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1.
Int J Mol Sci ; 24(22)2023 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-38003463

RESUMO

Stimulator of interferon genes (STING) agonists have shown potent anti-tumor efficacy in various mouse tumor models and have the potential to overcome resistance to immune checkpoint inhibitors (ICI) by linking the innate and acquired immune systems. First-generation STING agonists are administered intratumorally; however, a systemic delivery route would greatly expand the clinical use of STING agonists. Biochemical and cell-based experiments, as well as syngeneic mouse efficacy models, were used to demonstrate the anti-tumoral activity of ALG-031048, a novel STING agonist. In vitro, ALG-031048 is highly stable in plasma and liver microsomes and is resistant to degradation via phosphodiesterases. The high stability in biological matrices translated to good cellular potency in a HEK 293 STING R232 reporter assay, efficient activation and maturation of primary human dendritic cells and monocytes, as well as long-lasting, antigen-specific anti-tumor activity in up to 90% of animals in the CT26 mouse colon carcinoma model. Significant reductions in tumor growth were observed in two syngeneic mouse tumor models following subcutaneous administration. Combinations of ALG-031048 and ICIs further enhanced the in vivo anti-tumor activity. This initial demonstration of anti-tumor activity after systemic administration of ALG-031048 warrants further investigation, while the combination of systemically administered ALG-031048 with ICIs offers an attractive approach to overcome key limitations of ICIs in the clinic.


Assuntos
Neoplasias do Colo , Neoplasias , Camundongos , Animais , Humanos , Células HEK293 , Neoplasias/patologia , Neoplasias do Colo/tratamento farmacológico , Modelos Animais de Doenças , Imunoterapia , Microambiente Tumoral
2.
Molecules ; 27(8)2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35458620

RESUMO

Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2'-hydroxy- and 2'-hydroxymethyl-apionucleosides, 4 and 5, corresponding triphosphates and phosphoramidate prodrugs. Triphosphate 38 of 2'-hydroxymethyl-apionucleoside 5 exhibited potent inhibition of HBV polymerase with an IC50 value of 120 nM. In an HBV cell-based assay, the phosphoramidate prodrug 39 demonstrated potent activity with an EC50 value of 7.8 nM.


Assuntos
Antivirais , Pró-Fármacos , Antivirais/farmacologia , Vírus da Hepatite B , Nucleosídeos/farmacologia , Pró-Fármacos/farmacologia
3.
Antiviral Res ; 143: 151-161, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28412183

RESUMO

Recent cases of severe toxicity during clinical trials have been associated with antiviral ribonucleoside analogs (e.g. INX-08189 and balapiravir). Some have hypothesized that the active metabolites of toxic ribonucleoside analogs, the triphosphate forms, inadvertently target human mitochondrial RNA polymerase (POLRMT), thus inhibiting mitochondrial RNA transcription and protein synthesis. Others have proposed that the prodrug moiety released from the ribonucleoside analogs might instead cause toxicity. Here, we report the mitochondrial effects of several clinically relevant and structurally diverse ribonucleoside analogs including NITD-008, T-705 (favipiravir), R1479 (parent nucleoside of balapiravir), PSI-7851 (sofosbuvir), and INX-08189 (BMS-986094). We found that efficient substrates and chain terminators of POLRMT, such as the nucleoside triphosphate forms of R1479, NITD-008, and INX-08189, are likely to cause mitochondrial toxicity in cells, while weaker chain terminators and inhibitors of POLRMT such as T-705 ribonucleoside triphosphate do not elicit strong in vitro mitochondrial effects. Within a fixed 3'-deoxy or 2'-C-methyl ribose scaffold, changing the base moiety of nucleotides did not strongly affect their inhibition constant (Ki) against POLRMT. By swapping the nucleoside and prodrug moieties of PSI-7851 and INX-08189, we demonstrated that the cell-based toxicity of INX-08189 is mainly caused by the nucleoside component of the molecule. Taken together, these results show that diverse 2' or 4' mono-substituted ribonucleoside scaffolds cause mitochondrial toxicity. Given the unpredictable structure-activity relationship of this ribonucleoside liability, we propose a rapid and systematic in vitro screen combining cell-based and biochemical assays to identify the early potential for mitochondrial toxicity.


