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[PMID]:29353724
[Au] Autor:Jin K; Yin H; De Clercq E; Pannecouque C; Meng G; Chen F
[Ad] Endereço:Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China.
[Ti] Título:Discovery of biphenyl-substituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1.
[So] Source:Eur J Med Chem;145:726-734, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of diarylpyrimidine (DAPY) derivatives bearing the biphenyl motif with multiple substituted groups was synthesized as human immunodeficiency virus (HIV)-1 non-nucleoside reverse transcriptase inhibitors. All of the target compounds were evaluated for their in vitro activity against HIV in MT-4 cells. Most of the compounds exhibited excellent activity with low nanomolar EC values against wild-type, single and double mutant HIV-1 strains. Compound 4b displayed an EC value of 1 nM against HIV-1 IIIB, 1.3 nM against L100I, 0.84 nM against K103 N, 1.5 nM against Y181C, 11 nM against Y188L, 2 nM against E138K, 10 nM against K103 N + Y181C, and almost 110 nM against F227L + V106. The improvement in the selectivity and potency of the target molecules against the wild-type and mutant HIV-1 strains validated our hypothesis. The biphenyl ring in the DAPY derivatives could strengthen the π-π stacking effect between the target molecule and the non-nucleoside inhibitor-binding pocket in the reverse transcriptase by extending the conjugating systems. This research represented a significant step toward the discovery of novel therapeutic DAPYs for treating acquired immunodeficiency syndrome in patients infected with HIV-1.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Compostos de Bifenilo/farmacologia
Transcriptase Reversa do HIV/antagonistas & inibidores
HIV-1/efeitos dos fármacos
Pirimidinas/farmacologia
Inibidores da Transcriptase Reversa/farmacologia
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/síntese química
Fármacos Anti-HIV/química
Compostos de Bifenilo/química
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Descoberta de Drogas
Transcriptase Reversa do HIV/metabolismo
HIV-1/genética
Seres Humanos
Testes de Sensibilidade Microbiana
Simulação de Acoplamento Molecular
Estrutura Molecular
Mutação
Pirimidinas/síntese química
Pirimidinas/química
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Biphenyl Compounds); 0 (Pyrimidines); 0 (Reverse Transcriptase Inhibitors); 2L9GJK6MGN (diphenyl); EC 2.7.7.49 (HIV Reverse Transcriptase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:29247893
[Au] Autor:Chaturonrutsamee S; Kuhakarn C; Surawatanawong P; Prabpai S; Kongsaeree P; Jaipetch T; Piyachaturawat P; Jariyawat S; Akkarawongsapat R; Suksen K; Limthongkul J; Napaswad C; Nuntasaen N; Reutrakul V
[Ad] Endereço:Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand; Research and Development Department, International Laboratories Corp., Ltd., Bang Phli, Samut Prakan 10540, Thailand.
[Ti] Título:Polycyclic polyprenylated acylphloroglucinols and biphenyl derivatives from the roots of Garcinia nuntasaenii Ngerns. & Suddee.
[So] Source:Phytochemistry;146:63-74, 2018 Feb.
[Is] ISSN:1873-3700
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Seven previously undescribed compounds, including three polycyclic polyprenylated acylphloroglucinols (garcinuntins A-C), three biphenyl derivatives (garcinuntabiphenyls A-C) and a lanostane triterpene (garcinuntine), along with thirteen known compounds were isolated from the root of Garcinia nuntasaenii Ngerns. & Suddee. Their structures were elucidated on the basis of spectroscopic techniques. For garcinuntins A-C, the absolute configurations were confirmed by the combination of single X-ray crystallography and ECD calculations. Anti-HIV activity using anti-HIV-1 reverse transcriptase and syncytium inhibition assays, and cytotoxic activity against a panel of cultured mammalian cancer cell lines of isolated compounds were investigated.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Antineoplásicos Fitogênicos/farmacologia
Compostos de Bifenilo/farmacologia
Garcinia/química
Transcriptase Reversa do HIV/antagonistas & inibidores
HIV-1/efeitos dos fármacos
Floroglucinol/farmacologia
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/química
Fármacos Anti-HIV/isolamento & purificação
Antineoplásicos Fitogênicos/química
Antineoplásicos Fitogênicos/isolamento & purificação
Compostos de Bifenilo/química
Compostos de Bifenilo/isolamento & purificação
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Células HEK293
Transcriptase Reversa do HIV/metabolismo
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Floroglucinol/análogos & derivados
Floroglucinol/isolamento & purificação
Raízes de Plantas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Antineoplastic Agents, Phytogenic); 0 (Biphenyl Compounds); 2L9GJK6MGN (diphenyl); DHD7FFG6YS (Phloroglucinol); EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1); EC 2.7.7.49 (HIV Reverse Transcriptase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180119
[Lr] Data última revisão:
180119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


