RESUMO
The Alphavirus genus includes viruses that cause encephalitis due to neuroinvasion and viruses that cause arthritis due to acute and chronic inflammation. There is no approved therapeutic for alphavirus infections, but significant efforts are ongoing, more so in recent years, to develop vaccines and therapeutics for alphavirus infections. This review article highlights some of the major advances made so far to identify small molecules that can selectively target the structural and the nonstructural proteins in alphaviruses with the expectation that persistent investigation of an increasingly expanding chemical space through a variety of structure-based design and high-throughput screening strategies will yield candidate drugs for clinical studies. While most of the works discussed are still in the early discovery to lead optimization stages, promising avenues remain for drug development against this family of viruses.
Assuntos
Alphavirus , Antivirais , Proteínas não Estruturais Virais , Alphavirus/efeitos dos fármacos , Alphavirus/química , Antivirais/farmacologia , Antivirais/química , Humanos , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/virologia , Animais , Proteínas Estruturais Virais/química , Proteínas Estruturais Virais/antagonistas & inibidoresRESUMO
Various low-density lipoprotein receptors (LPRs) have been identified as entry factors for alphaviruses, and structures of the corresponding virion-receptor complexes have been determined. Here, we analyze the similarities and differences in the receptor binding modes of multiple alphaviruses to understand their ability to infect a wide range of hosts. We further discuss the challenges associated with the development of broad-spectrum treatment strategies against a diverse range of alphaviruses.
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Alphavirus , Antivirais , Receptores de LDL , Internalização do Vírus , Animais , Humanos , Alphavirus/efeitos dos fármacos , Alphavirus/fisiologia , Alphavirus/genética , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/virologia , Antivirais/uso terapêutico , Antivirais/farmacologia , Ligação Proteica , Receptores de LDL/metabolismo , Receptores de LDL/genética , Receptores Virais/metabolismo , Receptores Virais/química , Vírion/metabolismo , Internalização do Vírus/efeitos dos fármacosRESUMO
INTRODUCTION: Mayaro fever is an emerging viral disease that manifests as an acute febrile illness. The disease is self-limiting, however joint pain can persist for months leading to chronic arthralgia. There is no specific treatment available, which ultimately leads to socioeconomic losses in populations at risk as well as strains to the public health systems. AREAS COVERED: We reviewed the candidate treatments proposed for Mayaro virus (MAYV) infection and disease, including antiviral compounds targeting viral or host mechanisms, and pathways involved in disease development and pathogenicity. We assessed compound screening technologies and experimental infection models used in these studies and indicated the advantages and limitations of available technologies and intended therapeutic strategies. EXPERT OPINION: Although several compounds have been suggested as candidate treatments against MAYV infection, notably those with antiviral activity, most compounds were assessed only in vitro. Compounds rarely progress toin vivo or preclinical studies, and such difficulty may be associated with limited experimental models. MAYV biology is largely inferred from related alphaviruses and reflected by few studies focusing on target proteins or mechanisms of action for MAYV. Therapeutic strategies targeting pathogenic inflammatory responses have shown potential against MAYV-induced disease in vivo, which might reduce long-term sequelae.
