Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 393
Filtrar
1.
J Med Chem ; 63(9): 4837-4848, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32293182

RESUMO

The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Animais , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Ensaios Enzimáticos , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Tiofenos/metabolismo , Tiofenos/farmacocinética
2.
J Med Chem ; 63(3): 1298-1312, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935327

RESUMO

Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 µM), and reduced hERG inhibition (IC50 > 30 µM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.


Assuntos
Fármacos Anti-HIV/farmacologia , Canal de Potássio ERG1/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Animais , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas , Feminino , Flúor/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Ratos Wistar , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacocinética , Tiofenos/toxicidade
3.
Xenobiotica ; 50(5): 570-579, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31403353

RESUMO

HIV replication in the brain is unopposed due to reduced antiretroviral drug penetration into the central nervous system (CNS). Prevalence of HIV-associated neurocognitive disorder (HAND) has increased severely in patients living with HIV despite current treatments. The aims of this study were to evaluate the brain bio-distribution of alternative nucleoside reverse transcriptase inhibitors, abacavir, stavudine and didanosine in the CNS and to determine their localization patterns in the brain.Sprague-Dawley rats received 50 mg kg-1 single i.p dose of each drug. Mass spectrometric techniques were then used to investigate the pharmacokinetics and localization patterns of these drugs in the brain using LC-MS/MS and mass spectrometric imaging (MSI), respectively.Abacavir, stavudine and didanosine reached the Brain Cmax with concentration of 831.2, 1300 and 43.37 ngmL-1, respectively. Based on MSI analysis Abacavir and Stavudine were located in brain regions that are strongly implicated in the progression of HAND.Abacavir and Stavudine penetrated into CNS, reaching a Cmax that was above the IC50 for HIV (457.6 and 112.0 ngmL-1, respectively), however, it was noted ddI showed poor entry within the brain, therefore, it is recommended that this drug cannot be considered for treating CNS-HIV.


Assuntos
Encéfalo/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Animais , Didanosina/metabolismo , Didesoxinucleosídeos/metabolismo , Infecções por HIV , Ratos , Estavudina/metabolismo , Espectrometria de Massas em Tandem
4.
Eur J Med Chem ; 176: 11-20, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091477

RESUMO

A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti-HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC50 values ranging from 0.61 µM to 0.84 nM. The most potent inhibitor, compound 4b, had an EC50 value of 0.84 nM against HIV-1 strain IIIB, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC50 values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC50 values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC50 value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization.


Assuntos
Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Quinazolinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Aminas/síntese química , Aminas/metabolismo , Aminas/toxicidade , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/toxicidade , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade
5.
Bioorg Chem ; 89: 102974, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31102693

RESUMO

The present work follows our preliminary discovery of biphenyl diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors. Further structural optimization of biphenyl-DAPYs led to the identification of a new series of biphenyl-substituted thiophene[3,2-d]pyrimidine analogues by a scaffold-hopping strategy. Biological evaluation of this series showed that these compounds possessed up to single-digit nanomolar potency (EC50 = 7.8-526.2 nM) and prominently low toxicity (CC50 = 18.5-280.8 µM) against wild-type (WT) HIV-1-infected cells. Furthermore, the results also demonstrated that compounds 29-32 exhibited high, broad-spectrum antiviral effects against clinically observed HIV-1 mutants. Specifically, compound 30, which had the highest selectivity index (SI = 16094) and the best anti-reverse transcriptase ability (IC50 = 39 nM), displayed marked inhibitory activity (EC50 = 13.5, 9.4, 17.0, 52.0, and 58.2 nM) against WT, K103N, E138K, L100I, Y181C mutants and moderate activity against double mutants. This study provides important avenues for the further design of HIV-1 inhibitors.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Pirimidinas/química , Inibidores da Transcriptase Reversa/química , Sítios de Ligação , Compostos de Bifenilo/química , Linhagem Celular , Desenho de Fármacos , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Mutação , Estrutura Terciária de Proteína , Pirimidinas/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Relação Estrutura-Atividade
6.
Biochemistry ; 58(16): 2176-2187, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30900874

