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1.
Science ; 370(6514): 360-364, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33060363

RESUMO

The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Capsídeo/química , HIV-1/química , Capsídeo/efeitos dos fármacos , Microscopia Crioeletrônica , Cristalografia por Raios X , Medição da Troca de Deutério , Células HEK293 , HIV-1/efeitos dos fármacos , Células HeLa , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/química , Domínios Proteicos , Fatores de Poliadenilação e Clivagem de mRNA/química
2.
J Am Chem Soc ; 142(40): 17024-17038, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-32926779

RESUMO

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the "phosphate tweezer" CLR01, a "carboxylate tweezer" CLR05, and a "phosphate clip" PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.


Assuntos
Antivirais/química , Antivirais/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Organofosfatos/farmacologia , Proteínas do Envelope Viral/efeitos dos fármacos , Fosfatase Ácida/química , Fosfatase Ácida/metabolismo , Amiloide/antagonistas & inibidores , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Arginina/química , Betacoronavirus/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/química , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/virologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Lipídeos/química , Lisina/química , Espectroscopia de Ressonância Magnética , Organofosfatos/química , Proteínas Secretadas pela Vesícula Seminal/química , Proteínas Secretadas pela Vesícula Seminal/metabolismo , Relação Estrutura-Atividade , Proteínas do Envelope Viral/metabolismo , Zika virus/efeitos dos fármacos
3.
Proc Natl Acad Sci U S A ; 117(36): 22436-22442, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32820072

RESUMO

Cholesterol-PIE12-trimer (CPT31) is a potent d-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV , Vírus da Imunodeficiência Símia , Internalização do Vírus/efeitos dos fármacos , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , HIV/efeitos dos fármacos , HIV/genética , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Macaca mulatta , Masculino , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética
4.
Nature ; 584(7822): 614-618, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32612233

RESUMO

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.


Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Proteínas do Capsídeo/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Adolescente , Adulto , Fármacos Anti-HIV/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Células Cultivadas , Farmacorresistência Viral/genética , Feminino , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Replicação Viral/efeitos dos fármacos , Adulto Jovem
5.
J Med Chem ; 63(13): 6991-7007, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32515595

RESUMO

The antiviral efficacy of many nucleoside analogues is strongly dependent on their intracellular activation by host cellular kinases to yield ultimately the bioactive nucleoside analogue triphosphates (NTP). The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. We developed a nucleoside triphosphate (NTP) delivery system (the TriPPPro approach), in which the γ-phosphate is covalently modified by two different biodegradable masking units, one is the acyloxybenzyl (AB) moiety and the other is the alkoxycarbonyloxybenzyl (ACB) group. Such compounds formed NTPs with high selectivity by an enzyme-triggered mechanism in human T-lymphocyte CEM cell extracts loosing first the AB moiety, followed by the ACB group. This enables the bypass of all steps of the intracellular phosphorylation. This approach was applied here to convert some modestly active or even inactive nucleoside analogues into powerful biologically active metabolites. Potent antiviral activity profiles were obtained depending on the lipophilicity of the TriPPPro-NTP prodrugs against HIV-1 and HIV-2 replication in cultures of infected wild-type CD4+ CEM T-cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK-). This TriPPPro strategy offers high potential for future antiviral and antitumoral chemotherapies.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Nucleosídeos/química , Nucleosídeos/metabolismo , Polifosfatos/química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , HIV-2/efeitos dos fármacos , HIV-2/fisiologia , Humanos , Nucleosídeos/farmacologia , Replicação Viral/efeitos dos fármacos
6.
J Med Chem ; 63(11): 6003-6027, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32421343

RESUMO

We disclose a study on nucleoside triphosphate (NTP) analogues in which the γ-phosphate is covalently modified by two different biodegradable masking units and d4T as nucleoside analogue that enable the delivery of d4TTP with high selectivity in phosphate buffer (pH 7.3) and by enzyme-triggered reactions in human CD4+ T-lymphocyte CEM cell extracts. This allows the bypass of all steps normally needed in the intracellular phosphorylation. These TriPPPro-nucleotides comprising an acyloxybenzyl (AB; ester) or an alkoxycarbonyloxybenzyl (ACB; carbonate) in combination with an ACB moiety are described as NTP delivery systems. The introduction of these two different groups led to the selective formation of γ-(ACB)-d4TTPs by chemical hydrolysis and in particular by cell extract enzymes. γ-(AB)-d4TTPs are faster cleaved than γ-(ACB)-d4TTPs. In antiviral assays, the compounds are highly active against HIV-1 and HIV-2 in wild-type CEM/O cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK-).