Assuntos
Infecções por Alphavirus , Antivirais , Descoberta de Drogas , Animais , Antivirais/farmacologia , Humanos , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/virologia , Alphavirus , Artralgia/tratamento farmacológico , Desenvolvimento de Medicamentos , Terapia de Alvo Molecular , Modelos Animais de DoençasRESUMO
Arthritis and periodontitis are inflammatory diseases that share several immunopathogenic features. The expansion in the study of virus-induced arthritis has shed light on how this condition could impact other parts of the human body, including the mouth. Viral arthritis is an inflammatory joint disease caused by several viruses, most notably the alphaviruses Chikungunya virus (CHIKV), Sindbis virus (SINV), Ross River virus (RRV), Mayaro virus (MAYV), and O'nyong'nyong virus (ONNV). These viruses can induce an upsurge of matrix metalloproteinases and immune-inflammatory mediators such as Interleukin-6 (IL6), IL-1ß, tumor necrosis factor, chemokine ligand 2, and receptor activator of nuclear factor kappa-B ligand in the joint and serum of infected individuals. This can lead to the influx of inflammatory cells to the joints and associated muscles as well as osteoclast activation and differentiation, culminating in clinical signs of swelling, pain, and bone resorption. Moreover, several data indicate that these viral infections can affect other sites of the body, including the mouth. The human oral cavity is a rich and diverse microbial ecosystem, and viral infection can disrupt the balance of microbial species, causing local dysbiosis. Such events can result in oral mucosal damage and gingival bleeding, which are indicative of periodontitis. Additionally, infection by RRV, CHIKV, SINV, MAYV, or ONNV can trigger the formation of osteoclasts and upregulate pro-osteoclastogenic inflammatory mediators, interfering with osteoclast activation. As a result, these viruses may be linked to systemic conditions, including oral manifestations. Therefore, this review focuses on the involvement of alphavirus infections in joint and oral health, acting as potential agents associated with oral mucosal inflammation and alveolar bone loss. The findings of this review demonstrate how alphavirus infections could be linked to the comorbidity between arthritis and periodontitis and may provide a better understanding of potential therapeutic management for both conditions.
Assuntos
Infecções por Alphavirus , Artrite , Vírus Chikungunya , Periodontite , Humanos , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/patologia , Vírus Chikungunya/fisiologia , Mediadores da Inflamação/uso terapêutico , Ligantes , Ross River virus/fisiologiaRESUMO
Mayaro virus is an emerging arbovirus that causes nonspecific febrile illness or arthralgia syndromes similar to the Chikungunya virus, a virus closely related from the Togaviridae family. MAYV outbreaks occur more frequently in the northern and central-western states of Brazil; however, in recent years, virus circulation has been spreading to other regions. Due to the undifferentiated initial clinical symptoms between MAYV and other endemic pathogenic arboviruses with geographic overlapping, identification of patients infected by MAYV might be underreported. Additionally, the lack of specific prophylactic approaches or antiviral drugs limits the pharmacological management of patients to treat symptoms like pain and inflammation, as is the case with most pathogenic alphaviruses. In this context, this review aims to present the state-of-the-art regarding the screening and development of compounds/molecules which may present anti-MAYV activity and infection inhibition.
Assuntos
Infecções por Alphavirus , Alphavirus , Arbovírus , Vírus Chikungunya , Alphavirus/fisiologia , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/epidemiologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Vírus Chikungunya/fisiologia , Desenvolvimento de Medicamentos , HumanosRESUMO
The discovery and the development of safe and efficient therapeutics against arthritogenic alphaviruses (e.g., chikungunya virus) remain a continuous challenge. Alkaloids are structurally diverse and naturally occurring compounds in plants, with a wide range of biological activities including beneficial effects against prominent pathogenic viruses and inflammation. In this short review, we discuss the effects of some alkaloids of three biologically relevant structural classes (isoquinolines, indoles and quinolizidines). Based on various experimental models (viral infections and chronic diseases), we highlight the immunomodulatory effects of these alkaloids. The data established the capacity of these alkaloids to interfere in host antiviral and inflammatory responses through key components (antiviral interferon response, ROS production, inflammatory signaling pathways and pro- and anti-inflammatory cytokines production) also involved in alphavirus infection and resulting inflammation. Thus, these data may provide a convincing perspective of research for the use of alkaloids as immunomodulators against arthritogenic alphavirus infection and induced inflammation.
