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1.
Nat Commun ; 12(1): 2500, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947853

RESUMO

Reverse transcription of the HIV-1 viral RNA genome (vRNA) is an integral step in virus replication. Upon viral entry, HIV-1 reverse transcriptase (RT) initiates from a host tRNALys3 primer bound to the vRNA genome and is the target of key antivirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Initiation proceeds slowly with discrete pausing events along the vRNA template. Despite prior medium-resolution structural characterization of reverse transcriptase initiation complexes (RTICs), higher-resolution structures of the RTIC are needed to understand the molecular mechanisms that underlie initiation. Here we report cryo-EM structures of the core RTIC, RTIC-nevirapine, and RTIC-efavirenz complexes at 2.8, 3.1, and 2.9 Å, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA-tRNALys3 initiation complex and reveal a specific structural mechanism of nucleic acid conformational stabilization during initiation. Finally, our results show that NNRTIs inhibit the RTIC and exacerbate discrete pausing during early reverse transcription.


Assuntos
Transcriptase Reversa do HIV/química , HIV-1/efeitos dos fármacos , RNA de Transferência de Lisina/química , RNA Viral/química , Inibidores da Transcriptase Reversa/química , Alcinos/química , Alcinos/farmacologia , Benzoxazinas/química , Benzoxazinas/farmacologia , Domínio Catalítico , Microscopia Crioeletrônica , Ciclopropanos/química , Ciclopropanos/farmacologia , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , HIV-1/metabolismo , Modelos Moleculares , Nevirapina/química , Nevirapina/farmacologia , Conformação de Ácido Nucleico/efeitos dos fármacos , RNA de Transferência de Lisina/genética , RNA Viral/genética , Inibidores da Transcriptase Reversa/farmacologia
2.
J Med Chem ; 64(8): 5067-5081, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33851529

RESUMO

Considering the nonideal metabolic stability of the difluoro-biphenyl-diarylpyrimidine lead compound 4, a series of novel alkylated difluoro-biphenyl-diarylpyrimidines were designed and synthesized based on their structure. Introducing alkyl or substituted alkyl groups on the linker region to block the potential metabolic sensitive sites generated 22 derivatives. Among them, compound 12a with an N-methyl group displayed excellent anti-HIV-1 activity and selectivity. The methyl group was hopped to the central pyrimidine to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound 4 with RT. The resulting compound 16y exhibited an improved anti-HIV-1 activity, much lower cytotoxicity, and nanomolar activity toward multiple mutants. In addition, 16y has a better stability in human liver microsomes than 4. Moreover, no apparent in vivo acute toxicity was observed in 16y-treated female, especially pregnant mice. This series of alkylated compounds with highly potency and safety represent a promising lead template for future discovery.


Assuntos
Compostos de Bifenilo/química , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirimidinas/química , Inibidores da Transcriptase Reversa/química , Alquilação , Animais , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Feminino , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Meia-Vida , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Mutação , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
3.
J Med Chem ; 64(7): 4239-4256, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33734714

RESUMO

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c. 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c 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 , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Células HEK293 , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mutação , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 214: 113204, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33567378

RESUMO

With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC50 values ranging from 0.007 µM to 0.043 µM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC50 > 217.5 µM) and improved water solubility (S = 49.3 µg/mL at pH 7.0) compared to the lead 25a (S < 1 µg/mL at pH 7.0, CC50 = 2.30 µM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.


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 , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
5.
Science ; 371(6535)2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33542150

RESUMO

HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to targeting immutable components are needed to clear HIV-1 infection. Here, we report that the caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4+ T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for the clearance of persistent HIV-1 infection.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Infecções por HIV/virologia , Protease de HIV/metabolismo , HIV-1/fisiologia , Inflamassomos/metabolismo , Proteínas de Neoplasias/metabolismo , Piroptose , Alcinos/farmacologia , Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Proteínas Adaptadoras de Sinalização CARD/química , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD4-Positivos/virologia , Caspase 1/metabolismo , Ciclopropanos/farmacologia , Ativação Enzimática , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Macrófagos/fisiologia , Macrófagos/virologia , Proteínas de Neoplasias/química , Inibidores da Transcriptase Reversa/farmacologia , Rilpivirina/farmacologia , Células THP-1 , Latência Viral
6.
Viruses ; 13(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477685