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Nucleotídeos/química , Pró-Fármacos/química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Esterases/metabolismo , Meia-Vida , Humanos , Hidrólise , Fígado/enzimologia , Nucleotídeos/metabolismo , Nucleotídeos/farmacologia , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Suínos
7.
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 , RNA Replicase/metabolismo , Inibidores da Transcriptase Reversa/química
8.
Eur J Med Chem ; 200: 112319, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32446036

RESUMO

The huge resources that had gone into Human Immunodeficiency virus (HIV) research led to the development of potent antivirals able to suppress viral load in the majority of treated patients, thus dramatically increasing the life expectancy of people living with HIV. However, life-long treatments could result in the emergence of drug-resistant viruses that can progressively reduce the number of therapeutic options, facilitating the progression of the disease. In this scenario, we previously demonstrated that inhibitors of the human DDX3X helicase can represent an innovative approach for the simultaneous treatment of HIV and other viral infections such as Hepatitis c virus (HCV). We reported herein 6b, a novel DDX3X inhibitor that thanks to its distinct target of action is effective against HIV-1 strains resistant to currently approved drugs. Its improved in vitro ADME properties allowed us to perform preliminary in vivo studies in mice, which highlighted optimal biocompatibility and an improved bioavailability. These results represent a significant advancement in the development of DDX3X inhibitors as a novel class of broad spectrum and safe anti-HIV-1 drugs.


Assuntos
RNA Helicases DEAD-box/antagonistas & inibidores , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , HIV-1/fisiologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Camundongos , Viroses/tratamento farmacológico
9.
Toxicol Lett ; 329: 26-30, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380124

RESUMO

QF-036 is a novel human immunodeficiency virus (HIV) maturation inhibitor that is a lupine triterpenoid derivative. The objective of this study was to evaluate the safety of QF-036. A single oral toxicity and a 4-week repeated oral toxicity were investigated in Sprague-Dawley (SD) rats. The single oral toxicity study of QF-036 in SD rats showed that no mortality or visible pathological changes were noted at doses of 100, 300, and 1000 mg/kg. QF-036 exhibited a non-linear toxicokinetic profile over the dose range of 100-1000 mg/kg in the single dose study, and a saturation trend appeared at doses of 100 and 300 mg/kg. In the 4-week oral toxicity and toxicokinetic study, SD rats were given 0, 50, 100, and 200 mg/kg QF-036 once daily for 4 weeks, followed by a 4-week recovery period. No mortality or significant effects on food consumption, body weight, or behavior were observed. In addition, there were no test article-related changes in hematology, clinical biochemistry and histopathology. The no observed adverse effect level (NOAEL) was 200 mg/kg. The toxicokinetic study demonstrated a dose-dependent increase in the systemic exposure to QF-036 after 4 weeks of oral administration. There were no marked sex differences or drug accumulation observed for repeated doses of QF-036.


Assuntos
Fármacos Anti-HIV/toxicidade , Triterpenos/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade , Triterpenos/toxicidade
10.
Sci Rep ; 10(1): 7190, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32346097

RESUMO

Small synthetic molecules mimicking the three-dimensional structure of α-helices may find applications as inhibitors of therapeutically relevant protein-protein and protein-nucleic acid interactions. However, the design and use of multi-facial helix mimetics remains in its infancy. Here we describe the synthesis and application of novel bilaterally substituted p-terphenyl compounds containing positively-charged aminoalkyl groups in relative 1,4 positions across the aromatic scaffold. These compounds were specifically designed to mimic all faces of the arginine-rich α-helix of the HIV-1 protein Rev, which forms deeply embedded RNA complexes and plays key roles in the virus replication cycle. Two of these molecules recognized the Rev site in the viral RNA and inhibited the formation of the RRE-Rev ribonucleoprotein complex, a currently unexploited target in HIV chemotherapy. Cellular assays revealed that the most active compounds blocked HIV-1 replication with little toxicity, and likely exerted this effect through a multi-target mechanism involving inhibition of viral LTR promoter-dependent transcription and Rev function. Further development of this scaffold may open new avenues for targeting nucleic acids and may complement current HIV therapies, none of which involve inhibitors interfering with the gene regulation processes of the virus.