Assuntos
Alcaloides , Infecções por Alphavirus , Vírus Chikungunya , Quinolizidinas , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/patologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Vírus Chikungunya/fisiologia , Humanos , Indóis/uso terapêutico , Inflamação , Isoquinolinas , Quinolizidinas/farmacologiaRESUMO
Enteric pathogens overcome barrier immunity within the intestinal environment that includes the endogenous flora. The microbiota produces diverse ligands, and the full spectrum of microbial products that are sensed by the epithelium and prime protective immunity is unknown. Using Drosophila, we find that the gut presents a high barrier to infection, which is partially due to signals from the microbiota, as loss of the microbiota enhances oral viral infection. We report cyclic dinucleotide (CDN) feeding is sufficient to protect microbiota-deficient flies from enhanced oral infection, suggesting that bacterial-derived CDNs induce immunity. Mechanistically, we find CDN protection is dSTING- and dTBK1-dependent, leading to NF-kB-dependent gene expression. Furthermore, we identify the apical nucleoside transporter, CNT2, as required for oral CDN protection. Altogether, our studies define a role for bacterial products in priming immune defenses in the gut.
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Infecções por Alphavirus/imunologia , Antivirais/farmacologia , Drosophila melanogaster/imunologia , Enterócitos/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Nucleotídeos Cíclicos/administração & dosagem , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/virologia , Animais , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Enterócitos/efeitos dos fármacos , Enterócitos/virologia , Feminino , Imunidade Inata , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Sindbis virus/imunologiaRESUMO
Mayaro virus (MAYV) is a neglected arthropod-borne virus found in the Americas. MAYV infection results in Mayaro fever, a non-lethal debilitating disease characterized by a strong inflammatory response affecting the joints and muscles. MAYV was once considered endemic to forested areas in Brazil but has managed to adapt and spread to urban regions using new vectors, such as Aedes aegypti, and has the potential to cause serious epidemics in the future. Currently, there are no vaccines or specific treatments against MAYV. In this study, the antiviral activity of a series of synthetic cyclic ketones were evaluated for the first time against MAYV. Twenty-four compounds were screened in a cell viability assay, and eight were selected for further evaluation. Effective concentration (EC50) and selectivity index (SI) were calculated and compound 9-(5-(4-chlorophenyl]furan-2-yl)-3,6-dimethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2))-dione (9) (EC50 = 21.5 µmol·L-1, SI = 15.8) was selected for mechanism of action assays. The substance was able to reduce viral activity by approximately 70% in both pre-treatment and post-treatment assays.
Assuntos
Infecções por Alphavirus/virologia , Alphavirus/efeitos dos fármacos , Antivirais/farmacologia , Cetonas/farmacologia , Aedes/virologia , Alphavirus/fisiologia , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/transmissão , Animais , Antivirais/química , Brasil , Avaliação Pré-Clínica de Medicamentos , Humanos , Cetonas/química , Mosquitos Vetores/virologiaRESUMO
Mayaro virus (MAYV) is an emergent alphavirus that causes MAYV fever. It is often associated with debilitating symptoms, particularly arthralgia and myalgia. MAYV infection is becoming a considerable health issue that, unfortunately, lacks a specific antiviral treatment. Favipiravir, a broad-spectrum antiviral drug, has recently been shown to exert anti-MAYV activity in vitro. In the present study, the potential of Favipiravir to inhibit MAYV replication in an in vivo model was evaluated. Immunocompetent mice were orally administrated 300 mg/kg/dose of Favipiravir at pre-, concurrent-, or post-MAYV infection. The results showed a significant reduction in infectious viral particles and viral RNA transcripts in the tissues and blood of the pre- and concurrently treated infected mice. A significant reduction in the presence of both viral RNA transcript and infectious viral particles in the tissue and blood of pre- and concurrently treated infected mice was observed. By contrast, Favipiravir treatment post-MAYV infection did not result in a reduction in viral replication. Interestingly, Favipiravir strongly decreased the blood levels of the liver disease markers aspartate- and alanine aminotransferase in the pre- and concurrently treated MAYV-infected mice. Taken together, these results suggest that Favipiravir is a potent antiviral drug when administered in a timely manner.