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered noncompetitive inhibitors that structurally alter reverse transcriptase (RT) and dramatically decrease catalysis. In this report, biochemical analysis with various divalent cations was used to demonstrate that NNRTIs and divalent cation-dNTP complexes are mutually exclusive, inhibiting each other's binding to RT/primer/template (RT-P/T) complexes. The binding of catalytically competent divalent cation-dNTP complexes to RT-P/T was measured with Mg2+, Mn2+, Zn2+, Co2+, and Ni2+ using Ca2+, a noncatalytic cation, for displacement. Binding strength order was Mn2+ ≈ Zn2+ ≫ Co2+ > Mg2+ ≈ Ni2+. Consistent with but not exclusive to mutually exclusive binding, primer extension assays showed that stronger divalent cation-dNTP complexes were more resistant to NNRTIs (efavirenz (EFV), rilpivirine (RPV), and nevirapine (NVP)). Filtration assays demonstrated that divalent cation-dNTP complexes inhibited the binding of 14C-labeled EFV to RT-P/T with stronger binding complexes formed with Mn2+ inhibiting more potently than those with Mg2+. Conversely, filter binding assays demonstrated that EFV inhibited 3H-labeled dNTP binding to RT-P/T complexes with displacement of Mn2+-dNTP complexes requiring much greater concentrations of EFV than the more weakly bound Mg2+-dNTP complexes. EFV bound relatively weakly to the NNRTI resistant K103N RT; but, binding was modestly enhanced in the presence of P/T, and EFV was easily displaced by divalent cation-dNTP complexes. This suggests that K103N overcomes EFV inhibition mostly by binding more weakly to the drug and is in contrast to other reports that indicate K103N has little to no effect on drug or dNTP binding. Overall, this biochemical analysis supports recent biophysical analyses of NNRTI-RT interactions that indicate mutually exclusive binding.


Assuntos
Benzoxazinas/metabolismo , Cátions Bivalentes/metabolismo , Transcriptase Reversa do HIV/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Rilpivirina/metabolismo , Alquinos , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Sequência de Bases , Benzoxazinas/farmacologia , Ligação Competitiva , Cátions Bivalentes/farmacologia , Ciclopropanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Nucleotídeos/genética , Nucleotídeos/metabolismo , Ligação Proteica , Inibidores da Transcriptase Reversa/farmacologia , Rilpivirina/farmacologia
7.
J Antimicrob Chemother ; 74(3): 699-709, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535366

RESUMO

BACKGROUND: There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz. OBJECTIVES: We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance. METHODS: We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. RESULTS: We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (ß = 0.38, P = 2.7 × 10-03), plasma 7-hydroxy-efavirenz (ß = 0.59, P = 3.7 × 10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (ß = -0.31, P = 1.8 × 10-04) and CSF efavirenz (ß = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (ß = -0.55, P = 3.5 × 10-05), ABCB1 rs115780656 (ß = -0.65, P = 4.1 × 10-05) and CYP2A6 -48A→C (ß = -0.59, P = 0.01). CYP2A6 -48A→C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (ß = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance. CONCLUSIONS: We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.


Assuntos
Benzoxazinas/metabolismo , Benzoxazinas/farmacocinética , Sistema Nervoso Central/metabolismo , Farmacogenética , Variantes Farmacogenômicos , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Idoso , Alquinos , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ciclopropanos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Polimorfismo Genético , Carga Viral , Adulto Jovem
8.
Eur J Drug Metab Pharmacokinet ; 44(2): 179-187, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30168000

RESUMO

BACKGROUND AND OBJECTIVE: Efavirenz is commonly used in Africa and is frequently associated with neurocognitive toxicity, which may compromise clinical outcomes. Older individuals are at increased risk for drug toxicity and clinical outcomes may be worse in older age, particularly among those individuals with cytochrome P450 (CYP) 2B6 polymorphisms associated with slower efavirenz metabolism. The aim of this study was to determine if the CYP2B6 polymorphisms differentially impacts loss to care in older people. METHODS: We conducted a prospective cohort study of 914 treatment-naïve HIV+ adults initiating efavirenz-based antiretroviral treatment at public HIV clinics in Gaborone, Botswana between 2009 and 2013. Older age, defined as age ≥ 50 years, was the primary exposure and loss to care at 6 months was the primary outcome. Interaction between age and CYP2B6 516G>T and 983T>C polymorphisms, defined as extensive, intermediate, and slow metabolism, was assessed. Neurocognitive toxicity was measured using a symptom questionnaire. Age-stratified logistic regression was performed to identify factors associated with loss to care. RESULTS: Older age was associated with loss to care (OR 1.95, 95% CI 1.30-2.92). Age modified the effect of CYP2B6 genotype on loss to care with older, slow metabolizers at over four-fold higher risk when compared to older, intermediate metabolizers (OR 4.06 95% CI 1.38-11.89); neurocognitive toxicity did not mediate this risk. CYP2B6 metabolism genotype did not increase risk of loss to care in younger participants. CONCLUSION: Older age was associated with loss to care, especially among those with slow efavirenz metabolism. Understanding the relationship between older age and CYP2B6 genotype will be important to improving outcomes in an aging population initiating efavirenz-based ART in similar settings.