Assuntos
Antivirais/toxicidade , Mitocôndrias/efeitos dos fármacos , Ribonucleosídeos/química , Ribonucleosídeos/toxicidade , Adenosina/análogos & derivados , Amidas/toxicidade , Linhagem Celular/efeitos dos fármacos , Citidina/análogos & derivados , Citidina/toxicidade , RNA Polimerases Dirigidas por DNA/efeitos dos fármacos , Guanosina Monofosfato/análogos & derivados , Guanosina Monofosfato/toxicidade , Humanos , Concentração Inibidora 50 , Proteínas Mitocondriais/metabolismo , Nucleosídeos/toxicidade , Pró-Fármacos/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Pirazinas/toxicidade , RNA/metabolismo , RNA Mitocondrial , Sofosbuvir/toxicidade , Relação Estrutura-Atividade , Sítio de Iniciação de Transcrição/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos
4.
J Med Chem ; 59(10): 4611-24, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27120583

RESUMO

Influenza viruses are responsible for seasonal epidemics and occasional pandemics which cause significant morbidity and mortality. Despite available vaccines, only partial protection is achieved. Currently, there are two classes of widely approved anti-influenza drugs: M2 ion channel blockers and neuraminidase inhibitors. However, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action. Favipiravir (T-705), a broad-spectrum antiviral agent, has shown potent anti-influenza activity in cell-based assays, and its riboside (2) triphosphate inhibited influenza polymerase. In one of our approaches to treat influenza infection, we designed, prepared, and tested a series of C-nucleoside analogues, which have an analogy to 2 and were expected to act by a similar antiviral mechanism as favipiravir. Compound 3c of this report exhibited potent inhibition of influenza virus replication in MDCK cells, and its triphosphate was a substrate of and demonstrated inhibitory activity against influenza A polymerase. Metabolites of 3c are also presented.


Assuntos
Antivirais/farmacologia , Nucleosídeos/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Piridazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Feminino , Humanos , Células Madin Darby de Rim Canino/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Piridazinas/síntese química , Piridazinas/química , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
5.
Antimicrob Agents Chemother ; 60(3): 1264-73, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26666922

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children. In addition, RSV causes significant morbidity and mortality in hospitalized elderly and immunocompromised patients. Currently, only palivizumab, a monoclonal antibody against the RSV fusion (F) protein, and inhaled ribavirin are approved for the prophylactic and therapeutic treatment of RSV, respectively. Therefore, there is a clinical need for safe and effective therapeutic agents for RSV infections. GS-5806, discovered via chemical optimization of a hit from a high-throughput antiviral-screening campaign, selectively inhibits a diverse set of 75 RSV subtype A and B clinical isolates (mean 50% effective concentration [EC50] = 0.43 nM). The compound maintained potency in primary human airway epithelial cells and exhibited low cytotoxicity in human cell lines and primary cell cultures (selectivity > 23,000-fold). Time-of-addition and temperature shift studies demonstrated that GS-5806 does not block RSV attachment to cells but interferes with virus entry. Follow-up experiments showed potent inhibition of RSV F-mediated cell-to-cell fusion. RSV A and B variants resistant to GS-5806, due to mutations in F protein (RSV A, L138F or F140L/N517I, and RSV B, F488L or F488S), were isolated and showed cross-resistance to other RSV fusion inhibitors, such as VP-14637, but remained fully sensitive to palivizumab and ribavirin. In summary, GS-5806 is a potent and selective RSV fusion inhibitor with antiviral activity against a diverse set of RSV clinical isolates. The compound is currently under clinical investigation for the treatment of RSV infection in pediatric, immunocompromised, and elderly patients.