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Alphavirus/efeitos dos fármacos , Amidas/farmacologia , Antivirais/farmacologia , Pirazinas/farmacologia , Alanina Transaminase/efeitos dos fármacos , Infecções por Alphavirus/virologia , Animais , Aspartato Aminotransferases/efeitos dos fármacos , Linhagem Celular , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Infection caused by Mayaro virus (MAYV) is responsible for causing acute nonspecific fever, in which the majority of patients develop incapacitating and persistent arthritis/arthralgia. Mayaro fever is a neglected and underreported disease without treatment or vaccine, which has gained attention in recent years after the competence of Aedes aegypti to transmit MAYV was observed in the laboratory, coupled with the fact that cases are being increasingly reported outside of endemic forest areas, calling attention to the potential of an urban cycle arising in the near future. Thus, to mitigate the lack of information about the pathological aspects of MAYV, we previously described the involvement of oxidative stress in MAYV infection in cultured cells and in a non-lethal mouse model. Additionally, we showed that silymarin, a natural compound, attenuated MAYV-induced oxidative stress and inhibited MAYV replication in cells. The antioxidant and anti-MAYV effects prompted us to determine whether silymarin could also reduce oxidative stress and MAYV replication after infection in an immunocompetent animal model. We show that infected mice exhibited reduced weight gain, hepatomegaly, splenomegaly, anaemia, thrombocytopenia, leukopenia, increased liver transaminases, increased pro-inflammatory cytokines and liver inflammation, increased oxidative damage biomarkers, and reduced antioxidant enzyme activity. However, in animals infected and treated with silymarin, all these parameters were reversed or significantly improved, and the detection of viral load in the liver, spleen, brain, thigh muscle, and footpad was significantly reduced. This work reinforces the potent hepatoprotective, antioxidant, anti-inflammatory, and antiviral effects of silymarin against MAYV infection, demonstrating its potential against Mayaro fever disease.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Alphavirus/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antivirais/farmacologia , Silimarina/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia/métodosRESUMO
Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O'nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1ß was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1ß treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Antivirais/farmacologia , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Irinotecano/farmacologia , Citocinas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Cultura Primária de Células , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologiaRESUMO
The antiviral innate immune response mainly involves type I interferon (IFN) in mammalian cells. The contribution of the RNA silencing machinery remains to be established, but several recent studies indicate that the ribonuclease DICER can generate viral siRNAs in specific conditions. It has also been proposed that type I IFN and RNA silencing could be mutually exclusive antiviral responses. In order to decipher the implication of DICER during infection of human cells with alphaviruses such as the Sindbis virus and Semliki forest virus, we determined its interactome by proteomics analysis. We show that DICER specifically interacts with several double-stranded RNA binding proteins and RNA helicases during viral infection. In particular, proteins such as DHX9, ADAR-1 and the protein kinase RNA-activated (PKR) are enriched with DICER in virus-infected cells. We demonstrate that the helicase domain of DICER is essential for this interaction and that its deletion confers antiviral properties to this protein in an RNAi-independent, PKR-dependent, manner.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Antivirais/farmacologia , RNA Helicases DEAD-box/metabolismo , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Ribonuclease III/metabolismo , Vírus da Floresta de Semliki/efeitos dos fármacos , Replicação Viral , eIF-2 Quinase/metabolismo , Infecções por Alphavirus/metabolismo , Infecções por Alphavirus/patologia , RNA Helicases DEAD-box/genética , Células HEK293 , Humanos , Interferon Tipo I/farmacologia , Ribonuclease III/genética , eIF-2 Quinase/genéticaRESUMO