Assuntos
Grupo com Ancestrais do Continente Africano , Fármacos Anti-HIV/metabolismo , Benzoxazinas/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Adulto , Grupo com Ancestrais do Continente Africano/genética , Fatores Etários , Alquinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Botsuana/epidemiologia , Estudos de Coortes , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Feminino , Infecções por HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Adulto Jovem
9.
J Med Chem ; 62(10): 4851-4883, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-30516990

RESUMO

Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clinical requirements for drugs.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Ensaios Clínicos como Assunto , HIV-1/enzimologia , Humanos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo
10.
Chem Biol Drug Des ; 93(4): 430-437, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30381875

RESUMO

Two novel series of human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2-d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild-type (WT) HIV-1 strain in MT-4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV-1. Compound 7 (EC50  = 0.014, 0.031 µM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50  = 7.572, 0.190 µM) and comparable to that of etravirine (ETV, EC50  = 0.004, 0.014 µM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.


Assuntos
Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/química , Sítios de Ligação , Domínio Catalítico , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Nevirapina/química , Nevirapina/metabolismo , Nitrilos , Piridazinas/química , Piridazinas/metabolismo , Pirimidinas , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Solventes/química , Relação Estrutura-Atividade
11.
J Phys Chem B ; 123(8): 1741-1748, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30571126

RESUMO

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs), which bind to an allosteric site 10-15 Å from the polymerase active site, play a central role in anti-HIV chemotherapy. Though NNRTIs have been known for 30 years, the pathways by which they bind and unbind from HIV-RT have not been characterized. In crystal structures for complexes, three channels are found to extend from the NNRTI binding site to the exterior of the protein, while added mystery comes from the fact that the binding site is collapsed in the unliganded protein. To address this issue, metadynamics simulations have been performed to elucidate the unbinding of four NNRTIs from HIV-RT. A general and transferable collective variable defined by the distance between the center-of-mass (COM) of the binding pocket and COM of the ligand is used to follow the dynamics while minimizing the bias. The metadynamics also allows computation of the barriers to unbinding, which are compared with the observed potencies of the compounds in an antiviral assay.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Simulação de Dinâmica Molecular , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Transcriptase Reversa do HIV/química , Ligação Proteica , Conformação Proteica , Inibidores da Transcriptase Reversa/química
12.
ChemMedChem ; 13(21): 2332-2348, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30257071

RESUMO

The pathway by which HIV-1 enters host cells is a prime target for novel drug discovery because of its critical role in the life cycle of HIV-1. The HIV-1 envelope glycoprotein gp120 plays an important role in initiating virus entry by targeting the primary cell receptor CD4. We explored the substitution of bulky molecular groups in region I in the NBD class of entry inhibitors. Previous attempts at bulky substituents in that region abolished antiviral activity, even though the binding site is hydrophobic. We synthesized a series of entry inhibitors containing the 1,3-benzodioxolyl moiety or its bioisostere, 2,1,3-benzothiadiazole. The introduction of the bulkier groups was well tolerated, and despite only minor improvements in antiviral activity, the selectivity index of these compounds improved significantly.


Assuntos
Fármacos Anti-HIV/farmacologia , Benzodioxóis/farmacologia , Proteína gp120 do Envelope de HIV/metabolismo , Pirróis/farmacologia , Internalização do Vírus/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Benzodioxóis/síntese química , Benzodioxóis/química , Benzodioxóis/metabolismo , Sítios de Ligação , Proteína gp120 do Envelope de HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/química , HIV-1/enzimologia , Humanos , Leucócitos Mononucleares/virologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Pirróis/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química , Tiadiazóis/metabolismo , Tiadiazóis/farmacologia
13.
J Med Chem ; 61(20): 9218-9228, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30265808

RESUMO

MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the synthesis and antiviral evaluation of carbocyclic derivatives. Synthesized analogs were evaluated for their antiviral activity, and the corresponding triphosphates were synthesized and evaluated in a biochemical assay. 4'-Ethynyl-G derivative (±)-29 displayed a promising IC50 of 33 nM in a hPBMC cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC50 of 324 nM in a biochemical RT-polymerase assay. Improved TP anabolite delivery resulting in improved in vitro potency was achieved by preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying a significantly improved IC50 of 3.0 nM, paving the way for new directions for this novel class of nucleoside analogs.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Desoxiadenosinas/síntese química , Desoxiadenosinas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Animais , Antivirais/metabolismo , Antivirais/farmacocinética , Linhagem Celular , Técnicas de Química Sintética , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacocinética , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Distribuição Tecidual
14.
J Antimicrob Chemother ; 73(9): 2460-2467, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29868865