Assuntos
Antivirais/farmacologia , Pirazóis/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Sulfonamidas/farmacologia , Brônquios/citologia , Brônquios/virologia , Fusão Celular , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Humanos , Indazóis , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/isolamento & purificação , Vírus Sincicial Respiratório Humano/patogenicidade , Internalização do Vírus/efeitos dos fármacos
6.
J Med Chem ; 58(4): 1630-43, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25574686

RESUMO

GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Pirazóis/farmacologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Sulfonamidas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/química , Cães , Relação Dose-Resposta a Droga , Humanos , Indazóis , Macaca fascicularis , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazóis/administração & dosagem , Pirazóis/química , Ratos , Vírus Sinciciais Respiratórios/fisiologia , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/química
7.
PLoS One ; 2(7): e655, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17668043

RESUMO

BACKGROUND: The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals. METHODOLOGY/PRINCIPAL FINDINGS: Endpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions. CONCLUSION: Given the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Camundongos SCID/genética , Imunodeficiência Combinada Severa/genética , Síndrome da Imunodeficiência Adquirida/genética , Animais , Antirretrovirais/uso terapêutico , DNA Viral/genética , Modelos Animais de Doenças , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/fisiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Camundongos , RNA Viral/genética , Imunodeficiência Combinada Severa/imunologia , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
8.
J Exp Med ; 204(5): 1217-25, 2007 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-17485516

RESUMO

The salivary glands represent a major site of cytomegalovirus replication and transmission to other hosts. Despite control of viral infection by strong T cell responses in visceral organs cytomegalovirus replication continues in the salivary glands of mice, suggesting that the virus exploits the mucosal microenvironment. Here, we show that T cell immunity in the salivary glands is limited by the induction of CD4 T cells expressing the regulatory cytokine interleukin (IL)-10. Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced viral load in the salivary glands, but not in the spleen. The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumulation of CD4 T cells expressing interferon gamma, suggesting that IL-10R signaling limits effector T cell differentiation. Consistent with this, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced effector T cell differentiation and increased the number of interferon gamma-producing T cells, thus limiting virus replication in the salivary glands. Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/imunologia , Infecções por Herpesviridae/imunologia , Interleucina-10/metabolismo , Muromegalovirus/fisiologia , Glândulas Salivares/imunologia , Replicação Viral/fisiologia , Animais , Anticorpos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Primers do DNA , Feminino , Citometria de Fluxo , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia , Receptores de Interleucina-10/antagonistas & inibidores , Receptores OX40/agonistas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Glândulas Salivares/virologia
9.
Trends Immunol ; 27(8): 362-7, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16807107

RESUMO

Is there a "conspiracy" at work among viral pathogens? Apparently, yes. Rabies virus, lenti- and retroviruses, and herpesviruses, the "co-conspirators", target select members of the tumor necrosis factor (TNF) receptor superfamily to invade the cells of their host. The intrigue deepens, as several reports have revealed that the viral envelope proteins interact with the cellular TNF receptor in a highly conserved region of previously unknown function. Targeting of this region by diverse pathogens suggests that a selective advantage is acquired. This advantage might involve regulation of the immune response, because recent investigations of the herpesvirus entry receptor demonstrated that this conserved region engages an inhibitory co-receptor governing T-cell activation.


Assuntos
Vírus de DNA/fisiologia , Sistema do Grupo Sanguíneo Duffy/genética , Sistema do Grupo Sanguíneo Duffy/imunologia , Vírus de RNA/fisiologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia , Sequência de Aminoácidos , Cisteína/genética , Vírus de DNA/genética , Vírus de DNA/metabolismo , Modelos Biológicos , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Vírus de RNA/genética , Vírus de RNA/metabolismo , Homologia de Sequência de Aminoácidos
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