Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Med Rep ; 20(6): 4749-4762, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702817

RESUMO

Transposases are ubiquitous mobile genetic elements responsible for genome development, driving rearrangements, such as insertions, deletions and translocations. Across species evolution, some transposases are tamed by their host and are made part of complex cellular systems. The proliferation of retroviruses is also dependent on transposase related enzymes termed integrases. Recombination­activating gene protein (RAG)1 and metnase are just two examples of transposase domestication and together with retroviral integrases (INs), they belong to the DDE polynucleotidyl transferases superfamily. They share mechanistic and structural features linked to the RNase H­like fold, harboring a DDE(D) metal dependent catalytic motif. Recent antiretroviral compounds target the catalytic domain of integrase, but they also have the potential of inhibiting other related enzymes. In this review, we report the activity of different classes of integrase inhibitors on various DDE transposases. Computational simulations are useful to predict the extent of off­target activity and have been employed to study the interactions between RAG1 recombinase and compounds from three different pharmacologic classes. We demonstrate that strand­transfer inhibitors display a higher affinity towards the RAG1 RNase H domain, as suggested by experimental data compared to allosteric inhibitors. While interference with RAG1 and 2 recombination is associated with a negative impact on immune function, the inhibition of metnase or HTLV­1 integrase opens the way for the development of novel therapies for refractory cancers.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Diclorodifenil Dicloroetileno , HIV-1/genética , Proteínas de Homeodomínio/metabolismo , Inibidores de Integrase/farmacologia , Proteínas Nucleares/metabolismo , Recombinação Genética/genética , Transposases/efeitos dos fármacos , Domínio Catalítico , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , HIV-1/metabolismo , Compostos Heterocíclicos com 3 Anéis , Histona-Lisina N-Metiltransferase , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/genética , Inibidores de Integrase/química , Simulação de Acoplamento Molecular , Proteínas Nucleares/química , Proteínas Nucleares/genética , Oxazinas , Piperazinas , Conformação Proteica , Piridonas , Retroviridae/genética , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo
2.
Viruses ; 11(9)2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443391

RESUMO

Foamy viruses (FV) are retroviruses belonging to the Spumaretrovirinae subfamily. They are non-pathogenic viruses endemic in several mammalian hosts like non-human primates, felines, bovines, and equines. Retroviral DNA integration is a mandatory step and constitutes a prime target for antiretroviral therapy. This activity, conserved among retroviruses and long terminal repeat (LTR) retrotransposons, involves a viral nucleoprotein complex called intasome. In the last decade, a plethora of structural insights on retroviral DNA integration arose from the study of FV. Here, we review the biochemistry and the structural features of the FV integration apparatus and will also discuss the mechanism of action of strand transfer inhibitors.


Assuntos
Integrases , Spumavirus , Integração Viral , Animais , Antirretrovirais/química , Antirretrovirais/farmacologia , Domínio Catalítico , DNA Viral/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Inibidores de Integrase/química , Inibidores de Integrase/farmacologia , Integrases/química , Integrases/metabolismo , Modelos Moleculares , Nucleoproteínas/química , Nucleoproteínas/metabolismo , Retroviridae/genética , Retroviridae/metabolismo , Spumavirus/genética , Spumavirus/metabolismo , Sequências Repetidas Terminais
3.
J Pharmacol Exp Ther ; 370(2): 269-277, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31175220