RESUMO

Objectives: There are limited data regarding efavirenz pharmacogenetics in admixed populations. The Brazilian population is highly admixed. In a Brazilian cohort, we sought to characterize associations between efavirenz adverse effects (all-cause and CNS) and polymorphisms in seven genes known or suspected to affect efavirenz metabolism and transport. Methods: We studied 225 HIV-positive individuals who had been prescribed efavirenz-containing regimens at a hospital in Rio de Janeiro, Brazil. Eighty-nine cases had efavirenz adverse effects, including 43 with CNS adverse effects, while 136 controls had no adverse effect of any antiretroviral after treatment for at least 6 months. A total of 67 candidate polymorphisms in ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3 genes were selected for association analysis. Admixture was assessed using 28 ancestry-informative polymorphisms previously validated for the Brazilian population. Associations were evaluated with logistic regression models adjusted for sex and genetic ancestry. Results: There was extensive African, European and Native American admixture in the cohort. Increased all-cause adverse effects were associated with the CYP2B6 genotype combination 15582CC-516TT-983TT (OR = 7.26, P = 0.003) and with the CYP2B6 slow metabolizer group 516TT or 516GT-983CT (OR = 3.10, P = 0.04). CNS adverse effects were nominally associated with CYP3A4 rs4646437 (OR = 4.63, P = 0.014), but not after adjusting for multiple comparisons. Conclusions: In a highly admixed Brazilian cohort, the CYP2B6 slow metabolizer genotype was associated with an increased risk of efavirenz adverse effects.


Assuntos
Benzoxazinas/efeitos adversos , Benzoxazinas/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Infecções por HIV/tratamento farmacológico , Inativação Metabólica/genética , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/metabolismo , Adulto , Idoso , Alquinos , Benzoxazinas/administração & dosagem , Brasil , Ciclopropanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Inibidores da Transcriptase Reversa/administração & dosagem
15.
S Afr Med J ; 108(4): 271-274, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29629676

RESUMO

A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases.


Assuntos
Algoritmos , Benzoxazinas/toxicidade , Encefalopatias/induzido quimicamente , Encefalopatias/prevenção & controle , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/prevenção & controle , Infecções por HIV/tratamento farmacológico , Neurotoxinas/toxicidade , Inibidores da Transcriptase Reversa/toxicidade , Adulto , Alquinos , Antituberculosos/metabolismo , Antituberculosos/toxicidade , Benzoxazinas/metabolismo , Ciclopropanos , Eletroencefalografia , Feminino , Humanos , Isoniazida/metabolismo , Isoniazida/toxicidade , Neurotoxinas/metabolismo , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/metabolismo , África do Sul , Testes de Toxicidade
16.
Bioorg Med Chem ; 26(8): 2051-2060, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29559197

RESUMO

By means of structure-based molecular hybridization strategy, a series of novel diarylpyri(mi)dine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were designed, synthesized and evaluated as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs). Encouragingly, all the tested compounds showed good activities against wild-type (WT) HIV-1 (IIIB) with EC50 in the range of 1.36 nM-29 nM, which is much better than those of nevirapine (NVP, EC50 = 125.42 nM) and azidothymidine (AZT, EC50 = 11.36 nM). Remarkably, these compounds also displayed effective activity against the most of the single and double-mutated HIV-1 strains with low EC50 values, which is comparable to the control drugs. Besides, these compounds were also exhibited favorable enzymatic inhibitory activity. Moreover, preliminary structure-activity relationships (SARs) and molecular modeling study were investigated and discussed in detail. Unexpectedly, four diarylpyrimidines yielded moderate anti-HIV-2 activities. To our knowledge, this is rarely reported that diarylpyrimidine-based NNRTIs have potent activity against both HIV-1 and HIV-2 in cell culture.