RESUMO

HIV reverse transcriptases (RTs) convert viral genomic RNA into double-stranded DNA. During reverse transcription, polypurine tracts (PPTs) resilient to RNase H cleavage are used as primers for plus-strand DNA synthesis. Nonnucleoside RT inhibitors (NNRTIs) can interfere with the initiation of plus-strand DNA synthesis by enhancing PPT removal, while HIV RT connection subdomain mutations N348I and N348I/T369I mitigate this effect by altering RNase H cleavage specificity. Now, we demonstrate that among approved nonnucleoside RT inhibitors (NNRTIs), nevirapine and doravirine show the largest effects. The combination N348I/T369I in HIV-1BH10 RT has a dominant effect on the RNase H cleavage specificity at the PPT/U3 site. Biochemical studies showed that wild-type HIV-1 and HIV-2 RTs were able to process efficiently and accurately all tested HIV PPT sequences. However, the cleavage accuracy at the PPT/U3 junction shown by the HIV-2EHO RT was further improved after substituting the sequence YQEPFKNLKT of HIV-1BH10 RT (positions 342-351) for the equivalent residues of the HIV-2 enzyme (HQGDKILKV). Our results highlight the role of ß-sheets 17 and 18 and their connecting loop (residues 342-350) in the connection subdomain of the large subunit, in determining the RNase H cleavage window of HIV RTs.


Assuntos
Genoma Viral , Infecções por HIV/virologia , Repetição Terminal Longa de HIV , HIV-1/fisiologia , RNA Viral , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Bases , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Mutagênese , Ligação Proteica , Proteólise , RNA Viral/química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Ribonuclease H do Vírus da Imunodeficiência Humana/química
7.
Molecules ; 25(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322154

RESUMO

The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle-a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/química , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Sequência de Aminoácidos , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/enzimologia , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Ligação Proteica , Relação Estrutura-Atividade
8.
PLoS One ; 15(12): e0243650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33347449

RESUMO

Human immunodeficiency virus-1 (HIV-1) exhibits high diversity and complexity in China, challenging the disease surveillance and antiretroviral therapy. Between July 1, 2014 and January 30, 2017, we investigated the profiles of HIV-1 infection stages, genotype distribution and drug resistance mutations (DRMs) using plasma samples from HIV Western blot (WB) confirmed blood donors from five Chinese blood centers (Chongqing, Guangxi, Luoyang, Mianyang, and Urumqi). HIV pol regions consisted of whole protease and partial reverse transcriptase were genotyped and analyzed for DRMs. Lag-Avidity testing was performed to identify the infection stages. Of the 356 HIV-1 WB positive samples tested by Lag-avidity assay, 19.1% (68/356) were recent infections. Genotyping on 356 amplified sequences presented the subtype distributions as following: CRF07_BC (65.7%), CRF08_BC (7.3%), CRF01_AE (19.1%), B (4.2%), CRF55_01B (3.1%), CRF59_01B (0.3%) and CRF68_01B (0.3%). No significant difference in genotype distribution was observed between recent and long-term infections. 48 DRMs were identified from 43 samples, indicating a drug resistance prevalence of 12.1% (43/356), which include seven protease inhibitors (PIs) accessory DRMs (Q58E, L23I and I84M), two PIs major DRMs (M46I, M46L), seven nucleoside RT inhibitors DRMs (D67N, K70Q, K219R and M184L), and 32 non-nucleoside RT inhibitors DRMs (K103N, V179E, K238N, V179D, E138G, G190E, A98G, Y188D and E138A). In addition, we had also identified CRFs from the 01B subtype including CRF55_01B (3.1%), CRF59_01B (0.3%) and CRF68_01B (0.3%). As an important part of the continuous monitoring of HIV-1 circulating strains among blood donors, our findings were expected to contribute to the comprehensive AIDS control and development of proper diagnostics for HIV-1 in China.


Assuntos
Doadores de Sangue/estatística & dados numéricos , Farmacorresistência Viral/genética , Infecções por HIV/epidemiologia , HIV-1/genética , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , China/epidemiologia , Genótipo , Técnicas de Genotipagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Protease de HIV/genética , HIV-1/isolamento & purificação , Humanos , Mutação , Filogenia , RNA Viral/genética , RNA Viral/isolamento & purificação , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Estudos Soroepidemiológicos , Adulto Jovem
9.
Nat Commun ; 11(1): 4737, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968070

RESUMO

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Reposicionamento de Medicamentos , Inflamassomos/efeitos dos fármacos , Resistência à Insulina , Inibidores da Transcriptase Reversa/farmacologia , Adipócitos/metabolismo , Animais , Sobrevivência Celular , RNA Helicases DEAD-box/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , HIV-1/efeitos dos fármacos , Hepatite B , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Musculares/metabolismo , Ribonuclease III/metabolismo
10.
PLoS One ; 15(6): e0234937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555643