RESUMO

Cabotegravir, a novel integrase inhibitor under development for treatment and prevention of HIV, is primarily metabolized by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A9 to a direct ether glucuronide metabolite. The aim of these studies was to elucidate the mechanistic basis of cabotegravir-glucuronide disposition in humans. Cabotegravir glucuronidation was predominantly hepatic (>95%) with minimal intestinal and renal contribution. Rat liver perfusions demonstrated that cabotegravir-glucuronide formed in the liver undergoes comparable biliary and sinusoidal excretion, consistent with high concentrations of the glucuronide in human bile and urine. Cabotegravir-glucuronide biliary excretion was mediated by multidrug resistance-associated protein (MRP)2 (not transported by breast cancer resistance protein or P-glycoprotein), whereas hepatic basolateral excretion into sinusoidal blood was via both MRP3 [fraction transport (Ft) = 0.81] and MRP4 (Ft = 0.19). Surprisingly, despite high urinary recovery of hepatically-formed cabotegravir-glucuronide, metabolite levels in circulation were negligible, a phenomenon consistent with rapid metabolite clearance. Cabotegravir-glucuronide was transported by hepatic uptake transporters organic anion-transporting (OAT) polypeptide (OATP)1B1 and OATP1B3; however, metabolite clearance by hepatic uptake from circulation was low (2.7% of hepatic blood flow) and unable to explain the minimal systemic exposure. Instead, circulating cabotegravir-glucuronide undergoes efficient renal clearance, where uptake into the proximal tubule would be mediated by OAT3 (not transported by OAT1), and subsequent secretion into urine by MRP2 (Ft = 0.66) and MRP4 (Ft = 0.34). These studies provide mechanistic insight into the disposition of cabotegravir-glucuronide, a hepatically-formed metabolite with appreciable urinary recovery and minimal systemic exposure, including fractional contribution of redundant transporters to any given process based on quantitative proteomics. SIGNIFICANCE STATEMENT: The role of membrane transporters in metabolite disposition, especially glucuronides, and as sites of unexpected drug-drug interactions, which alter drug efficacy and safety, has been established. Cabotegravir-glucuronide, formed predominantly by direct glucuronidation of parent drug in liver, was the major metabolite recovered in human urine (27% of oral dose) but was surprisingly not detected in systemic circulation. To our knowledge, this is the first mechanistic description of this phenomenon for a major hepatically-formed metabolite to be excreted in the urine to a large extent, but not circulate at detectable levels. The present study elucidates the mechanistic basis of cabotegravir-glucuronide disposition in humans. Specific hepatic and renal transporters involved in the disposition of cabotegravir-glucuronide, with their fractional contribution, have been provided.


Assuntos
Glucuronídeos/química , Inibidores de Integrase/química , Inibidores de Integrase/metabolismo , Piridonas/química , Piridonas/metabolismo , Animais , Transporte Biológico , Células HEK293 , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Microssomos/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla , Ratos
4.
J Photochem Photobiol B ; 189: 258-266, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30419521

RESUMO

Plants from the Asteraceae family are known to contain a wide spectrum of phytochemicals with various nutraceutical properties. One important phytochemical, chicoric acid (CA), is reported to exist in plants, such as Sonchus oleraceus and Bidens pilosa, as stereoisomers. These CA molecules occur either as the naturally abundant RR-chicoric acid (RR-CA), or the less abundant RS-chicoric acid (RS-CA), also known as meso-chicoric acid. To date, little is known about the biological activity of RS-CA, but there is evidence of its anti-human immunodeficiency virus (HIV) properties. In this study, a reliable analytical method was developed to distinguish between the two stereoisomers detected in S. oleraceus and B. pilosa. For structure identification and characterization of CA molecules, liquid chromatography-mass spectrometry (LC-MS) was used in combination with ultraviolet radiation (UV)-induced geometrical isomerization, molecular dynamics (MD) simulations, and density functional theory (DFT) models. Optimized structures from DFT calculations were used for docking studies against the HIV-1 integrase enzyme. Different retention times on the reverse phase chromatograms revealed that the plants produce two different CA stereoisomers: S. oleraceus produced the RR-CA isomer, while B. pilosa produced the RS-CA isomer. DFT results demonstrated the RR-CA molecule was more stable than RS-CA due to the stabilizing force of intra-molecular hydrogen bonding. Differences in the HIV-1 integrase enzyme binding modes were observed, with the RR-CA being a more potent inhibitor than the RS-CA molecule. The results highlight the significance of plant metabolite structural complexity from both chemical and biological perspectives. Furthermore, the study demonstrates that induced-formation of geometrical isomers, in combination with the predictive ability of DFT models and the resolving power of the LC-MS, can be exploited to distinguish structurally closely related compounds, such as stereoisomers.


Assuntos
Asteraceae/química , Ácidos Cafeicos/química , Integrase de HIV/química , Succinatos/química , Sítios de Ligação , Cromatografia de Fase Reversa , Teoria da Densidade Funcional , Humanos , Inibidores de Integrase/química , Estereoisomerismo , Espectrometria de Massas em Tandem
5.
Curr Top Med Chem ; 16(10): 1135-53, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26324045

RESUMO

Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (<300 Da) screened using primarily biophysical assays. FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Integrase de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores de Integrase/química , Inibidores de Integrase/farmacologia , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
6.
Biomed Pharmacother ; 68(8): 917-21, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25451165

