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1.
Cell Mol Life Sci ; 81(1): 148, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509419

RESUMO

Propagation of viruses requires interaction with host factors in infected cells and repression of innate immune responses triggered by the host viral sensors. Cytosolic DNA sensing pathway of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) is a major component of the antiviral response to DNA viruses, also known to play a relevant role in response to infection by RNA viruses, including foot-and-mouth disease virus (FMDV). Here, we provide supporting evidence of cGAS degradation in swine cells during FMDV infection and show that the two virally encoded proteases, Leader (Lpro) and 3Cpro, target cGAS for cleavage to dampen the cGAS/STING-dependent antiviral response. The specific target sequence sites on swine cGAS were identified as Q140/T141 for the FMDV 3Cpro and the KVKNNLKRQ motif at residues 322-330 for Lpro. Treatment of swine cells with inhibitors of the cGAS/STING pathway or depletion of cGAS promoted viral infection, while overexpression of a mutant cGAS defective for cGAMP synthesis, unlike wild type cGAS, failed to reduce FMDV replication. Our findings reveal a new mechanism of RNA viral antagonism of the cGAS-STING innate immune sensing pathway, based on the redundant degradation of cGAS through the concomitant proteolytic activities of two proteases encoded by an RNA virus, further proving the key role of cGAS in restricting FMDV infection.


Assuntos
Vírus da Febre Aftosa , Animais , Suínos , Vírus da Febre Aftosa/metabolismo , Peptídeo Hidrolases/metabolismo , Transdução de Sinais , Imunidade Inata , Endopeptidases/genética , Endopeptidases/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Antivirais/metabolismo
2.
Biochem Biophys Res Commun ; 706: 149728, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38479246

RESUMO

Influenza A virus is the cause of a widespread human disease with high morbidity and mortality rates. The influenza virus encodes non-structural protein 1 (NS1), an exceedingly multifunctional virulence component. NS1 plays essential roles in viral replication and evasion of the cellular innate immune system. Protein kinase RNA-activated also known as protein kinase R (PKR) phosphorylates translation initiation factor eIF-2α on serine 51 to inhibit protein synthesis in virus-infected mammalian cells. Consequently, PKR activation inhibits mRNA translation, which results in the assert of both viral protein synthesis and cellular and possibly apoptosis in response to virus infection. Host signaling pathways are important in the replication of influenza virus, but the mechanisms involved remain to be characterized. Herein, the structure of NS1 and PKR complex was determined using Cryo-EM. We found the N91, E94, and G95 residues of PKR bind directly with N188, D125, and K126, respectively, of NS1. Furthermore, the study shows that PKR peptide offers a potential treatment for Influenza A virus infections.


Assuntos
Vírus da Influenza A , eIF-2 Quinase , Animais , Humanos , eIF-2 Quinase/metabolismo , Proteínas não Estruturais Virais/química , Vírus da Influenza A/genética , Microscopia Crioeletrônica , Linhagem Celular , Antivirais/metabolismo , Replicação Viral , Mamíferos/metabolismo
3.
J Virol ; 98(4): e0177123, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38440982

RESUMO

Endogenous retroviruses (ERVs) are remnants of ancestral viral infections. Feline leukemia virus (FeLV) is an exogenous and endogenous retrovirus in domestic cats. It is classified into several subgroups (A, B, C, D, E, and T) based on viral receptor interference properties or receptor usage. ERV-derived molecules benefit animals, conferring resistance to infectious diseases. However, the soluble protein encoded by the defective envelope (env) gene of endogenous FeLV (enFeLV) functions as a co-factor in FeLV subgroup T infections. Therefore, whether the gene emerged to facilitate viral infection is unclear. Based on the properties of ERV-derived molecules, we hypothesized that the defective env genes possess antiviral activity that would be advantageous to the host because FeLV subgroup B (FeLV-B), a recombinant virus derived from enFeLV env, is restricted to viral transmission among domestic cats. When soluble truncated Env proteins from enFeLV were tested for their inhibitory effects against enFeLV and FeLV-B, they inhibited viral infection. Notably, this antiviral machinery was extended to infection with the Gibbon ape leukemia virus, Koala retrovirus A, and Hervey pteropid gammaretrovirus. Although these viruses used feline phosphate transporter 1 (fePit1) and phosphate transporter 2 as receptors, the inhibitory mechanism involved competitive receptor binding in a fePit1-dependent manner. The shift in receptor usage might have occurred to avoid the inhibitory effect. Overall, these findings highlight the possible emergence of soluble truncated Env proteins from enFeLV as a restriction factor against retroviral infection and will help in developing host immunity and antiviral defense by controlling retroviral spread.IMPORTANCERetroviruses are unique in using reverse transcriptase to convert RNA genomes into DNA, infecting germ cells, and transmitting to offspring. Numerous ancient retroviral sequences are known as endogenous retroviruses (ERVs). The soluble Env protein derived from ERVs functions as a co-factor that assists in FeLV-T infection. However, herein, we show that the soluble Env protein exhibits antiviral activity and provides resistance to mammalian retrovirus infection through competitive receptor binding. In particular, this finding may explain why FeLV-B transmission is not observed among domestic cats. ERV-derived molecules can benefit animals in an evolutionary arms race, highlighting the double-edged-sword nature of ERVs.


Assuntos
Retrovirus Endógenos , Gammaretrovirus , Leucemia Felina , Infecções por Retroviridae , Animais , Gatos , Produtos do Gene env/genética , Vírus da Leucemia Felina/genética , Vírus da Leucemia Felina/metabolismo , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Mamíferos/genética , Gammaretrovirus/genética , Gammaretrovirus/metabolismo , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Antivirais/metabolismo
4.
Cell Rep ; 43(3): 113882, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38457341

RESUMO

Numerous viruses alter host microtubule (MT) networks during infection, but how and why they induce these changes is unclear in many cases. We show that the vaccinia virus (VV)-encoded A51R protein is a MT-associated protein (MAP) that directly binds MTs and stabilizes them by both promoting their growth and preventing their depolymerization. Furthermore, we demonstrate that A51R-MT interactions are conserved across A51R proteins from multiple poxvirus genera, and highly conserved, positively charged residues in A51R proteins mediate these interactions. Strikingly, we find that viruses encoding MT interaction-deficient A51R proteins fail to suppress a reactive oxygen species (ROS)-dependent antiviral response in macrophages that leads to a block in virion morphogenesis. Moreover, A51R-MT interactions are required for VV virulence in mice. Collectively, our data show that poxviral MAP-MT interactions overcome a cell-intrinsic antiviral ROS response in macrophages that would otherwise block virus morphogenesis and replication in animals.


Assuntos
Poxviridae , Replicação Viral , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Poxviridae/genética , Vírus Vaccinia/fisiologia , Proteínas Virais/metabolismo , Microtúbulos/metabolismo , Antivirais/metabolismo
5.
J Virol ; 98(4): e0017124, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38488361

RESUMO

The global impact of emerging viral infections emphasizes the urgent need for effective broad-spectrum antivirals. The cellular organelle, lipid droplet (LD), is utilized by many types of viruses for replication, but its reduction does not affect cell survival. Therefore, LD is a potential target for developing broad-spectrum antivirals. In this study, we found that 2-bromopalmitate (2 BP), a previously defined palmitoylation inhibitor, depletes LD across all studied cell lines and exerts remarkable antiviral effects on different coronaviruses. We comprehensively utilized 2 BP, alongside other palmitoylation inhibitors such as cerulenin and 2-fluoro palmitic acid (2-FPA), as well as the enhancer palmostatin B and evaluated their impact on LD and the replication of human coronaviruses (hCoV-229E, hCoV-Oc43) and murine hepatitis virus (MHV-A59) at non-cytotoxic concentrations. While cerulenin and 2-FPA exhibited moderate inhibition of viral replication, 2 BP exhibited a much stronger suppressive effect on MHV-A59 replication, although they share similar inhibitory effects on palmitoylation. As expected, palmostatin B significantly enhanced viral replication, it failed to rescue the inhibitory effects of 2 BP, whereas it effectively counteracted the effects of cerulenin and 2-FPA. This suggests that the mechanism that 2 BP used to inhibit viral replication is beyond palmitoylation inhibition. Further investigations unveil that 2 BP uniquely depletes LDs, a phenomenon not exhibited by 2-FPA and cerulenin. Importantly, the depletion of LDs was closely associated with the inhibition of viral replication because the addition of oleic acid to 2 BP significantly rescued LD depletion and its inhibitory effects on MHV-A59. Our findings indicate that the inhibitory effects of 2 BP on viral replication primarily stem from LD disruption rather than palmitoylation inhibition. Intriguingly, fatty acid (FA) assays demonstrated that 2 BP reduces the FA level in mitochondria while concurrently increasing FA levels in the cytoplasm. These results highlight the crucial role of LDs in viral replication and uncover a novel biological activity of 2 BP. These insights contribute to the development of broad-spectrum antiviral strategies. IMPORTANCE: In our study, we conducted a comparative investigation into the antiviral effects of palmitoylation inhibitors including 2-bromopalmitate (2-BP), 2-fluoro palmitic acid (2-FPA), and cerulenin. Surprisingly, we discovered that 2-BP has superior inhibitory effects on viral replication compared to 2-FPA and cerulenin. However, their inhibitory effects on palmitoylation were the same. Intrigued by this finding, we delved deeper into the underlying mechanism of 2-BP's potent antiviral activity, and we unveiled a novel biological activity of 2-BP: depletion of lipid droplets (LDs). Importantly, we also highlighted the crucial role of LDs in viral replication. Our insights shed new light on the antiviral mechanism of LD depletion paving the way for the development of broad-spectrum antiviral strategies by targeting LDs.


Assuntos
Coronavirus , Gotículas Lipídicas , Palmitatos , Propiolactona/análogos & derivados , Camundongos , Animais , Humanos , Gotículas Lipídicas/metabolismo , Ácido Palmítico/farmacologia , Ácido Palmítico/metabolismo , Cerulenina/metabolismo , Cerulenina/farmacologia , Replicação Viral , Antivirais/farmacologia , Antivirais/metabolismo
6.
J Virol ; 98(4): e0030824, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38497663

RESUMO

Host antiviral proteins inhibit primate lentiviruses and other retroviruses by targeting many features of the viral life cycle. The lentiviral capsid protein and the assembled viral core are known to be inhibited through multiple, directly acting antiviral proteins. Several phenotypes, including those known as Lv1 through Lv5, have been described as cell type-specific blocks to infection against some but not all primate lentiviruses. Here we review important features of known capsid-targeting blocks to infection together with several blocks to infection for which the genes responsible for the inhibition still remain to be identified. We outline the features of these blocks as well as how current methodologies are now well suited to find these antiviral genes and solve these long-standing mysteries in the HIV and retrovirology fields.


Assuntos
HIV-1 , Lentivirus , Animais , Lentivirus/genética , Lentivirus/metabolismo , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Capsídeo/metabolismo , HIV-1/fisiologia , Antivirais/metabolismo
7.
Proc Natl Acad Sci U S A ; 121(14): e2315982121, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38536757

RESUMO

Throughout evolution, arboviruses have developed various strategies to counteract the host's innate immune defenses to maintain persistent transmission. Recent studies have shown that, in addition to bacteria and fungi, the innate Toll-Dorsal immune system also plays an essential role in preventing viral infections in invertebrates. However, whether the classical Toll immune pathway is involved in maintaining the homeostatic process to ensure the persistent and propagative transmission of arboviruses in insect vectors remain unclear. In this study, we revealed that the transcription factor Dorsal is actively involved in the antiviral defense of an insect vector (Laodelphax striatellus) by regulating the target gene, zinc finger protein 708 (LsZN708), which mediates downstream immune-related effectors against infection with the plant virus (Rice stripe virus, RSV). In contrast, an antidefense strategy involving the use of the nonstructural-protein (NS4) to antagonize host antiviral defense through competitive binding to Dorsal from the MSK2 kinase was employed by RSV; this competitive binding inhibited Dorsal phosphorylation and reduced the antiviral response of the host insect. Our study revealed the molecular mechanism through which Toll-Dorsal-ZN708 mediates the maintenance of an arbovirus homeostasis in insect vectors. Specifically, ZN708 is a newly documented zinc finger protein targeted by Dorsal that mediates the downstream antiviral response. This study will contribute to our understanding of the successful transmission and spread of arboviruses in plant or invertebrate hosts.


Assuntos
Arbovírus , Hemípteros , Oryza , Tenuivirus , Animais , Arbovírus/genética , Hemípteros/fisiologia , Tenuivirus/fisiologia , Insetos Vetores , Antivirais/metabolismo , Oryza/genética , Doenças das Plantas
8.
PLoS Pathog ; 20(3): e1011830, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38512975

