 could be an important component of combination pills for clinic use in HIV treatment.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Avaliação Pré-Clínica de Medicamentos/métodos
Integrase de HIV/metabolismo
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/metabolismo
Biocatálise
Linhagem Celular
Integrase de HIV/química
HIV-1/efeitos dos fármacos
HIV-1/metabolismo
HIV-1/fisiologia
Peptídeos e Proteínas de Sinalização Intercelular/química
Simulação de Acoplamento Molecular
Ligação Proteica
Conformação Proteica
Software
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Intercellular Signaling Peptides and Proteins); 0 (lens epithelium-derived growth factor); 0 (p31 integrase protein, Human immunodeficiency virus 1); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170825
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00402


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[PMID]:28835492
[Au] Autor:Anstett K; Brenner B; Mesplède T; Wainberg MA
[Ad] Endereço:Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Canada.
[Ti] Título:HIV-1 Resistance to Dolutegravir Is Affected by Cellular Histone Acetyltransferase Activity.
[So] Source:J Virol;91(21), 2017 Nov 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretrovirals to be approved for the treatment of HIV infection. Canonical resistance to these competitive inhibitors develops through substitutions in the integrase active site that disrupt drug-protein interactions. However, resistance against the newest integrase inhibitor, dolutegravir (DTG), is associated with an R263K substitution at the C terminus of integrase that causes resistance through an unknown mechanism. The integrase C-terminal domain is involved in many processes over the course of infection and is posttranslationally modified via acetylation of three lysine residues that are important for enzyme activity, integrase multimerization, and protein-protein interactions. Here we report that regulation of the acetylation of integrase is integral to the replication of HIV in the presence of DTG and that the R263K mutation specifically disrupts this regulation, likely due to enhancement of interactions with the histone deacetylase I complex, as suggested by coimmunoprecipitation assays. Although no detectable differences in the levels of cell-free acetylation of the wild-type (WT) and mutated R263K enzymes were observed, the inhibition of cellular histone acetyltransferase enzymes sensitized the NL4.3 virus to DTG, while NL4.3 was almost completely unaffected. When levels of endogenous acetylation were manipulated in virus-producing cells, inhibitors of acetylation enhanced the replication of NL4.3 , whereas inhibition of deacetylation greatly diminished the replication of NL4.3 Taken together, these results point to a pivotal role of acetylation in the resistance mechanism of HIV to some second-generation integrase strand transfer inhibitors, such as DTG. This is, to our knowledge, the first report of the influence of posttranslational modifications on HIV drug resistance. Both viral replication and resistance to second-generation integrase strand transfer inhibitors of both WT and INSTI-resistant HIV strains were differentially affected by acetylation, likely as a result of altered interactions between integrase and the cellular deacetylation machinery. Many "shock and kill" strategies to eradicate HIV manipulate endogenous levels of acetylation in order to reactivate latent HIV. However, our results suggest that some drug-resistant viruses may differentially respond to such stimulation, which may complicate the attainment of this goal. Our future work will further illuminate the mechanisms involved.
[Mh] Termos MeSH primário: Farmacorresistência Viral
Infecções por HIV/tratamento farmacológico
Integrase de HIV/química
HIV-1/efeitos dos fármacos
Compostos Heterocíclicos com 3 Anéis/farmacologia
Histona Acetiltransferases/metabolismo
Replicação Viral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilação
Células Cultivadas
Infecções por HIV/virologia
Inibidores de Integrase de HIV/farmacologia
HIV-1/enzimologia
Histona Acetiltransferases/genética
Seres Humanos
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); DKO1W9H7M1 (dolutegravir); EC 2.3.1.48 (Histone Acetyltransferases); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170825
[St] Status:MEDLINE


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[PMID]:28791894
[Au] Autor:Weber IT; Harrison RW
[Ad] Endereço:Department of Biology, Georgia State University, PO Box 4010, Atlanta, GA 30302-4010, USA.
[Ti] Título:Decoding HIV resistance: from genotype to therapy.
[So] Source:Future Med Chem;9(13):1529-1538, 2017 Sep.
[Is] ISSN:1756-8927
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Genetic variation in HIV poses a major challenge for prevention and treatment of the AIDS pandemic. Resistance occurs by mutations in the target proteins that lower affinity for the drug or alter the protein dynamics, thereby enabling viral replication in the presence of the drug. Due to the prevalence of drug-resistant strains, monitoring the genotype of the infecting virus is recommended. Computational approaches for predicting resistance from genotype data and guiding therapy are discussed. Many prediction methods rely on rules derived from known resistance-associated mutations, however, statistical or machine learning can improve the classification accuracy and assess unknown mutations. Adding classifiers such as information on the atomic structure of the protein can further enhance the predictions.
[Mh] Termos MeSH primário: Farmacorresistência Viral/genética
HIV-1/genética
[Mh] Termos MeSH secundário: Antirretrovirais/uso terapêutico
Sítios de Ligação
Genótipo
Infecções por HIV/tratamento farmacológico
Infecções por HIV/genética
Integrase de HIV/química
Integrase de HIV/metabolismo
Protease de HIV/química
Protease de HIV/metabolismo
Transcriptase Reversa do HIV/antagonistas & inibidores
Transcriptase Reversa do HIV/metabolismo
Seres Humanos
Simulação de Dinâmica Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Retroviral Agents); EC 2.7.7.- (HIV Integrase); EC 2.7.7.49 (HIV Reverse Transcriptase); EC 3.4.23.- (HIV Protease)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.4155/fmc-2017-0048


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[PMID]:28737946
[Au] Autor:Zhao XZ; Smith SJ; Maskell DP; Métifiot M; Pye VE; Fesen K; Marchand C; Pommier Y; Cherepanov P; Hughes SH; Burke TR
[Ti] Título:Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors.
[So] Source:J Med Chem;60(17):7315-7332, 2017 Sep 14.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.
[Mh] Termos MeSH primário: Inibidores de Integrase de HIV/química
Inibidores de Integrase de HIV/farmacologia
Integrase de HIV/metabolismo
HIV-1/efeitos dos fármacos
Naftiridinas/química
Naftiridinas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Cristalografia por Raios X
Farmacorresistência Viral
Infecções por HIV/tratamento farmacológico
Infecções por HIV/virologia
Integrase de HIV/química
Integrase de HIV/genética
HIV-1/enzimologia
HIV-1/genética
HIV-1/fisiologia
Seres Humanos
Modelos Moleculares
Mutação
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Naphthyridines); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00596


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[PMID]:28615207
[Au] Autor:Madison MK; Lawson DQ; Elliott J; Ozantürk AN; Koneru PC; Townsend D; Errando M; Kvaratskhelia M; Kutluay SB
[Ad] Endereço:Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USA.
[Ti] Título:Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells.
[So] Source:J Virol;91(17), 2017 Sep 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent evidence indicates that inhibition of HIV-1 integrase (IN) binding to the viral RNA genome by allosteric integrase inhibitors (ALLINIs) or through mutations within IN yields aberrant particles in which the viral ribonucleoprotein complexes (vRNPs) are eccentrically localized outside the capsid lattice. These particles are noninfectious and are blocked at an early reverse transcription stage in target cells. However, the basis of this reverse transcription defect is unknown. Here, we show that the viral RNA genome and IN from ALLINI-treated virions are prematurely degraded in target cells, whereas reverse transcriptase remains active and stably associated with the capsid lattice. The aberrantly shaped cores in ALLINI-treated particles can efficiently saturate and be degraded by a restricting TRIM5 protein, indicating that they are still composed of capsid proteins arranged in a hexagonal lattice. Notably, the fates of viral core components follow a similar pattern in cells infected with eccentric particles generated by mutations within IN that inhibit its binding to the viral RNA genome. We propose that IN-RNA interactions allow packaging of both the viral RNA genome and IN within the protective capsid lattice to ensure subsequent reverse transcription and productive infection in target cells. Conversely, disruption of these interactions by ALLINIs or mutations in IN leads to premature degradation of both the viral RNA genome and IN, as well as the spatial separation of reverse transcriptase from the viral genome during early steps of infection. Recent evidence indicates that HIV-1 integrase (IN) plays a key role during particle maturation by binding to the viral RNA genome. Inhibition of IN-RNA interactions yields aberrant particles with the viral ribonucleoprotein complexes (vRNPs) eccentrically localized outside the conical capsid lattice. Although these particles contain all of the components necessary for reverse transcription, they are blocked at an early reverse transcription stage in target cells. To explain the basis of this defect, we tracked the fates of multiple viral components in infected cells. Here, we show that the viral RNA genome and IN in eccentric particles are prematurely degraded, whereas reverse transcriptase remains active and stably associated within the capsid lattice. We propose that IN-RNA interactions ensure the packaging of both vRNPs and IN within the protective capsid cores to facilitate subsequent reverse transcription and productive infection in target cells.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Proteínas de Transporte/metabolismo
Genoma Viral
Inibidores de Integrase de HIV/farmacologia
Integrase de HIV/metabolismo
Transcriptase Reversa do HIV/metabolismo
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Células HEK293
HIV-1/efeitos dos fármacos
HIV-1/genética
Seres Humanos
RNA Viral/genética
Montagem de Vírus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (HIV Integrase Inhibitors); 0 (RNA, Viral); 0 (TRIM5 protein, human); 0 (p31 integrase protein, Human immunodeficiency virus 1); EC 2.7.7.- (HIV Integrase); EC 2.7.7.49 (HIV Reverse Transcriptase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170903
[Lr] Data última revisão:
170903
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE


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[PMID]:28610923
[Au] Autor:George A; Raghavendra NK
[Ad] Endereço:Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, 502285, Telangana, India.
[Ti] Título:L368F/V408F double mutant of IBD of LEDGF/p75 retains interaction with M178I mutant of HIV-1 integrase.
[So] Source:Biochem Biophys Res Commun;490(2):271-275, 2017 Aug 19.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lens-epithelium-derived-growth factor (LEDGF/p75) is an essential host protein for integration of HIV-1 DNA into host genome. Earlier alanine scanning mutational analysis has revealed that residues I365, D366 and F406 in the integrase binding domain (IBD) of p75 are critical for interaction with HIV-1 integrase (IN), while K364, V408 have intermediate effect and residues N367, L368, R405, K407 show wild type binding with IN. To gain insight into contribution of side chains of L368 and V408 that are adjacent to critical residues I365 and F406, respectively, site directed mutation of these residues to Ile/Leu, Met and Phe has been performed and characterized in this study. In contrast to alanine substitution, L368F mutation showed a ∼25% decrease, while V408L and V408F showed wild type binding, to IN. Docking analysis of I365, D366 and F406 mutants of IBD with IN predicts that interaction between residue M178(IN) and I365(IBD) might lead to an encounter complex formation. Accordingly, M178I mutant of IN failed to interact with IBD. Interestingly, a L368F/V408F double mutant of IBD restored binding to M178I mutant of IN, indicating that altered hydrophobicity in the inter helical loops of IBD might make I365 more accessible for interaction with IN.
[Mh] Termos MeSH primário: Integrase de HIV/genética
Integrase de HIV/metabolismo
Peptídeos e Proteínas de Sinalização Intercelular/genética
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Mutação
[Mh] Termos MeSH secundário: Integrase de HIV/química
Peptídeos e Proteínas de Sinalização Intercelular/química
Ligação Proteica
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Intercellular Signaling Peptides and Proteins); 0 (lens epithelium-derived growth factor); 0 (p31 integrase protein, Human immunodeficiency virus 1); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE


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[PMID]:28478035
[Au] Autor:El Khoury L; Piquemal JP; Fermandjian S; Maroun RG; Gresh N; Hobaika Z
[Ad] Endereço:UR EGP, Centre d'Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, B.P. 11-514 Riad El Solh, Beirut 1107 2050, Lebanon; Laboratoire de Chimie Théorique, UMR7616 CNRS, UPMC, Sorbonne Universités, Paris 75005, France. Electronic address: lea.khoury4@net.usj.edu.lb.
[Ti] Título:The inhibition process of HIV-1 integrase by diketoacids molecules: Understanding the factors governing the better efficiency of dolutegravir.
[So] Source:Biochem Biophys Res Commun;488(3):433-438, 2017 Jul 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Human Immunodeficiency Virus-1 integrase is responsible for the covalent insertion of a newly synthesized double-stranded viral DNA into the host cells, and is an emerging target for antivirus drug design. Raltegravir (RAL) and elvitegravir (EVG) are the first two integrase strand transfer inhibitors used in therapy. However, treated patients eventually develop detrimental resistance mutations. By contrast, a recently approved drug, dolutegravir (DTG), presents a high barrier to resistance. This study aims to understand the increased efficiency of DTG upon focusing on its interaction properties with viral DNA. The results showed DTG to be involved in more extended interactions with viral DNA than EVG. Such interactions involve the halobenzene and scaffold of DTG and EVG and bases 5'G 3', 3'A 5'and 3'C 5'.
[Mh] Termos MeSH primário: Inibidores de Integrase de HIV/farmacologia
Integrase de HIV/metabolismo
Compostos Heterocíclicos com 3 Anéis/farmacologia
Cetoácidos/farmacologia
[Mh] Termos MeSH secundário: DNA Viral/efeitos dos fármacos
Relação Dose-Resposta a Droga
Polarização de Fluorescência
Inibidores de Integrase de HIV/química
Compostos Heterocíclicos com 3 Anéis/química
Cetoácidos/química
Modelos Moleculares
Conformação Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Viral); 0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); 0 (Keto Acids); 0 (p31 integrase protein, Human immunodeficiency virus 1); DKO1W9H7M1 (dolutegravir); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170508
[St] Status:MEDLINE



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