Assuntos
HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Pirimidinas/química , Inibidores da Transcriptase Reversa/farmacologia , Regulação Alostérica , Sítios de Ligação , Desenho de Fármacos , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-2/enzimologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Relação Estrutura-Atividade
17.
J Virol ; 92(11)2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29593034

RESUMO

The apolipoprotein B editing complex 3 (APOBEC3) proteins are potent retroviral restriction factors that are under strong positive selection, both in terms of gene copy number and sequence diversity. A common feature of all the members of the APOBEC3 family is the presence of one or two cytidine deamination domains, essential for cytidine deamination of retroviral reverse transcripts as well as packaging into virions. Several studies have indicated that human and mouse APOBEC3 proteins restrict retrovirus infection via cytidine deaminase (CD)-dependent and -independent means. To understand the relative contribution of CD-independent restriction in vivo, we created strains of transgenic mice on an APOBEC3 knockout background that express a deaminase-dead mouse APOBEC3 due to point mutations in both CD domains (E73Q/E253Q). Here, we show that the CD-dead APOBEC3 can restrict murine retroviruses in vivo Moreover, unlike the wild-type protein, the mutant APOBEC3 is not packaged into virions but acts only as a cell-intrinsic restriction factor that blocks reverse transcription by incoming viruses. Finally, we show that wild-type and CD-dead mouse APOBEC3 can bind to murine leukemia virus (MLV) reverse transcriptase. Our findings suggest that the mouse APOBEC3 cytidine deaminase activity is not required for retrovirus restriction.IMPORTANCE APOBEC3 proteins are important host cellular restriction factors essential for restricting retrovirus infection by causing mutations in the virus genome and by blocking reverse transcription. While both methods of restriction function in vitro, little is known about their role during in vivo infection. By developing transgenic mice with mutations in the cytidine deamination domains needed for enzymatic activity and interaction with viral RNA, we show that APOBEC3 proteins can still restrict in vivo infection by interacting with reverse transcriptase and blocking its activity. These studies demonstrate that APOBEC3 proteins have evolved multiple means for blocking retrovirus infection and that all of these means function in vivo.


Assuntos
Citidina Desaminase/genética , Vírus da Leucemia Murina/genética , Infecções por Retroviridae/prevenção & controle , Inibidores da Transcriptase Reversa/metabolismo , Transcrição Reversa/genética , Animais , Linhagem Celular , Citidina Desaminase/metabolismo , Desaminação/genética , Células HEK293 , Humanos , Vírus da Leucemia Murina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Viral/genética , DNA Polimerase Dirigida por RNA/genética
18.
Bioorg Med Chem Lett ; 28(8): 1348-1351, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29534929

RESUMO

In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50 = 0.264 µM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug.


Assuntos
Fármacos Anti-HIV/farmacologia , Pró-Fármacos/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Alquinos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Benzoxazinas/farmacologia , Linhagem Celular Tumoral , Ciclopropanos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Hidrólise , Mutação , Nevirapina/farmacologia , Nitrilos , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Piridazinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirróis/síntese química , Pirróis/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia
19.
Chem Biol Drug Des ; 91(2): 398-407, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28816417

RESUMO

HIV-1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for antiretroviral therapy. Pyrimidine analogues reportedly have selective inhibition on HIV-1 RT with favorable antiviral activities in our previous study. To further explore the relationship between inhibitory activity and pharmacophoric characteristics, field-based QSAR models were generated and validated using Schrodinger Suite (correlation coefficient of .8078, cross-validated value of 0.5397 for training set and Q2 of 0.4669, Pearson's r of .7357 for test set). Docking, pocket surfaces, and pharmacophore study were also investigated to define the binding pattern and pharmacophoric features, including (i) π-π interaction with residue Tyr181, Tyr188, and Trp229 and p-π interaction with His235 and (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The pharmacophore features of six-point hypothesis AADRRR.184, AAADRR.38, and AADRRR.26 further complimented to the docking and QSAR results. We also found that the protein-ligand complex exhibited high relative binding free energy. These observations could be potentially utilized to guide the rational design and optimization of novel HIV-1 RT inhibitors.


Assuntos
Transcriptase Reversa do HIV/metabolismo , Pirimidinas/química , Relação Quantitativa Estrutura-Atividade , Inibidores da Transcriptase Reversa/química , Sítios de Ligação , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Ligação de Hidrogênio , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Pirimidinas/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Termodinâmica
20.
Artigo em Inglês | MEDLINE | ID: mdl-28696229

RESUMO

Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Didesoxinucleosídeos/metabolismo , Interações Medicamentosas/fisiologia , Absorção Intestinal/fisiologia , Proteínas de Membrana Transportadoras/metabolismo , Rilpivirina/metabolismo , Animais , Transporte Biológico/fisiologia , Células CACO-2 , Linhagem Celular , Linhagem Celular Tumoral , Didesoxinucleosídeos/farmacologia , Cães , Humanos , Lamivudina/metabolismo , Lamivudina/farmacologia , Células Madin Darby de Rim Canino , Masculino , Ratos , Ratos Wistar , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Rilpivirina/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA