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1.
Virology ; 540: 195-206, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31929001

RESUMO

Respiratory syncytial virus (RSV) infection can cause mucus overproduction and bronchiolitis in infants leading to severe disease and hospitalization. As a therapeutic strategy, immune modulatory agents may help prevent RSV-driven immune responses that cause severe airway disease. We developed a high throughput screen to identify compounds that reduced RSV-driven mucin 5AC (Muc5AC) expression and identified dexamethasone. Despite leading to a pronounced reduction in RSV-driven Muc5AC, dexamethasone increased RSV infection in vitro and delayed viral clearance in mice. This correlated with reduced expression of a subset of immune response genes and reduced lymphocyte infiltration in vivo. Interestingly, dexamethasone increased RSV infection levels without altering antiviral interferon signaling. In summary, the immunosuppressive activities of dexamethasone had favorable inhibitory effects on RSV-driven mucus production yet prevented immune defense activities that limit RSV infection in vitro and in vivo. These findings offer an explanation for the lack of efficacy of glucocorticoids in RSV-infected patients.


Assuntos
Dexametasona/farmacologia , Interferons/metabolismo , Muco/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Camundongos , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/genética
2.
Sci Transl Med ; 11(491)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068442

RESUMO

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targets Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination of Wolbachia in the in vivo Litomosoides sigmodontis filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify Wolbachia elimination in Brugia pahangi filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed in L. sigmodontis, Brugia malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease and in vitro selectivity against Loa loa (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.


Assuntos
Antibacterianos/uso terapêutico , Descoberta de Drogas , Filariose/tratamento farmacológico , Filariose/parasitologia , Filarioidea/fisiologia , Quinazolinas/uso terapêutico , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Modelos Animais de Doenças , Feminino , Filarioidea/efeitos dos fármacos , Filarioidea/microbiologia , Ensaios de Triagem em Larga Escala , Camundongos , Fenótipo , Quinazolinas/química , Quinazolinas/farmacologia , Bibliotecas de Moléculas Pequenas , Wolbachia/efeitos dos fármacos
3.
Proc Natl Acad Sci U S A ; 115(42): 10750-10755, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30282735

RESUMO

The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of "drug repurposing" has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.


Assuntos
Antiprotozoários/farmacologia , Criptosporidiose/tratamento farmacológico , Cryptosporidium/efeitos dos fármacos , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Criptosporidiose/parasitologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL
4.
ACS Med Chem Lett ; 5(8): 947-50, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25147620

RESUMO

Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.

5.
Antimicrob Agents Chemother ; 58(9): 5060-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24913172

RESUMO

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.


Assuntos
Antimaláricos/farmacologia , Imidazóis/farmacologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/transmissão , Piperazinas/farmacologia , Animais , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos ICR , Plasmodium falciparum/efeitos dos fármacos , Esporozoítos/efeitos dos fármacos
6.
Nature ; 504(7479): 248-253, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24284631

RESUMO

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.


Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Malária/tratamento farmacológico , Malária/parasitologia , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , 1-Fosfatidilinositol 4-Quinase/química , 1-Fosfatidilinositol 4-Quinase/genética , 1-Fosfatidilinositol 4-Quinase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Sítios de Ligação , Citocinese/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Ácidos Graxos/metabolismo , Feminino , Hepatócitos/parasitologia , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Macaca mulatta , Masculino , Modelos Biológicos , Modelos Moleculares , Fosfatos de Fosfatidilinositol/metabolismo , Plasmodium/classificação , Plasmodium/crescimento & desenvolvimento , Pirazóis/metabolismo , Pirazóis/farmacologia , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Reprodutibilidade dos Testes , Esquizontes/citologia , Esquizontes/efeitos dos fármacos , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
7.
Science ; 334(6061): 1372-7, 2011 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-22096101

RESUMO

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.