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[PMID]:27777304
[Au] Autor:Li A; Gong S; Johnson KA
[Ad] Endereço:From the University of Texas at Austin, Institute for Cell and Molecular Biology, Department of Molecular Biosciences, Austin, Texas 78712.
[Ti] Título:Rate-limiting Pyrophosphate Release by HIV Reverse Transcriptase Improves Fidelity.
[So] Source:J Biol Chem;291(51):26554-26565, 2016 Dec 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous measurements of the rates of polymerization and pyrophosphate release with DNA templates showed that pyrophosphate (PP ) dissociation was fast after nucleotide incorporation so that it did not contribute to enzyme specificity (k /K ). Here, kinetic parameters governing nucleotide incorporation and PP release were determined using an RNA template. Compared with a DNA template of the same sequence, the rate of chemistry increased by up to 10-fold (250 versus 24 s ), whereas the rate of PP release decreased to approximately 58 s so that PP release became the rate-limiting step. During processive nucleotide incorporation, the first nucleotide (TTP) was incorporated at a fast rate (152 s ), whereas the rates of incorporation of remaining nucleotides (CGTCG) were much slower with an average rate of 24 s , suggesting that sequential incorporation events were limited by the relatively slow PP release step. The accompanying paper shows that slow PP release allows polymerization and RNase H to occur at comparable rates. Although PP release is the rate-determining step, it is not the specificity-determining step for correct incorporation based on our current estimates of the rate of reversal of the chemistry step (3 s ). In contrast, during misincorporation, PP release became extremely slow, which we estimated to be ∼0.002 s These studies establish the mechanistic basis for DNA polymerase fidelity during reverse transcription and provide a free energy profile. We correct previous underestimates of discrimination by including the slow PP release step. Our current estimate of 2.4 × 10 is >20-fold greater than estimated previously.
[Mh] Termos MeSH primário: Difosfatos/química
Transcriptase Reversa do HIV/química
HIV-1/enzimologia
Ribonuclease H/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diphosphates); 4E862E7GRQ (diphosphoric acid); EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1); EC 2.7.7.49 (HIV Reverse Transcriptase); EC 3.1.26.4 (Ribonuclease H)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171216
[Lr] Data última revisão:
171216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:27777303
[Au] Autor:Li A; Li J; Johnson KA
[Ad] Endereço:From the The University of Texas at Austin, Institute for Cell and Molecular Biology, Department of Molecular Biosciences, Austin, Texas 78712.
[Ti] Título:HIV-1 Reverse Transcriptase Polymerase and RNase H (Ribonuclease H) Active Sites Work Simultaneously and Independently.
[So] Source:J Biol Chem;291(51):26566-26585, 2016 Dec 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV reverse transcriptase plays a central role in viral replication and requires coordination of both polymerase and RNase H activities. Although this coordination is crucial in viral replication, whether a DNA/RNA hybrid can simultaneously engage both active sites has yet to be determined as structural and kinetic analyses have provided contradictory results. Single nucleotide incorporation and RNase H cleavage were examined using presteady-state kinetics with global data analysis. The results revealed three interconverting reverse transcriptase-DNA/RNA species; 43% were active for both sites simultaneously, 27% showed only polymerase activity, and the remaining 30% were nonproductive. Our data clearly demonstrated that the DNA/RNA hybrid could contact both active sites simultaneously, although the single nucleotide incorporation (105 s ) was ∼5-fold faster than the cleavage (23 s ). By using a series of primers with different lengths, we found that a string of at least 4-6 nucleotides downstream of the cleaving site was required for efficient RNA cleavage. This was corroborated by our observations that during processive nucleotide incorporation, sequential rounds of RNA cleavage occurred each time after ∼6 nucleotides were incorporated. More importantly, during processive primer extension, pyrophosphate (PP ) release was rate-limiting so that the average rate of nucleotide incorporation (∼28 s ) was comparable with that of net RNA cleavage (∼27 nucleotides(s)). Although polymerization is efficient and processive, RNase H is inefficient and periodic. This combination allows the two catalytic centers of HIVRT to work simultaneously at similar speeds without being tightly coupled.
[Mh] Termos MeSH primário: DNA/química
Transcriptase Reversa do HIV/química
HIV-1/enzimologia
RNA/química
Ribonuclease H/química
[Mh] Termos MeSH secundário: Domínio Catalítico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
63231-63-0 (RNA); 9007-49-2 (DNA); EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1); EC 2.7.7.49 (HIV Reverse Transcriptase); EC 3.1.26.4 (Ribonuclease H)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171216
[Lr] Data última revisão:
171216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