RESUMO

We have previously reported on HIV-1 infected patients who fail anti-retroviral therapy but manage to re-suppress without a regimen change despite harbouring major drug resistance mutations. Here we explore phenotypic drug resistance in such patients in order to better understand this phenomenon. Patients (n = 71) failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, but who subsequently re-suppressed on the same regimen, were assessed for HIV-1 genotypic drug resistance through Sanger sequencing. A subset (n = 23) of these samples, as well as genotypically matched samples from patients who did not re-suppress (n = 19), were further assessed for phenotypic drug resistance in an in vitro single cycle assay. Half of the patients (n = 36/71, 51%) harboured genotypic drug resistance, with M184V (n = 18/36, 50%) and K103N (n = 16/36, 44%) being the most prevalent mutations. No significant difference in the median time to re-suppression (31-39 weeks) were observed for either group (p = 0.41). However, re-suppressors with mutant virus rebounded significantly earlier than those with wild-type virus (16 vs. 33 weeks; p = 0.014). Similar phenotypic drug resistance profiles were observed between patients who re-suppressed and patients who failed to re-suppress. While most remained susceptible to stavudine (d4T) and zidovudine (AZT), both groups showed a reduced susceptibility to 3TC and NNRTIs. HIV- 1 infected patients on an NNRTI-based regimen can achieve viral re-suppression on the same regimen despite harbouring viruses with genotypic and phenotypic drug resistance. However, re-suppression was less durable in those with resistance, reinforcing the importance of appropriate regimen choices, ongoing viral load monitoring and adherence counselling.


Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Inibidores da Transcriptase Reversa , Carga Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Fenótipo , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico
11.
Molecules ; 25(10)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429580

RESUMO

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'-O-fatty acyl conjugates of NRTIs, 5'-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Fármacos Anti-HIV/química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Linhagem Celular , Coronavirus Humano 229E/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores da Transcriptase Reversa/química
12.
Eur J Med Chem ; 194: 112255, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32244098

RESUMO

Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 µM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 µM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.


Assuntos
4-Quinolonas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonucleosídeos/farmacologia , 4-Quinolonas/síntese química , 4-Quinolonas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Transcriptase Reversa do HIV/metabolismo , HIV-1/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonucleosídeos/síntese química , Ribonucleosídeos/química , Relação Estrutura-Atividade
13.
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
14.
Artigo em Inglês | MEDLINE | ID: mdl-32164970

RESUMO

Emtricitabine (Emtriva, FTC) is an antiviral medicine which decreases the body's amount of HIV. Emtricitabine on of Anti-HIV drugs slow down or protect the immune system against damage and reduce the risk of diseases related to developing of AIDS. Emtricitabine use also for treatment of hepatitis B virus. Emtricitabine is a drug class known as nucleoside reversing transcriptase inhibitors (NRTIs). In view of Emtricitabine's clinical significance, a thorough review of the physical and pharmaceutical characteristics and details of the multiple analytical techniques used to test the drug in pharmaceutical and biological systems was conducted. The methods investigated include identification test, Spectroscopy, chromatography, electrochemicals, and Thermal. Beside the analytical profile, the degradation and stability of Emtricitabine, its pharmacology and pharmacokinetics, Pharmaceutical Applications, Mechanism of Action, dosage forms and dose, ADME profile, and interactions have been debated.


Assuntos
Fármacos Anti-HIV/farmacologia , Emtricitabina/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Infecções por HIV/tratamento farmacológico , Hepatite B/tratamento farmacológico , Humanos
15.
Eur J Med Chem ; 193: 112237, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200201

RESUMO

HIV-1 RT has been considered as one of the most important targets for the development of anti-HIV-1 drugs for their well-solved three-dimensional structure and well-known mechanism of action. In this study, with HIV-1 RT as target, we used miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening to discover novel potent HIV-1 NNRTIs. A 156 triazole-containing inhibitor library was assembled in microtiter plates and in millimolar scale. The enzyme inhibition screening results showed that 22 compounds exhibited improved inhibitory activity. Anti-HIV-1 activity results demonstrated that A3N19 effected the most potent activity against HIV-1 IIIB (EC50 = 3.28 nM) and mutant strain RES056 (EC50 = 481 nM). The molecular simulation analysis suggested that the hydrogen bonding interactions of A3N19 with the main chain of Lys101 and Lys104 was responsible for its potency. Overall, the results indicated the in situ click chemistry-based strategy was rational and might be amenable for the future discovery of more potent HIV-1 NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sítios de Ligação/efeitos dos fármacos , Química Click , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
16.
Curr HIV/AIDS Rep ; 17(2): 118-124, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32052271

RESUMO

PURPOSE OF REVIEW: Combination antiretroviral therapy (cART) has had dramatic effects on morbidity and mortality for persons living with HIV (PLWH). Despite significant progress in treatment efficacy, tolerability, and reducing pill burden, new agents are needed to address issues of resistance, drug-drug interactions, end organ disease, and adherence. This review covers novel ART agents recently approved or in development. RECENT FINDINGS: Capsid inhibitors (CAI) demonstrate high potency and potential for extended-duration dosing in pre-clinical trials. While previous maturation inhibitors (MI) were hampered by issues of drug resistance, a recent phase IIa trial for a second-generation MI demonstrated promising antiviral activity. A phase I trial to evaluate a transdermal implant of islatravir, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), maintained concentrations above the target pharmacokinetic threshold at 12 weeks. The attachment inhibitor fostemsavir is available in the USA for compassionate use in multi-drug-resistant (MDR) HIV. New antiretroviral agents show promise for both extended-duration dosing and MDR HIV.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Capsídeo/efeitos dos fármacos , Desoxiadenosinas/farmacologia , Descoberta de Drogas/métodos , Quimioterapia Combinada/métodos , Humanos , Organofosfatos/farmacologia , Piperazinas/farmacologia
17.
Eur J Med Chem ; 189: 112071, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004936

RESUMO

From an aqueous decoction of the traditional Chinese medicine "ban lan gen" (the Isatis indigotica root), an antiviral natural product CI - 39 was isolated as an NNRTI (non-nucleoside reverse transcriptase inhibitor) (EC50 = 3.40 µM). Its novel structure was determined as methyl (1-methoxy-1H-indol-3-yl)acetamidobenzoate by spectroscopic data and confirmed by single crystal X-ray diffraction. Through synthesis and structure-activity relationship (SAR) investigation of CI - 39 and 57 new derivatives (24 with EC50 values of 0.06-8.55 µM), two optimized derivatives 10f and 10i (EC50: 0.06 µM and 0.06 µM) having activity comparable to that of NVP (EC50 = 0.03 µM) were obtained. Further evaluation verified that 10f and 10i were RT DNA polymerase inhibitors and exhibited better activities and drug resistance folds compared to NVP against seven NNRTI-resistant strains carrying different mutations. Especially, 10i (EC50 = 0.43 µM) was more active to the L100I/K103N double-mutant strain as compared to both NVP (EC50 = 0.76 µM) and EFV (EC50 = 1.08 µM). The molecular docking demonstrated a possible binding pattern between 10i and RT and revealed activity mechanism of 10i against the NNRTI-resistant strains.


Assuntos
Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Indóis/síntese química , Indóis/farmacologia , Isatis/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Farmacorresistência Viral , Células HEK293 , Infecções por HIV/virologia , HIV-1/enzimologia , Humanos , Ácidos Indolacéticos/química , Estrutura Molecular , Mutação , Extratos Vegetais/farmacologia , Relação Estrutura-Atividade
18.
Sci Rep ; 10(1): 3021, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080249

RESUMO

Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIVY115F/F116Y/Q151M) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIVY115F/F116Y/Q151M with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RTY115F/F116Y/Q151M:DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RTY115F/F116Y/Q151M/F160M/M184V:DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.


Assuntos
Farmacorresistência Viral/efeitos dos fármacos , Guanina/análogos & derivados , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Lamivudina/química , Lamivudina/farmacologia , Nucleosídeos/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Sequência de Bases , Cristalografia por Raios X , DNA Viral/química , Nucleotídeos de Desoxicitosina , Nucleotídeos de Desoxiguanina , Desenho de Fármacos , Guanina/química , Guanina/farmacologia , HIV-1/genética , Mutação/genética , Conformação de Ácido Nucleico , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia
19.
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
20.
J Virol ; 94(8)2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31969438

RESUMO

As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear.IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Profilaxia Pré-Exposição/métodos , Rilpivirina/farmacologia , Vagina/virologia , Animais , Modelos Animais de Doenças , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Camundongos , Mutação , Inibidores da Transcriptase Reversa/farmacologia , Replicação Viral/efeitos dos fármacos , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
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