Assuntos
Fármacos Anti-HIV/química , HIV-1/química , Conformação de Ácido Nucleico , RNA Viral/química , Compostos de Terfenil/química , Produtos do Gene rev do Vírus da Imunodeficiência Humana/química , Linhagem Celular , Humanos , Conformação Proteica em alfa-Hélice
11.
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
12.
J Nat Med ; 74(3): 571-578, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32328863

RESUMO

Three new quassinoids, javanicinols A and B (1 and 2) and 4-keto-(16S)-methoxyjavanicin B (3), together with three known quassinoids (4-6) were isolated from the chloroform-soluble fraction of the methanol extract of the Picrasma javanica wood. The structures of 1-3 were determined by spectroscopic analyses, including 1D and 2D NMR, HRESIMS, and CD. The anti-HIV-1 viral protein R (Vpr) assay revealed that 1 and 2 exhibited potent anti-Vpr activities at 1.25 µM. Furthermore, the assay also revealed the potent anti-Vpr activities of (16R)-methoxyjavanicin B (7) and (16S)-methoxyjavanicin B (8), which were previously isolated from the Picrasma javanica wood.


Assuntos
Fármacos Anti-HIV/farmacologia , Produtos do Gene vpr/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Picrasma/química , Quassinas/farmacologia , Fármacos Anti-HIV/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Quassinas/química , Quassinas/isolamento & purificação , Madeira/química
13.
Nat Chem Biol ; 16(5): 529-537, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152540

RESUMO

Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional molecular targets. Here, we have identified several small-molecule fusion inhibitors, guided by a neutralizing antibody, against an extensively studied vaccine target-the membrane proximal external region (MPER) of the HIV-1 envelope spike. These compounds specifically inhibit the HIV-1 envelope-mediated membrane fusion by blocking CD4-induced conformational changes. An NMR structure of one compound complexed with a trimeric MPER construct reveals that the compound partially inserts into a hydrophobic pocket formed exclusively by the MPER residues, thereby stabilizing its prefusion conformation. These results suggest that the MPER is a potential therapeutic target for developing fusion inhibitors and that strategies employing an antibody-guided search for novel therapeutics may be applied to other human diseases.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/metabolismo , Internalização do Vírus/efeitos dos fármacos , Sítios de Ligação , Antígenos CD4/metabolismo , Membrana Celular/metabolismo , Dequalínio/química , Dequalínio/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Polarização de Fluorescência , Células HEK293 , Proteína gp41 do Envelope de HIV/genética , HIV-1/patogenicidade , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Mutação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície
14.
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
15.
Sci Rep ; 10(1): 3835, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123217

RESUMO

The use of antiretroviral therapy (ART) has remarkably decreased the morbidity associated with HIV-1 infection, however, the prevalence of HIV-1-associated neurocognitive disorders (HAND) is still increasing. The blood-brain barrier (BBB) is the major impediment for penetration of antiretroviral drugs, causing therapeutics to reach only suboptimal level to the brain. Conventional antiretroviral drug regimens are not sufficient to improve the treatment outcomes of HAND. In our recent report, we have developed a poloxamer-PLGA nanoformulation loaded with elvitegravir (EVG), a commonly used antiretroviral drug. The nanoformulated EVG is capable of elevating intracellular drug uptake and simultaneously enhance viral suppression in HIV-1-infected macrophages. In this work, we identified the clinical parameters including stability, biocompatibility, protein corona, cellular internalization pathway of EVG nanoformulation for its potential clinical translation. We further assessed the ability of this EVG nanoformulation to cross the in vitro BBB model and suppress the HIV-1 in macrophage cells. Compared with EVG native drug, our EVG nanoformulation demonstrated an improved BBB model penetration cross the in vitro BBB model and an enhanced HIV-1 suppression in HIV-1-infected human monocyte-derived macrophages after crossing the BBB model without altering the BBB model integrity. Overall, this is an innovative and optimized treatment strategy that has a potential for therapeutic interventions in reducing HAND.


Assuntos
Barreira Hematoencefálica/metabolismo , Composição de Medicamentos , HIV-1/efeitos dos fármacos , Macrófagos/virologia , Nanopartículas/química , Quinolonas/química , Quinolonas/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Humanos , Teste de Materiais , Tamanho da Partícula , Poloxâmero/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Quinolonas/metabolismo
16.
J Agric Food Chem ; 68(7): 2024-2030, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32037814

RESUMO

Artocarpus heterophyllus (jack tree) is an evergreen fruit tree belonging to the genus Artocarpus (Moraceae), which is widely distributed in subtropical and tropical regions of Asia. Its fruits (jackfruit), well-known as the world's largest tree-borne fruit, are being consumed in our daily diets as a very popular tropical fruit throughout the world and have been confirmed to hold various health benefits. In this study, five new prenylated chromones, artocarheterones A-E (1-5), as well as seven known prenylated chromones (6-12) were purified and isolated from the ripe fruits of A. heterophyllus (jackfruit). Their chemical structures were determined through comprehensive spectroscopic methods. This is the first report on prenylated chromones isolated from A. heterophyllus. The anti-HIV-1 effects of all isolated chromones were assessed in vitro. As a result, prenylated chromones (1-12) showed remarkable anti-HIV-1 effects with EC50 values ranging from 0.09 to 9.72 µM. These research results indicate that the isolation and characterization of these prenylated chromones with remarkable anti-HIV-1 activities from the ripe fruits of A. heterophyllus could be significant to the discovery and development of new anti-HIV-1 drugs.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Artocarpus/química , Cromonas/química , Cromonas/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Frutas/química , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Estrutura Molecular , Prenilação
17.
Phys Chem Chem Phys ; 22(8): 4464-4480, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32057044