Assuntos
Antimaláricos/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Fígado/parasitologia , Malária/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Eritrócitos/parasitologia , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Plasmodium/citologia , Plasmodium/crescimento & desenvolvimento , Plasmodium/fisiologia , Plasmodium berghei/citologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/fisiologia , Plasmodium falciparum/citologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/fisiologia , Plasmodium yoelii/citologia , Plasmodium yoelii/efeitos dos fármacos , Plasmodium yoelii/crescimento & desenvolvimento , Plasmodium yoelii/fisiologia , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Distribuição Aleatória , Bibliotecas de Moléculas Pequenas , Esporozoítos/efeitos dos fármacos , Esporozoítos/crescimento & desenvolvimento
8.
Mol Biochem Parasitol ; 175(1): 21-9, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20813141

RESUMO

The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC(50) values below 1.25µM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.


Assuntos
Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Enzimas/metabolismo , Concentração Inibidora 50 , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/antagonistas & inibidores
9.
Cell ; 135(1): 49-60, 2008 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-18854154

RESUMO

Human Immunodeficiency Viruses (HIV-1 and HIV-2) rely upon host-encoded proteins to facilitate their replication. Here, we combined genome-wide siRNA analyses with interrogation of human interactome databases to assemble a host-pathogen biochemical network containing 213 confirmed host cellular factors and 11 HIV-1-encoded proteins. Protein complexes that regulate ubiquitin conjugation, proteolysis, DNA-damage response, and RNA splicing were identified as important modulators of early-stage HIV-1 infection. Additionally, over 40 new factors were shown to specifically influence the initiation and/or kinetics of HIV-1 DNA synthesis, including cytoskeletal regulatory proteins, modulators of posttranslational modification, and nucleic acid-binding proteins. Finally, 15 proteins with diverse functional roles, including nuclear transport, prostaglandin synthesis, ubiquitination, and transcription, were found to influence nuclear import or viral DNA integration. Taken together, the multiscale approach described here has uncovered multiprotein virus-host interactions that likely act in concert to facilitate the early steps of HIV-1 infection.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas/metabolismo , Replicação Viral , Linhagem Celular , Humanos , Interferência de RNA , Técnicas do Sistema de Duplo-Híbrido
10.
Virology ; 362(1): 16-25, 2007 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-17257639

RESUMO

Despite decades of research, HIV remains a global health threat. Issues of multi-drug resistance and lack of an effective vaccine have recently led to the targeting of host factors for anti-viral drug development. While a few genome-wide screens for novel HIV co-factors have been reported, the promise of finding a therapeutic target has yet to be realized. Here, we report a screen of a cDNA library representing 15,000 unique genes in an infectious HIV system, and show that genomic screening can lead to the identification of novel proviral host factors. Mixed lineage kinase 3 (MLK3/MAP3K11) was identified as one of the strongest enhancers of infection and mutant studies show that its activity is dependent on its kinase function. Consistent with its known role in the activation of the AP-1 pathway through JNK kinase, MLK3 was able to enhance Tat-dependent HIV transcription in vitro thus leading to an increase in infection signal. RNA interference studies confirm the involvement of endogenous MLK3 in HIV infection, further implicating this kinase as a potential therapeutic target.


Assuntos
DNA Complementar/análise , Infecções por HIV/genética , HIV/crescimento & desenvolvimento , MAP Quinase Quinase Quinases/fisiologia , Fármacos Anti-HIV/farmacologia , Biblioteca Gênica , Produtos do Gene tat/fisiologia , Genoma , Infecções por HIV/tratamento farmacológico , Células HeLa , Humanos , Células Jurkat , MAP Quinase Quinase Quinases/genética , Mutação , Provírus/crescimento & desenvolvimento , Interferência de RNA , Transcrição Gênica , Produtos do Gene tat do Vírus da Imunodeficiência Humana , MAP Quinase Quinase Quinase 11 Ativada por Mitógeno
11.
Bioorg Med Chem Lett ; 17(1): 260-5, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17035019

RESUMO

A series of 4-aminopyrimidines (1) was identified as novel HIV inhibitors of unknown molecular target. Structural modifications were carried out to establish its SAR and identify the linking site for target identification. A number of analogs were found to possess single digit inhibitory activity for HIV replication. Several analogs with various potential linkers, including a biotinated analog, also exhibited excellent potency, and could serve as tools for the identification of novel anti-HIV targets.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirimidinas/química , Fármacos Anti-HIV/síntese química , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 16(16): 4174-7, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16781149

RESUMO

A novel sulfanyltriazole was discovered as an HIV-1 non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Chemical modifications and molecular modeling studies were carried out to establish its SAR and understand its interactions with the enzyme. These modifications led to the identification of sulfanyltriazoles with low nanomolar potency for inhibiting HIV-1 replication and promising activities against selected NNRTI resistant mutants. These novel and potent sulfanyltriazoles could serve as advanced leads for further optimization.