O'nyong-nyong virus is an alphavirus closely related to chikungunya virus, causing arthralgia, rash and fever. Alphaviruses mainly target synovial fibroblasts and persists in the joints of patients, possibly leading to chronic arthritis. To date, no specific antiviral treatment is available for ONNV infection and induced-inflammation. Primary human synovial fibroblasts cells were used to assess infection by ONNV and the resulting cytokine responses. Phenolics (gallic acid, caffeic acid and chlorogenic acid, curcumin and quercetin) and a curcuminoids-rich extract from turmeric were tested for their antiviral and anti-inflammatory capacities. We showed that infection occurred in HSF cells and increased gene expression and protein secretion of two major proinflammatory CCL-2 and IL-1ß markers. In ONNV-infected HSF cells (MOI 1), we found that non-cytotoxic concentrations of phenolics (10 µM) reduced the level of viral RNA (E1, E2, nsP1, nsP2) and downregulated CCL-2 and IL-1ß expression and secretion. These results highlighted the high value of the flavonol quercetin to reduce viral RNA levels and inflammatory status induced by ONNV in HSF cells.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Quimiocina CCL2/genética , Imunidade Inata/genética , Interleucina-1beta/genética , Infecções por Alphavirus/genética , Infecções por Alphavirus/patologia , Infecções por Alphavirus/virologia , Ácidos Cafeicos/farmacologia , Ácido Clorogênico/farmacologia , Curcumina/farmacologia , Citocinas/genética , Fibroblastos/virologia , Ácido Gálico/farmacologia , Humanos , Imunidade Inata/efeitos dos fármacos , Vírus O'nyong-nyong/genética , Vírus O'nyong-nyong/patogenicidade , Quercetina/farmacologia , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/virologiaRESUMO
Tropical infectious diseases cause millions of deaths every year in developing countries, with about half of the world population living at risk. Mayaro virus (MAYV) is an emerging arbovirus that causes Mayaro fever, which is characterized by fever, headache, diarrhea, arthralgia, and rash. These symptoms can be clinically indistinguishable from other arboviruses, such as Dengue, Zika, and Chikungunya, which makes the diagnosis and treatment of the disease more difficult. Though, the Mayaro virus is a potential candidate to cause large-scale epidemics on the scale of ZIKV and CHIKV. Despite this, there is no licensed vaccine or antiviral for the treatment of Mayaro fever and most arboviruses, so the design and development of candidates for antiviral drugs are urgently needed. In this context, this mini-review aims to provide an overview of studies of anti-MAYV derivatives and highlight the importance of the discovery and development of promising drug candidates for Mayaro fever.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Alphavirus/efeitos dos fármacos , Alphavirus/fisiologia , Antivirais/farmacologia , Descoberta de Drogas , Antivirais/química , Antivirais/uso terapêutico , HumanosRESUMO
Arboviruses are a diverse group of viruses that are among the major causes of emerging infectious diseases. Arboviruses from the genera flavivirus and alphavirus are the most important human arboviruses from a public health perspective. During recent decades, these viruses have been responsible for millions of infections and deaths around the world. Over the past few years, several investigations have been carried out to identify antiviral agents to treat these arbovirus infections. The use of synthetic antiviral compounds is often unsatisfactory since they may raise the risk of viral mutation; they are costly and possess either side effects or toxicity. One attractive strategy is the use of plants as promising sources of novel antiviral compounds that present significant inhibitory effects on these viruses. In this review, we describe advances in the exploitation of compounds and extracts from natural sources that target the vital proteins and enzymes involved in arbovirus replication.