RESUMO

Infection by human immunodeficiency virus type 1 (HIV-1) not only destroys the immune system bringing about acquired immune deficiency syndrome (AIDS), but also induces serious neurological diseases including behavioral abnormalities, motor dysfunction, toxoplasmosis, and HIV-1 associated dementia. The emergence of HIV-1 multidrug-resistant mutants has become a major problem in the therapy of patients with HIV-1 infection. Focusing on the wild type (WT) and G48T/L89M mutated forms of HIV-1 protease (HIV-1 PR) in complex with amprenavir (APV), indinavir (IDV), ritonavir (RTV), and nelfinavir (NFV), we have investigated the conformational dynamics and the resistance mechanism due to the G48T/L89M mutations by conducting a series of molecular dynamics (MD) simulations and free energy (MM-PBSA and solvated interaction energy (SIE)) analyses. The simulation results indicate that alterations in the side-chains of G48T/L89M mutated residues cause the inner active site to increase in volume and induce more curling of the flap tips, which provide the main contributions to weaker binding of inhibitors to the HIV-1 PR. The results of energy analysis reveal that the decrease in van der Waals interactions of inhibitors with the mutated PR relative to the wild-type (WT) PR mostly drives the drug resistance of mutations toward these four inhibitors. The energy decomposition analysis further indicates that the drug resistance of mutations can be mainly attributed to the change in van der Waals and electrostatic energy of some key residues (around Ala28/Ala28' and Ile50/Ile50'). Our work can give significant guidance to design a new generation of anti-AIDS inhibitors targeting PR in the therapy of patients with HIV-1 infection.


Assuntos
Protease de HIV/metabolismo , Simulação de Dinâmica Molecular , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Protease de HIV/genética , Indinavir/química , Indinavir/metabolismo , Conformação Molecular , Mutação , Nelfinavir/química , Nelfinavir/metabolismo , Ligação Proteica , Ritonavir/química , Ritonavir/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
18.
Alkaloids Chem Biol ; 83: 1-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32098648

RESUMO

Lamellarins are marine alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. To date, more than 50 lamellarins have been isolated from a variety of marine organisms, such as mollusks, tunicates, and sponges. Many of them, especially fused type I lamellarins, exhibit impressive biological activity, such as potent cytotoxicity, topoisomerase I inhibition, protein kinases inhibition, and anti-HIV-1 activity. Due to their useful biological activity and limited availability from natural sources, a number of synthetic methods have been developed. In this chapter, we present an updated and comprehensive review on lamellarin alkaloids summarizing their isolation, synthesis, and biological activity.


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/isolamento & purificação , Pirróis/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Pirróis/síntese química , Pirróis/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação
19.
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
20.
Nat Prod Res ; 34(9): 1197-1205, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30618287

RESUMO

Two new compounds, 5-[2-hydroxypropane-1-yl]-2,6-dimethlbenzene-1,3-diol (1) and coniochaetone L (2), together with 19 known compounds (3-21), were isolated from a deep-sea fungus, Penicillium sp. SCSIO 06720. Their structures and absolute configurations were elucidated by detailed NMR, MS spectroscopic analyses, chiral-phase HPLC analysis, and electronic circular dichroism spectra. All the isolated compounds (1-21) were tested for their antibacterial and HIV latency-reversal activities. Among these compounds, compound 16 showed moderate antibacterial activities against Staphylococcus aureus ATCC 29213 and Methicillin-Resistant Staphylococcus Aureus-shh-1 with MIC values of 10.4 ± 3.7 µg/mL and 46.9 ± 29.7 µg/mL, respectively, which were comparable to that of the positive control ampicillin with MIC values of 0.5 ± 0.4 µg/mL and 2.7 ± 0.9 µg/mL, respectively.


Assuntos
Antibacterianos/isolamento & purificação , Fármacos Anti-HIV/isolamento & purificação , Penicillium/química , Policetídeos/isolamento & purificação , Antibacterianos/química , Antibacterianos/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Policetídeos/química , Policetídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos
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