RESUMO

The current therapy for the human immunodeficiency virus (HIV) infection is a combination of anti-HIV drugs targeting multiple steps of virus replication. The drugs for the acquired immunodeficiency syndrome (AIDS) treatment include reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, co-receptor inhibitor and the newly added integrase inhibitors. Raltegravir, elvitegravir and dolutegravir are the three Food and Drug Administration (FDA) approved integrase strand transfer inhibitors for clinical treatment of HIV infection. The addition of these integrase inhibitors benefits a lot to HIV infected patients. Although it is only seven years from the first integrase inhibitor, which was approved by FDA to now, multiple drug resistant HIV strains have emerged in clinical treatment. Most of the drug resistant virus strains are against raltegravir. Some are cross-resistant to elvitegravir. Dolutegravir is effective for suppression of the current drug resistant viruses. A number of clinical trials have been performed on the three integrase inhibitors. In this study, the application of the three integrase inhibitors in clinical treatment and the findings of drug resistance to integrase inhibitors are summarized.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Aprovação de Drogas/legislação & jurisprudência , Inibidores de Integrase/uso terapêutico , Síndrome da Imunodeficiência Adquirida/diagnóstico , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Inibidores de Integrase/química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Estados Unidos
7.
Molecules ; 19(6): 7169-88, 2014 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-24886942

RESUMO

Bis-naphtho-γ-pyrones are an important group of aromatic polyketides derived from fungi. They have a variety of biological activities including cytotoxic, antitumor, antimicrobial, tyrosine kinase and HIV-1 integrase inhibition properties, demonstrating their potential applications in medicine and agriculture. At least 59 bis-naphtho-γ-pyrones from fungi have been reported in the past few decades. This mini-review aims to briefly summarize their occurrence, biosynthesis, and structure, as well as their biological activities. Some considerations regarding to synthesis, production, and medicinal and agricultural applications of bis-naphtho-γ-pyrones are also discussed.


Assuntos
Fungos/química , Pironas/metabolismo , Pironas/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Inibidores de Integrase/química , Inibidores de Integrase/metabolismo , Inibidores de Integrase/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Policetídeos/química , Policetídeos/metabolismo , Policetídeos/farmacologia , Pironas/química
8.
Bioorg Med Chem ; 22(7): 2269-79, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24618511

RESUMO

Therapeutic treatment of AIDS is recently characterized by a crescent effort towards the identification of multiple ligands able to target different steps of HIV-1 life cycle. Taking into consideration our previously obtained SAR information and combining some important chemical structural features we report herein the synthesis of novel benzyl-indole derivatives as anti-HIV agents. Through this work we identified new dual target small molecules able to inhibit both IN-LEDGF/p75 interaction and the IN strand-transfer step considered as two crucial phases of viral life cycle.


Assuntos
Fármacos Anti-HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores de Integrase/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Replicação Viral/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Compostos de Benzil/síntese química , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Relação Dose-Resposta a Droga , HIV-1/fisiologia , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Inibidores de Integrase/síntese química , Inibidores de Integrase/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
9.
J Comput Aided Mol Des ; 28(4): 475-90, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24504704

RESUMO

As part of the SAMPL4 blind challenge, filtered AutoDock Vina ligand docking predictions and large scale binding energy distribution analysis method binding free energy calculations have been applied to the virtual screening of a focused library of candidate binders to the LEDGF site of the HIV integrase protein. The computational protocol leveraged docking and high level atomistic models to improve enrichment. The enrichment factor of our blind predictions ranked best among all of the computational submissions, and second best overall. This work represents to our knowledge the first example of the application of an all-atom physics-based binding free energy model to large scale virtual screening. A total of 285 parallel Hamiltonian replica exchange molecular dynamics absolute protein-ligand binding free energy simulations were conducted starting from docked poses. The setup of the simulations was fully automated, calculations were distributed on multiple computing resources and were completed in a 6-weeks period. The accuracy of the docked poses and the inclusion of intramolecular strain and entropic losses in the binding free energy estimates were the major factors behind the success of the method. Lack of sufficient time and computing resources to investigate additional protonation states of the ligands was a major cause of mispredictions. The experiment demonstrated the applicability of binding free energy modeling to improve hit rates in challenging virtual screening of focused ligand libraries during lead optimization.


Assuntos
Integrase de HIV/metabolismo , HIV/enzimologia , Inibidores de Integrase/química , Inibidores de Integrase/farmacologia , Simulação de Acoplamento Molecular , Termodinâmica , Desenho Assistido por Computador , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/enzimologia , Infecções por HIV/virologia , Integrase de HIV/química , Humanos , Ligantes , Ligação Proteica , Software
10.
Eur J Med Chem ; 68: 405-11, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23994868

RESUMO

The disruption of crucial interactions between HIV-1 Integrase and cellular cofactor LEDGF/p75 represents an emerging approach for the design and development of new antiretroviral agents. In this study we report the successful application of a structure-based virtual screening strategy for the discovery of natural hit structures able to inhibit Integrase-LEDGF/p75 interaction. The application of sequential filters (drug-likeness, 3D-pharmacophore mapping, docking, molecular dynamics simulations) yielded a hit list of compounds, out of which 9 were tested in the in vitro AlphaScreen assays and 8 exhibited a detectable inhibition of the interaction between the two proteins. The best inhibitors belong to different chemical classes and could be represent a good starting point for further optimization and structure-activity relationship studies.


Assuntos
Inibidores de Integrase/química , Inibidores de Integrase/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Bioensaio , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Peptídeos e Proteínas de Sinalização Intercelular/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular
11.
Bioorg Med Chem Lett ; 23(6): 1648-55, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23395655

RESUMO

In this study, four computational quantitative structure-activity relationship models were built to predict the biological activity of HIV-1 integrase strand transfer (ST) inhibitors. 551 Inhibitors whose bioactivities were detected by radiolabeling method were collected. The molecules were represented with 20 selected MOE descriptors. All inhibitors were divided into a training set and a test set with two methods: (1) by a Kohonen's self-organizing map (SOM); (2) by a random selection. For every training set and test set, a multilinear regression (MLR) analysis and a support vector machine (SVM) were used to establish models, respectively. For the test set divided by SOM, the correlation coefficients (rs) were over 0.91, and for the test set split randomly, the rs were over 0.86.


Assuntos
Integrase de HIV/química , HIV-1/enzimologia , Inibidores de Integrase/química , Integrase de HIV/metabolismo , Humanos , Inibidores de Integrase/metabolismo , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Análise de Regressão , Máquina de Vetores de Suporte
12.
J Biol Chem ; 287(20): 16801-11, 2012 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-22437836

RESUMO

The multifunctional HIV-1 enzyme integrase interacts with viral DNA and its key cellular cofactor LEDGF to effectively integrate the reverse transcript into a host cell chromosome. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Recently, 2-(quinolin-3-yl) acetic acid derivatives were reported to selectively inhibit the integrase-LEDGF interaction in vitro and impair HIV-1 replication in infected cells. Here, we show that this class of compounds impairs both integrase-LEDGF binding and LEDGF-independent integrase catalytic activities with similar IC(50) values, defining them as bona fide allosteric inhibitors of integrase function. Furthermore, we show that 2-(quinolin-3-yl) acetic acid derivatives block the formation of the stable synaptic complex between integrase and viral DNA by allosterically stabilizing an inactive multimeric form of integrase. In addition, these compounds inhibit LEDGF binding to the stable synaptic complex. This multimode mechanism of action concordantly results in cooperative inhibition of the concerted integration of viral DNA ends in vitro and HIV-1 replication in cell culture. Our findings, coupled with the fact that high cooperativity of antiviral inhibitors correlates with their increased instantaneous inhibitory potential, an important clinical parameter, argue strongly that improved 2-(quinolin-3-yl) acetic acid derivatives could exhibit desirable clinical properties.


Assuntos
DNA Viral/metabolismo , Integrase de HIV/metabolismo , HIV-1/fisiologia , Inibidores de Integrase/farmacologia , Replicação Viral/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/genética , DNA Viral/genética , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/enzimologia , Infecções por HIV/genética , Integrase de HIV/genética , Humanos , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacologia , Inibidores de Integrase/química , Ligação Proteica/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Replicação Viral/fisiologia
13.
J Mol Biol ; 410(5): 831-46, 2011 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-21295584

RESUMO

Integration of human immunodeficiency virus cDNA ends by integrase (IN) into host chromosomes involves a concerted integration mechanism. IN juxtaposes two DNA blunt ends to form the synaptic complex, which is the intermediate in the concerted integration pathway. The synaptic complex is inactivated by strand transfer inhibitors (STI) with IC(50) values of ∼20 nM for inhibition of concerted integration. We detected a new nucleoprotein complex on a native agarose gel that was produced in the presence of >200 nM STI, termed the IN-single DNA (ISD) complex. Two IN dimers appear to bind in a parallel fashion at the DNA terminus, producing an ∼32-bp DNase I protective footprint. In the presence of raltegravir (RAL), MK-2048, and L-841,411, IN incorporated ∼20-25% of the input blunt-ended DNA substrate into the stabilized ISD complex. Seven other STI also produced the ISD complex (≤5% of input DNA). The formation of the ISD complex was not dependent on 3'OH processing, and the DNA was predominantly blunt ended in the complex. The RAL-resistant IN mutant N155H weakly forms the ISD complex in the presence of RAL at ∼25% level of wild-type IN. In contrast, MK-2048 and L-841,411 produced ∼3-fold to 5-fold more ISD than RAL with N155H IN, which is susceptible to these two inhibitors. The results suggest that STI are slow-binding inhibitors and that the potency to form and stabilize the ISD complex is not always related to inhibition of concerted integration. Rather, the apparent binding and dissociation properties of each STI influenced the production of the ISD complex.


Assuntos
DNA/metabolismo , Integrase de HIV/metabolismo , HIV-1/enzimologia , Inibidores de Integrase/farmacologia , Pareamento de Bases/genética , Biocatálise/efeitos dos fármacos , Carbocianinas/metabolismo , Pegada de DNA , Desoxirribonuclease I/metabolismo , Farmacorresistência Viral/efeitos dos fármacos , Eletroforese em Gel de Ágar , Corantes Fluorescentes/metabolismo , Repetição Terminal Longa de HIV/genética , HIV-1/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Inibidores de Integrase/química , Cetoácidos/química , Cetoácidos/farmacologia , Proteínas Mutantes/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Raltegravir Potássico , Especificidade por Substrato/efeitos dos fármacos
14.
ChemMedChem ; 6(2): 228-41, 2011 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-21275045

RESUMO

HIV-1 integrase (IN) is one of three essential enzymes for viral replication, and is a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand-transfer-specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US Food and Drug Administration (FDA) approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been approved by the FDA for HIV-1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached phase III clinical trials. Although this is an undoubted success for the HIV-1 IN drug discovery field, the emergence of HIV-1 IN strand-transfer-specific drug-resistant viral strains upon clinical use of these compounds is expected. Furthermore, the problem of strand-transfer-specific IN drug resistance will be exacerbated by the development of cross-resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN-targeted therapeutic options for HIV-1 treatment-experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand-transfer drug-resistant viral strains, and would likely show synergy with all available FDA-approved antiretroviral HIV-1 therapeutics, including the IN strand-transfer-specific compounds. Herein we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non-active-site regions to inhibit IN function.


Assuntos
Desenho de Fármacos , Integrase de HIV/efeitos dos fármacos , Inibidores de Integrase/química , Regulação Alostérica , Inibidores de Integrase/farmacologia
15.
Chem Commun (Camb) ; 47(10): 2961-3, 2011 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-21243129

RESUMO

A straightforward and efficient synthesis of sesterstatins 4 and 5 is reported, in which the reductive Heck cyclisation was employed as the key step for constructing the D ring.


Assuntos
Organismos Aquáticos/química , Citotoxinas/síntese química , Inibidores de Integrase/síntese química , Terpenos/síntese química , Ciclização , Citotoxinas/química , Integrase de HIV/metabolismo , Inibidores de Integrase/química , Oxirredução , Terpenos/química
16.
Mini Rev Med Chem ; 10(11): 1046-57, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21044030

RESUMO

HIV-1 integrase (IN), which has no cellular counterpart, has been intensely studied over the past 15 years and has been fully validated as a therapeutic target with the first FDA approved IN inhibitor raltegravir. The quinolone acid GS-9137 (elvitegravir), which most probably will became the next candidate of IN inhibitors, is in the process of enrolling patients in the phase III clinical trials. This review focuses on small-molecules of quinolone acid derivatives, which have the similar pharmacophore of ß-diketoacids, as integrase inhibitors with antiviral activity.