  5 / 5307 MEDLINE  
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[PMID]:28465101
[Au] Autor:Wei L; Wang HL; Huang L; Chen CH; Morris-Natschke SL; Lee KH; Xie L
[Ad] Endereço:Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
[Ti] Título:Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus.
[So] Source:Bioorg Med Chem Lett;27(12):2788-2792, 2017 06 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R ) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes<3). The N-substituted amide-R side chains were superior to ester-R likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties.
[Mh] Termos MeSH primário: Compostos de Anilina/farmacologia
Fármacos Anti-HIV/farmacologia
Transcriptase Reversa do HIV/antagonistas & inibidores
HIV-1/efeitos dos fármacos
Inibidores da Transcriptase Reversa/farmacologia
Rilpivirina/farmacologia
[Mh] Termos MeSH secundário: Compostos de Anilina/síntese química
Compostos de Anilina/química
Fármacos Anti-HIV/química
Relação Dose-Resposta a Droga
Farmacorresistência Viral/efeitos dos fármacos
Transcriptase Reversa do HIV/metabolismo
HIV-1/genética
Testes de Sensibilidade Microbiana
Estrutura Molecular
Mutação
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Rilpivirina/química
Relação Estrutura-Atividade
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Anti-HIV Agents); 0 (Reverse Transcriptase Inhibitors); EC 2.7.7.49 (HIV Reverse Transcriptase); FI96A8X663 (Rilpivirine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  6 / 5307 MEDLINE  
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[PMID]:28829913
[Au] Autor:Derudas M; Vanpouille C; Carta D; Zicari S; Andrei G; Snoeck R; Brancale A; Margolis L; Balzarini J; McGuigan C
[Ad] Endereço:Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff, CF10 3NB, U.K.
[Ti] Título:Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides.
[So] Source:J Med Chem;60(18):7876-7896, 2017 Sep 28.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses. Several ProTide compounds showed substantial potency against HIV-1 at low micromolar range while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed.
[Mh] Termos MeSH primário: Aciclovir/análogos & derivados
Aciclovir/farmacologia
Fármacos Anti-HIV/química
Fármacos Anti-HIV/farmacologia
HIV-1/efeitos dos fármacos
Nucleosídeos/química
Nucleosídeos/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Desenho de Drogas
Infecções por HIV/tratamento farmacológico
Infecções por HIV/virologia
Transcriptase Reversa do HIV/metabolismo
HIV-1/enzimologia
Herpes Simples/tratamento farmacológico
Herpes Simples/virologia
Seres Humanos
Simulação de Acoplamento Molecular
Simplexvirus/efeitos dos fármacos
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Nucleosides); EC 2.7.7.49 (HIV Reverse Transcriptase); X4HES1O11F (Acyclovir)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b01009


  7 / 5307 MEDLINE  
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[PMID]:28811321
[Au] Autor:Zheng X; Mueller GA; Kim K; Perera L; DeRose EF; London RE
[Ad] Endereço:Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, U.S.A.
[Ti] Título:Identification of drivers for the metamorphic transition of HIV-1 reverse transcriptase.
[So] Source:Biochem J;474(19):3321-3338, 2017 Sep 24.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recent structural characterizations of the p51 and p66 monomers have established an important starting point for understanding the maturation pathway of the human immunodeficiency virus (HIV)-1 reverse transcriptase p66/p51 heterodimer. This process requires a metamorphic transition of the polymerase domain leading to formation of a p66/p66' homodimer that exists as a structural heterodimer. To better understand the drivers for this metamorphic transition, we have performed NMR studies of N-labeled RT216 - a construct that includes the fingers and most of the palm domains. These studies are consistent with the conclusion that the p66 monomer exists as a spring-loaded complex. Initial dissociation of the fingers/palm : connection complex allows the fingers/palm to adopt an alternate, more stable structure, reducing the rate of reassociation and facilitating subsequent maturation steps. One of the drivers for an initial extension of the fingers/palm domains is identified as a straightening of helix E relative to its conformation in the monomer by eliminating a bend of ∼50° near residue Phe160. NMR and circular dichroism data also are consistent with the conclusion that a hydrophobic surface of palm domain that becomes exposed after the initial dissociation, as well as the intrinsic conformational preferences of the palm domain C-terminal segment, facilitates the formation of the ß-sheet structure that is unique to the active polymerase subunit. Spectral comparisons based on N-labeled constructs are all consistent with previous structural conclusions based on studies of C-methyl-labeled constructs.
[Mh] Termos MeSH primário: Transcriptase Reversa do HIV/química
Transcriptase Reversa do HIV/metabolismo
[Mh] Termos MeSH secundário: Dicroísmo Circular
Transcriptase Reversa do HIV/genética
Espectroscopia de Ressonância Magnética
Modelos Moleculares
Simulação de Dinâmica Molecular
Isótopos de Nitrogênio
Conformação Proteica
Domínios Proteicos
Multimerização Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitrogen Isotopes); EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1); EC 2.7.7.49 (HIV Reverse Transcriptase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170817
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170480