RESUMO

Human myxovirus resistance 2 (MX2/MXB) is an interferon-induced GTPase that inhibits human immunodeficiency virus-1 (HIV-1) infection by preventing nuclear import of the viral preintegration complex. The HIV-1 capsid (CA) is the major viral determinant for sensitivity to MX2, and complex interactions between MX2, CA, nucleoporins (Nups), cyclophilin A (CypA), and other cellular proteins influence the outcome of viral infection. To explore the interactions between MX2, the viral CA, and CypA, we utilized a CRISPR-Cas9/AAV approach to generate CypA knock-out cell lines as well as cells that express CypA from its endogenous locus, but with specific point mutations that would abrogate CA binding but should not affect enzymatic activity or cellular function. We found that infection of CypA knock-out and point mutant cell lines with wild-type HIV-1 and CA mutants recapitulated the phenotypes observed upon cyclosporine A (CsA) addition, indicating that effects of CsA treatment are the direct result of blocking CA-CypA interactions and are therefore independent from potential interactions between CypA and MX2 or other cellular proteins. Notably, abrogation of GTP hydrolysis by MX2 conferred enhanced antiviral activity when CA-CypA interactions were abolished, and this effect was not mediated by the CA-binding residues in the GTPase domain, or by phosphorylation of MX2 at position T151. We additionally found that elimination of GTPase activity also altered the Nup requirements for MX2 activity. Our data demonstrate that the antiviral activity of MX2 is affected by CypA-CA interactions in a virus-specific and GTPase activity-dependent manner. These findings further highlight the importance of the GTPase domain of MX2 in regulation of substrate specificity and interaction with nucleocytoplasmic trafficking pathways.


Assuntos
Capsídeo , Complexo de Proteínas Formadoras de Poros Nucleares , Humanos , Capsídeo/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Ciclofilina A/genética , Ciclofilina A/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Antivirais/metabolismo , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo
9.
PLoS Pathog ; 20(3): e1012093, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38512999

RESUMO

Rift Valley fever virus (RVFV) is a viral zoonosis that causes severe disease in ruminants and humans. The nonstructural small (NSs) protein is the primary virulence factor of RVFV that suppresses the host's antiviral innate immune response. Bioinformatic analysis and AlphaFold structural modeling identified four putative LC3-interacting regions (LIR) motifs (NSs 1-4) in the RVFV NSs protein, which suggest that NSs interacts with the host LC3-family proteins. Using, isothermal titration calorimetry, X-ray crystallography, co-immunoprecipitation, and co-localization experiments, the C-terminal LIR motif (NSs4) was confirmed to interact with all six human LC3 proteins. Phenylalanine at position 261 (F261) within NSs4 was found to be critical for the interaction of NSs with LC3, retention of LC3 in the nucleus, as well as the inhibition of autophagy in RVFV infected cells. These results provide mechanistic insights into the ability of RVFV to overcome antiviral autophagy through the interaction of NSs with LC3 proteins.


Assuntos
Febre do Vale de Rift , Vírus da Febre do Vale do Rift , Animais , Humanos , Vírus da Febre do Vale do Rift/metabolismo , Proteínas não Estruturais Virais/metabolismo , Autofagia , Antivirais/metabolismo
10.
J Med Virol ; 96(3): e29540, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38529542

RESUMO

The sex disparity in COVID-19 outcomes with males generally faring worse than females has been associated with the androgen-regulated expression of the protease TMPRSS2 and the cell receptor ACE2 in the lung and fueled interest in antiandrogens as potential antivirals. In this study, we explored enzalutamide, an antiandrogen used commonly to treat prostate cancer, as a potential antiviral against the human coronaviruses which cause seasonal respiratory infections (HCoV-NL63, -229E, and -OC43). Using lentivirus-pseudotyped and authentic HCoV, we report that enzalutamide reduced 229E and NL63 entry and infection in both TMPRSS2- and nonexpressing immortalized cells, suggesting a TMPRSS2-independent mechanism. However, no effect was observed against OC43. To decipher this distinction, we performed RNA-sequencing analysis on 229E- and OC43-infected primary human airway cells. Our results show a significant induction of androgen-responsive genes by 229E compared to OC43 at 24 and 72 h postinfection. The virus-mediated effect on AR-signaling was further confirmed with a consensus androgen response element-driven luciferase assay in androgen-depleted MRC-5 cells. Specifically, 229E induced luciferase-reporter activity in the presence and absence of the synthetic androgen mibolerone, while OC43 inhibited induction. These findings highlight a complex interplay between viral infections and androgen-signaling, offering insights for disparities in viral outcomes and antiviral interventions.