Assuntos
Fármacos Anti-HIV/farmacologia , Química Farmacêutica/métodos , HIV-1/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/química , Desenho de Fármacos , Farmacorresistência Viral , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Mutação , Compostos de Enxofre/química , Temperatura , Replicação Viral
13.
Bioorg Med Chem Lett ; 16(16): 4246-51, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16782337

RESUMO

A novel series of quinolones was discovered as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a structure-based approach. The lead quinolones exhibited single digit nanomolar potency in the HIV-1 replication assays. The preliminary SAR of these quinolones was also established via systematic structural modifications. These novel and potent quinolones could serve as advanced leads for further optimization.


Assuntos
Inibidores da Transcriptase Reversa/farmacologia , Sítios de Ligação , Farmacorresistência Viral , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/metabolismo , Modelos Químicos , Modelos Moleculares , Mutação , Quinolonas/química , Relação Estrutura-Atividade , Replicação Viral
14.
Bioorg Med Chem Lett ; 16(8): 2105-8, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16480865

RESUMO

A novel oxindole was discovered as an HIV non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Systematic structural modifications were carried out to establish its SAR. These modifications led to the identification of oxindoles with low nanomolar potency for inhibiting HIV replication. These novel and potent oxindoles could serve as advanced leads for further optimizations.


Assuntos
HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Indóis/síntese química , Indóis/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral
15.
Bioorg Med Chem Lett ; 16(8): 2109-12, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16464578

RESUMO

A series of heterocycle-containing oxindoles was synthesized and their HIV antiviral activities were assessed. Some of these analogs exhibited potent inhibitory activities against both wild-type virus and a number of drug-resistant mutant viruses. In addition, oxindole 9z also showed promising pharmacokinetics.


Assuntos
HIV-1/efeitos dos fármacos , Indóis/síntese química , Indóis/farmacocinética , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinética , Replicação Viral/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Farmacorresistência Viral , Estereoisomerismo , Relação Estrutura-Atividade
16.
J Virol ; 80(1): 130-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16352537

RESUMO

In order to identify novel proviral host factors involved in human immunodeficiency virus (HIV) infection, we performed a screen of a small interfering RNA (siRNA) library targeting 5,000 genes with the highest potential for being targets for therapeutics. Many siRNAs in the library against known host factors, such as TSG101, furin, and CXCR4, were identified as inhibitors by the screen and thus served as internal validation. In addition, many novel factors whose knockdown inhibited infection were identified, including Pak3, a member of the serine/threonine group I PAK kinases. The HIV accessory factor Nef has been shown to associate with a PAK kinase, leading to enhanced viral production; however, the exact identity of the kinase has remained controversial. Prompted by the Pak3 screen hit, we further investigated the involvement of group I PAK kinases in HIV using siRNA. Contrary to the current literature, Pak1 depletion strongly inhibited HIV infection in multiple cell systems and decreased levels of integrated provirus, while Pak2 depletion showed no effect. Overexpression of a constitutively active Pak1 mutant also enhanced HIV infection, further supporting its role as the dominant PAK involved.


Assuntos
Regulação Viral da Expressão Gênica/efeitos dos fármacos , Infecções por HIV , Proteínas Serina-Treonina Quinases/fisiologia , RNA Interferente Pequeno/farmacologia , Replicação Viral/efeitos dos fármacos , HIV-1/fisiologia , Células HeLa , Humanos , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/genética , Receptores de Superfície Celular/genética , Receptores Virais/genética , Replicação Viral/genética , Quinases Ativadas por p21
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