  8 / 5307 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


  9 / 5307 MEDLINE  
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[PMID]:28778390
[Au] Autor:Yasukawa K; Iida K; Okano H; Hidese R; Baba M; Yanagihara I; Kojima K; Takita T; Fujiwara S
[Ad] Endereço:Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan. Electronic address: yasukawa@kais.kyoto-u.ac.jp.
[Ti] Título:Next-generation sequencing-based analysis of reverse transcriptase fidelity.
[So] Source:Biochem Biophys Res Commun;492(2):147-153, 2017 Oct 14.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this study, we devised a simple and rapid method to analyze fidelity of reverse transcriptase (RT) using next-generation sequencing (NGS). The method comprises a cDNA synthesis reaction from standard RNA with a primer containing a tag of 14 randomized bases and the RT to be tested, PCR using high-fidelity DNA polymerase, and NGS. By comparing the sequence of each read with the reference sequence, mutations were identified. The mutation can be identified to be due to an error introduced by either cDNA synthesis, PCR, or NGS based on whether the sequence reads with the same tag contain the same mutation or not. The error rates in cDNA synthesis with Moloney murine leukemia virus (MMLV) RT thermostable variant MM4 or the recently developed 16-tuple variant of family B DNA polymerase with RT activity, RTX, from Thermococcus kodakarensis, were 0.75-1.0 × 10 errors/base, while that in the reaction with the wild-type human immunodeficiency virus type 1 (HIV-1) RT was 2.6 × 10 errors/base. Overall, our method could precisely evaluate the fidelity of various RTs with different reaction conditions in a high-throughput manner without the use of expensive optics and troublesome adaptor ligation.
[Mh] Termos MeSH primário: DNA Complementar/genética
HIV-1/enzimologia
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Vírus da Leucemia Murina de Moloney/enzimologia
DNA Polimerase Dirigida por RNA/genética
Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
Thermococcus/enzimologia
[Mh] Termos MeSH secundário: Sequência de Bases
DNA Polimerase Dirigida por DNA/genética
Transcriptase Reversa do HIV/genética
HIV-1/genética
Vírus da Leucemia Murina de Moloney/genética
DNA Polimerase Dirigida por RNA/química
Thermococcus/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Complementary); EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1); EC 2.7.7.49 (HIV Reverse Transcriptase); EC 2.7.7.49 (RNA-Directed DNA Polymerase); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170806
[St] Status:MEDLINE


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[PMID]:28659246
[Au] Autor:Huang B; Wang X; Liu X; Chen Z; Li W; Sun S; Liu H; Daelemans D; De Clercq E; Pannecouque C; Zhan P; Liu X
[Ad] Endereço:Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
[Ti] Título:Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.
[So] Source:Bioorg Med Chem;25(16):4397-4406, 2017 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC values of 1.48µM and 1.61µM, respectively. They were much potent than the reference drug ddI (EC =76.0µM) and comparable to 3TC (EC =2.54µM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Descoberta de Drogas
Transcriptase Reversa do HIV/antagonistas & inibidores
HIV-1/efeitos dos fármacos
Inibidores da Transcriptase Reversa/farmacologia
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/síntese química
Fármacos Anti-HIV/química
Linhagem Celular
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Transcriptase Reversa do HIV/metabolismo
Seres Humanos
Indóis/química
Indóis/farmacologia
Testes de Sensibilidade Microbiana
Estrutura Molecular
Pirimidinas/química
Pirimidinas/farmacologia
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Relação Estrutura-Atividade
Sulfonas/química
Sulfonas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Indoles); 0 (Pyrimidines); 0 (Reverse Transcriptase Inhibitors); 0 (Sulfones); EC 2.7.7.49 (HIV Reverse Transcriptase); K8CXK5Q32L (pyrimidine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE



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