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Infecções por Alphavirus/tratamento farmacológico , Antivirais/farmacologia , Infecções por Flavivirus/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Alphavirus/efeitos dos fármacos , Alphavirus/genética , Alphavirus/patogenicidade , Infecções por Alphavirus/transmissão , Infecções por Alphavirus/virologia , Animais , Antivirais/uso terapêutico , Reservatórios de Doenças/virologia , Vetores de Doenças , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Flavivirus/efeitos dos fármacos , Flavivirus/genética , Flavivirus/patogenicidade , Infecções por Flavivirus/transmissão , Infecções por Flavivirus/virologia , Humanos , Mutação , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Alphaviruses are (mainly) arthropod-borne viruses that belong to the family of the Togaviridae. Based on the disease they cause, alphaviruses are divided into an arthritogenic and an encephalitic group. Arthritogenic alphaviruses such as the chikungunya virus (CHIKV), the Ross River virus (RRV) and the Mayaro virus (MAYV) have become a serious public health concern in recent years. Epidemics are associated with high morbidity and the infections cause in many patients debilitating joint pain that can persist for months to years. The recent (2013-2014) introduction of CHIKV in the Americas resulted in millions of infected persons. Massive outbreaks of CHIKV and other arthritogenic alphaviruses are likely to occur in the future. Despite the worldwide (re-)emergence of these viruses, there are no antivirals or vaccines available for the treatment or prevention of infections with alphaviruses. It is therefore of utmost importance to develop antiviral strategies against these viruses. We here review the possible molecular targets in the replication cycle of these viruses for the development of antivirals. In addition, we provide an overview of the currently available in vitro systems and mouse infection models that can be used to assess the potential antiviral effect against these viruses.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Alphavirus/efeitos dos fármacos , Antivirais/farmacologia , Artrite/tratamento farmacológico , Descoberta de Drogas/métodos , Alphavirus/genética , Alphavirus/metabolismo , Animais , Antivirais/química , Antivirais/uso terapêutico , Artrite/virologia , Efeito Citopatogênico Viral , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacosRESUMO
Chikungunya virus (CHIKV) is a rapidly emerging mosquito-borne RNA virus that causes epidemics of debilitating disease in tropical and sub-tropical regions with autochtonous transmission in regions with temperate climate. Currently, there is no licensed vaccine or specific antiviral drug available against CHIKV infection. In this study, we examine the role, in the CHIKV viral cycle, of fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1), two key lipogenic enzymes required for fatty acid production and early desaturation. We show that both enzymes and their upstream regulator PI3K are required for optimal CHIKV infection. We demonstrate that pharmacologic manipulation of FASN or SCD1 enzymatic activity by non-toxic concentrations of cerulenin or CAY10566 decreases CHIKV genome replication. Interestingly, a similar inhibitory effect was also obtained with Orlistat, an FDA-approved anti-obesity drug that targets FASN activity. These drugs were also effective against Mayaro virus (MAYV), an under-studied arthritogenic Old world Alphavirus endemic in South American countries with potential risk of emergence, urbanization and dispersion to other regions. Altogether, our results identify FASN and SCD1 as conserved druggable cofactors of Alphavirus genome replication and support the broad-spectrum activity of drugs targeting the host fatty acids metabolism.
