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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.
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
4.
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
5.
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
6.
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
7.
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
8.
J Med Chem ; 63(11): 5625-5663, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32031378

RESUMO

The use of an acetylene (ethynyl) group in medicinal chemistry coincides with the launch of the Journal of Medicinal Chemistry in 1959. Since then, the acetylene group has been broadly exploited in drug discovery and development. As a result, it has become recognized as a privileged structural feature for targeting a wide range of therapeutic target proteins, including MAO, tyrosine kinases, BACE1, steroid receptors, mGlu5 receptors, FFA1/GPR40, and HIV-1 RT. Furthermore, a terminal alkyne functionality is frequently introduced in chemical biology probes as a click handle to identify molecular targets and to assess target engagement. This Perspective is divided into three parts encompassing: (1) the physicochemical properties of the ethynyl group, (2) the advantages and disadvantages of the ethynyl group in medicinal chemistry, and (3) the impact of the ethynyl group on chemical biology approaches.


Assuntos
Acetileno/química , Química Farmacêutica , Alcinos/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Química Click , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Meia-Vida , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Inibidores da Transcriptase Reversa/química
9.
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
10.
Eur J Med Chem ; 188: 111987, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31893549

RESUMO

Infection by human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents, more active, less toxic and with increased tolerability to mutations. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase and HIV replication in cell culture. For these reasons we propose, in this work, the design, synthesis and biological evaluation of quinoxaline derivatives targeting HIV reverse transcriptase enzyme. For this, we first carried out a structure-based development of target-specific compound virtual chemical library of quinoxaline derivatives. The rational construction of the virtual chemical library was based on previously assigned pharmacophore features. This library was processed by a virtual screening protocol employing molecular docking and 3D-QSAR. Twenty-five quinoxaline compounds were selected for synthesis in the basis of their docking and 3D-QSAR scores and chemical synthetic simplicity. They were evaluated as inhibitors of the recombinant wild-type reverse transcriptase enzyme. Finally, the anti-HIV activity and cytotoxicity of the synthesized quinoxaline compounds with highest reverse transcriptase inhibitory capabilities was evaluated. This simple screening strategy led to the discovery of two selective and potent quinoxaline reverse transcriptase inhibitors with high selectivity index.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Quinoxalinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 186: 111900, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771827

RESUMO

Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 µM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 185: 111874, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735575

RESUMO

The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC50 values of 0.0249 µM against WT and 0.0104 µM against the K103N mutant strain, low cytotoxicity (CC50 > 221 µM) and a high selectivity index (SI WT > 8873, SI K103N > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.


Assuntos
Acetamidas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Acetamidas/síntese química , Acetamidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 186: 111864, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31767136

RESUMO

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064 µM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 µM), Y181C (EC50 = 0.11 µM), E138K (EC50 = 0.057 µM), and moderate activity against double mutants RES056 (EC50 = 8.7 µM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Indazóis/farmacologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Indazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
14.
Science ; 366(6470): 1255-1259, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806816

RESUMO

Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.


Assuntos
Biocatálise , Desoxiadenosinas/química , Inibidores da Transcriptase Reversa/química , Biotecnologia/métodos , Preparações Farmacêuticas/síntese química , Estereoisomerismo
15.
Commun Biol ; 2: 469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31872074

RESUMO

Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/K d) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (-)-FTC-TP and (-)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3'-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) K d for the L-nucleotides and moderately higher (>9-fold) K d for the D-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (-)-FTC-TP and shifts its triphosphate into a non-productive conformation.


Assuntos
Farmacorresistência Viral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Nucleotídeos/química , Inibidores da Transcriptase Reversa/química , Alelos , Substituição de Aminoácidos , Bases de Dados Genéticas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Mutação , Nucleotídeos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia
16.
J Med Chem ; 62(24): 11430-11436, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31714780

RESUMO

A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 exhibited an improved water solubility of 5.6 µg/mL compared with ETR (≪1 µg/mL), better stability in human and rat liver microsomes, and a great oral bioavailability of 44%, making it promising as a drug candidate. In addition, no apparent toxicity was observed in the acute toxicity assay (2 g/kg) and HE staining.


Assuntos
Fármacos Anti-HIV/farmacologia , Apoptose/efeitos dos fármacos , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Microssomos Hepáticos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Feminino , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Ligantes , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Ratos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Replicação Viral/efeitos dos fármacos
17.
Drug Res (Stuttg) ; 69(12): 671-682, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31698495

RESUMO

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(A-D): interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8A: and 8D: were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8A: was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.