Assuntos
Desenho de Fármacos , Inibidores de Integrase/química , Quinolonas/química , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Integrase de HIV/química , Integrase de HIV/metabolismo , Humanos , Inibidores de Integrase/farmacologia , Inibidores de Integrase/uso terapêutico , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Relação Estrutura-Atividade , Integração Viral/efeitos dos fármacos
17.
Artigo em Inglês | MEDLINE | ID: mdl-19940339

RESUMO

The collision-dissociation behavior of two novel dimeric G-quadruplexes of HIV-1 integrase inhibitors and their noncovalent complex ions with a perylene derivative (Tel03), polyamides (ImImImbetaDp and PyPyPybetaDp) was investigated by tandem-in-time electrospray ionization mass spectrometry (ESI-MS). It was found that the dimeric ion loses five ammonium ions one by one at activation energy of 10%, so the loss of NH(4)(+) is the predominant fragmentation pathway at lower collision energy. When the activation amplitude is increased to 16%, the loss of guanine nucleobases from backbones of the oligonucleotide is the predominant fragmentation pathway. And the stability of the complex ion of the dimeric G-quadruplex and Tel03 is higher than that of ImImImbetaDp and PyPyPybetaDp. The results of the MS/MS spectra of the complex ion indicated that Tel03 binding molecule favor the stabilization of the novel G-quadruplex structure.


Assuntos
Quadruplex G , Integrase de HIV , Inibidores de Integrase/química , Espectrometria de Massas em Tandem , Dimerização , HIV-1 , Nylons/química , Perileno/análogos & derivados , Perileno/química
19.
Antimicrob Agents Chemother ; 52(10): 3532-41, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18316517

RESUMO

The replication of the retrovirus human T-cell leukemia virus type 1 (HTLV-1) is linked to the development of lymphoid malignancies and inflammatory diseases. Data from in vitro, ex vivo, and in vivo studies have revealed that no specific treatment can prevent or block HTLV-1 replication and therefore that there is no therapy for the prevention and/or treatment of HTLV-1-associated diseases in infected individuals. HTLV-1 and human immunodeficiency virus type 1 (HIV-1) integrases, the enzymes that specifically catalyze the integration of these retroviruses in host cell DNA, share important structural properties, suggesting that compounds that inhibit HIV-1 integration could also inhibit HTLV-1 integration. We developed quantitative assays to test, in vitro and ex vivo, the efficiencies of styrylquinolines and diketo acids, the two main classes of HIV-1 integrase inhibitors. The compounds were tested in vitro in an HTLV-1 strand-transfer reaction and ex vivo by infection of fresh peripheral blood lymphocytes with lethally irradiated HTLV-1-positive cells. In vitro, four styrylquinoline compounds and two diketo acid compounds significantly inhibited HTLV-1 integration in a dose-dependent manner. All compounds active in vitro decreased cell proliferation ex vivo, although at low concentrations; they also dramatically decreased both normalized proviral loads and the number of integration events during experimental ex vivo primary infection. Accordingly, diketo acids and styrylquinolines are the first drugs that produce a specific negative effect on HTLV-1 replication in vitro and ex vivo, suggesting their potential efficiency for the prevention and treatment of HTLV-1-associated diseases.


Assuntos
Antivirais/farmacologia , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Inibidores de Integrase/farmacologia , Antivirais/química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Infecções por HTLV-I/tratamento farmacológico , Infecções por HTLV-I/virologia , Humanos , Técnicas In Vitro , Inibidores de Integrase/química , Cetonas/química , Cetonas/farmacologia , Provírus/efeitos dos fármacos , Provírus/fisiologia , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Integração Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
20.
J Am Soc Mass Spectrom ; 19(4): 550-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18313939

RESUMO

The dimeric G-quadruplex structures of d(GGGTGGGTGGGTGGGT) (S1) and d(GTGGTGGGTGGGTGGGT) (S2), the potent nanomolar HIV-1 integrase inhibitors, were detected by electrospray ionization mass spectrometry (ESI-MS) for the first time. The formation and conversion of the dimers were induced by NH(4)(+), DNA concentration, pH, and the binding molecules. We directly observed the specific binding of a perylene derivative (Tel03) and ImImImbetaDp in one system consisting of the intramolecular and the dimeric G-quadruplexes of the HIV-1 integrase inhibitor, which suggested that Tel03 could shift the equilibrium to the dimeric G-quadruplex formation, while ImImImbetaDp induces preferentially a structural change from the dimer to the intramolecular G-quadruplex. The results of this study indicated that Tel03 and ImImImbetaDp favor the stabilization of the dimeric G-quadruplex structures.


Assuntos
DNA/química , Quadruplex G , Integrase de HIV , Inibidores de Integrase/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Dicroísmo Circular , Imidazóis/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...