Assuntos
Alphavirus/efeitos dos fármacos , Ácido Graxo Sintases/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Replicação Viral/efeitos dos fármacos , Alphavirus/genética , Infecções por Alphavirus/tratamento farmacológico , Animais , Antivirais/farmacologia , Linhagem Celular , Cerulenina/farmacologia , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/genética , Chlorocebus aethiops , Ácido Graxo Sintases/efeitos dos fármacos , Genoma Viral , Células HEK293 , Humanos , Orlistate/farmacologia , Estearoil-CoA Dessaturase/efeitos dos fármacos , Células VeroRESUMO
Recently the anti-viral effects of prophylactic treatment with the low-molecular-weight heparan sulfate mimetic PG545 in Ross River virus (RRV) infected mice were reported. We further investigated the related, transient pathophysiology of PG545 drug treatment in RRV-infected and mock-infected PG545-treated mice. PG545 treatment resulted in mild lethargy and piloerection, on days after the drug administration. Mice were treated with two or three doses of PG545 within a ten-day period and were subsequently culled at peak disease or at disease resolution. The treatment responses of the spleen and liver were assessed through histology, flow cytometry, gene arrays and serum biochemistry. Microscopy showed an expanded red pulp in the spleen following either two or three treatments with PG545. The red pulp expansion was further demonstrated by the proliferation of megakaryocytes and erythrocyte precursors within the spleen. In addition, flow cytometry and gene array analyses revealed a reduction of lymphocytes within the spleens of PG545-treated mice. Previously unreported, RRV-induced elevations of aspartate aminotransferase (AST) and alanine transaminase (ALT) enzymes and creatinine were also noted in the RRV-infected mice. However, PG545 only reduced AST and ALT levels but not the creatinine levels in infected mice during treatment. Mice treated with three doses of PG545 also showed hepatosplenomegaly and anaemia, which were reversed upon discontinuation of the treatment. In summary, this study demonstrates that dose and frequency related haemopoietic pathophysiology such as hepatosplenomegaly and anaemia, occurred in C57BL/6 mice treated with PG545. However, this effect was reversible once drug administration is terminated.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Aspartato Aminotransferases/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Ross River virus/efeitos dos fármacos , Saponinas/farmacologia , Alanina Transaminase , Infecções por Alphavirus/metabolismo , Animais , Glucuronidase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/metabolismoRESUMO
Arthritogenic alphaviruses are a group of medically important arboviruses that cause inflammatory musculoskeletal disease in humans with debilitating symptoms, such as arthralgia, arthritis, and myalgia. The arthritogenic, or Old World, alphaviruses are capable of causing explosive outbreaks, with some viruses of major global concern. At present, there are no specific therapeutics or commercially available vaccines available to prevent alphaviral disease. Infected patients are typically treated with analgesics and non-steroidal anti-inflammatory drugs to provide often inadequate symptomatic relief. Studies to determine the mechanisms of arthritogenic alphaviral disease have highlighted the role of the host immune system in disease pathogenesis. This review discusses the current knowledge of the innate immune response to acute alphavirus infection and alphavirus-induced immunopathology. Therapeutic strategies to treat arthritogenic alphavirus disease by targeting the host immune response are also examined.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Artralgia/tratamento farmacológico , Artralgia/virologia , Imunidade Inata , Inflamação/tratamento farmacológico , Alphavirus/efeitos dos fármacos , Infecções por Alphavirus/complicações , Infecções por Alphavirus/imunologia , Animais , Artrite/tratamento farmacológico , Artrite/virologia , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/efeitos dos fármacos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Camundongos , Mialgia/tratamento farmacológico , Mialgia/virologiaRESUMO
Alphaviruses are arthropod-transmitted RNA viruses that can cause arthralgia, myalgia, and encephalitis in humans. Since the role of cellular kinases in alphavirus replication is unknown, we profiled kinetic changes in host kinase abundance and phosphorylation following chikungunya virus (CHIKV) infection of fibroblasts. Based upon the results of this study, we treated CHIKV-infected cells with kinase inhibitors targeting the Src family kinase (SFK)-phosphatidylinositol 3-kinase (PI3K)-AKT-mTORC signaling pathways. Treatment of cells with SFK inhibitors blocked the replication of CHIKV as well as multiple other alphaviruses, including Mayaro virus, O'nyong-nyong virus, Ross River virus, and Venezuelan equine encephalitis virus. Dissecting the effect of SFK inhibition on alphavirus replication, we found that viral structural protein levels were significantly reduced, but synthesis of viral genomic and subgenomic RNAs was unaffected. By measuring the association of viral RNA with polyribosomes, we found that the SFK inhibitor dasatinib blocks alphavirus subgenomic RNA translation. Our results demonstrate a role for SFK signaling in alphavirus subgenomic RNA translation and replication. Targeting host factors involved in alphavirus replication represents an innovative, perhaps paradigm-shifting, strategy for exploring the replication of CHIKV and other alphaviruses while promoting antiviral therapeutic development.