Assuntos
Diarilquinolinas/química , Diarilquinolinas/farmacologia , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Alcinos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzoxazinas/química , Benzoxazinas/farmacologia , Linhagem Celular Tumoral , Ciclopropanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Nevirapina/química , Nevirapina/farmacologia , Nitrilas , Piridazinas/química , Piridazinas/farmacologia , Pirimidinas , Rilpivirina/química , Rilpivirina/farmacologia
18.
J Med Chem ; 62(21): 9996-10002, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31603676

RESUMO

HIV-1 reverse transcriptase (RT) is an essential enzyme, targeting half of approved anti-AIDS drugs. While nucleoside RT inhibitors (NRTIs) are DNA chain terminators, the nucleotide-competing RT inhibitor (NcRTI) INDOPY-1 blocks dNTP binding to RT. Lack of structural information hindered INDOPY-1 improvement. Here we report the HIV-1 RT/DNA/INDOPY-1 crystal structure, revealing a unique mode of inhibitor binding at the polymerase active site without involving catalytic metal ions. The structure may enable new strategies for developing NcRTIs.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Indóis/química , Indóis/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Piridonas/química , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Transcriptase Reversa do HIV/química , Modelos Moleculares , Conformação Proteica
19.
Molecules ; 24(21)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652782

RESUMO

BACKGROUND: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research for the development of new inhibitors continues as the virus develops resistant strains. METHODS: The best features of available NNRTIs were taken into account for the design of novel inhibitors. PASS (Prediction of activity spectra for substances) prediction program and molecular docking studies for the selection of designed compounds were used for the synthesis. Compounds were synthesized using conventional and microwave irradiation methods and HIV RT inhibitory action was evaluated by colorimetric photometric immunoassay. RESULTS: The evaluation of HIV-1 RT inhibitory activity revealed that seven compounds have significantly lower ΙC50 values than nevirapine (0.3 µΜ). It was observed that the activity of compounds depends not only on the nature of substituent and it position in benzothiazole ring but also on the nature and position of substituents in benzene ring. CONCLUSION: Twenty four of the tested compounds exhibited inhibitory action lower than 4 µΜ. Seven of them showed better activity than nevirapine, while three of the compounds exhibited IC50 values lower than 5 nM. Two compounds 9 and 10 exhibited very good inhibitory activity with IC50 1 nM.


Assuntos
Síndrome de Imunodeficiência Adquirida , Fármacos Anti-HIV , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa , Tiazóis , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/enzimologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Transcriptase Reversa do HIV/metabolismo , Humanos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
20.
AAPS PharmSciTech ; 20(7): 286, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31410664

RESUMO

5-Chloro-3-phenylsulfonylindole-2-carboxamide (CSIC) is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with potential for use in topical prophylaxis against HIV transmission. However, the hydrophobic nature of CSIC limits its administration through vaginal route. In this study, we developed nanocrystals of CSIC to potentially improve the aqueous solubility and intracellular uptake of CSIC in vitro and in vivo. CSIC nanocrystals were manufactured and stabilized with Pluronic F98 and hydroxypropyl methylcellulose E5. Transmission electron microscopy showed CSIC nanocrystals to be needle-like. Dynamic light scattering measurements showed a hydrodynamic size of 243 nm (polydispersity index < 0.3) and near neutral surface charge (- 7.8 mV). Particle size was maintained for at least 7 days in the liquid state and for at least 5 months after lyophilization. Drug content in the CSIC nanocrystal formulation (nanosuspension) was 0.8 mg/mL, which is 1000 times higher than the aqueous solubility of CSIC. In vitro release study showed that over 90% of CSIC was released from the nanocrystal formulation in a linear fashion over a period of 4 days. Importantly, CSIC nanocrystals showed equivalent cell-based anti-HIV activity (EC50 ~ 1 nM) as that of non-formulated drug. In vitro studies demonstrated rapid macrophage uptake of CSIC nanocrystals via both energy-dependent (endocytosis) and independent processes. In vivo studies in Swiss Webster female mice showed that the nanocrystal formulation significantly improved CSIC delivery to mouse cervicovaginal tissues following intravaginal instillation. In summary, nanocrystals are a promising formulation approach for topical delivery of CSIC for protection against HIV sexual transmission.


Assuntos
Indóis/administração & dosagem , Nanopartículas/química , Inibidores da Transcriptase Reversa/administração & dosagem , Administração Intravaginal , Animais , Linhagem Celular , Composição de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/química , Camundongos , Gravidez , Inibidores da Transcriptase Reversa/química , Solubilidade
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