Assuntos
Androgênios , Benzamidas , Coronavirus Humano 229E , Nitrilas , Feniltioidantoína , Masculino , Feminino , Humanos , Androgênios/metabolismo , Androgênios/farmacologia , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/metabolismo , Estações do Ano , Antivirais/farmacologia , Antivirais/metabolismo , Luciferases
11.
PLoS Pathog ; 20(3): e1012110, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38498560

RESUMO

The interaction between influenza A virus (IAV) and host proteins is an important process that greatly influences viral replication and pathogenicity. PB2 protein is a subunit of viral ribonucleoprotein (vRNP) complex playing distinct roles in viral transcription and replication. BAG6 (BCL2-associated athanogene 6) as a multifunctional host protein participates in physiological and pathological processes. Here, we identify BAG6 as a new restriction factor for IAV replication through targeting PB2. For both avian and human influenza viruses, overexpression of BAG6 reduced viral protein expression and virus titers, whereas deletion of BAG6 significantly enhanced virus replication. Moreover, BAG6-knockdown mice developed more severe clinical symptoms and higher viral loads upon IAV infection. Mechanistically, BAG6 restricted IAV transcription and replication by inhibiting the activity of viral RNA-dependent RNA polymerase (RdRp). The co-immunoprecipitation assays showed BAG6 specifically interacted with the N-terminus of PB2 and competed with PB1 for RdRp complex assembly. The ubiquitination assay indicated that BAG6 promoted PB2 ubiquitination at K189 residue and targeted PB2 for K48-linked ubiquitination degradation. The antiviral effect of BAG6 necessitated its N-terminal region containing a ubiquitin-like (UBL) domain (17-92aa) and a PB2-binding domain (124-186aa), which are synergistically responsible for viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly. These findings unravel a novel antiviral mechanism via the interaction of viral PB2 and host protein BAG6 during avian or human influenza virus infection and highlight a potential application of BAG6 for antiviral drug development.


Assuntos
Vírus da Influenza A , Influenza Humana , Animais , Humanos , Camundongos , Antivirais/metabolismo , Vírus da Influenza A/genética , Chaperonas Moleculares/metabolismo , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral/genética
12.
Vet Microbiol ; 291: 110033, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38432077

RESUMO

The genomes of many pathogens contain high-CpG content, which is less common in most vertebrate host genomes. Such a distinct di-nucleotide composition in a non-self invader constitutes a special feature recognized by its host's immune system. The zinc-finger antiviral protein (ZAP) is part of the pattern recognition receptors (PRRs) that recognize CpG-rich viral RNA and subsequently initiate RNA degradation as an antiviral defense measure. To counteract such ZAP-mediated restriction, some viruses evolve to either suppress the CpG content in their genome or produce an antagonistic factor to evade ZAP sensing. We have previously shown that a coronavirus, Porcine epidermic diarrhea virus (PEDV), employs its nucleocapsid protein (PEDV-N) to suppress the ZAP-dependent antiviral activity. Here, we propose a mechanism by which PEDV-N suppresses ZAP function by interfering with the interaction between ZAP and its essential cofactor, Tripartite motif-containing protein 25 (TRIM25). PEDV-N was found to interact with ZAP through its N-terminal domain and with TRIM25 through its C-terminal domain. We showed that PEDV-N and ZAP compete for binding to the SPla and the RYanodine Receptor (SPRY) domain of TRIM25, resulting in PEDV-N preventing TRIM25 from interacting with and promoting ZAP. Our result also showed that the presence of PEDV-N in the complex reduces the E3 ligase activity of TRIM25 on ZAP, which is required for the antiviral activity of ZAP. The host-pathogen interaction mechanism presented herein provides an insight into the new function of this abundant and versatile viral protein from a coronavirus which could be a key target for development of antiviral interventions.


Assuntos
Ubiquitina-Proteína Ligases , Vírus , Animais , Suínos , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Antivirais/farmacologia , Antivirais/metabolismo , Nucleocapsídeo , Zinco
13.
J Med Virol ; 96(4): e29522, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38533889

RESUMO

The tick-borne encephalitis virus (TBEV) serocomplex includes several medically important flavivirus members endemic to Europe, Asia, and North America, which can induce severe neuroinvasive or viscerotropic diseases with unclear mechanisms of pathogenesis. Langat virus (LGTV) shares a high sequence identity with TBEV but exhibits lower pathogenic potential in humans and serves as a model for virus-host interactions. In this study, we demonstrated that LGTV infection inhibits the activation of gp130/JAK/STAT (Janus kinases (JAK) and signal transducer and activator of transcription (STAT)) signaling, which plays a pivotal role in numerous biological processes. Our data show that the LGTV-infected cells had significantly lower phosphorylated STAT3 (pSTAT3) protein upon oncostatin M (OSM) stimulation than the mock-infected control. LGTV infection blocked the nuclear translocation of STAT3 without a significant effect on total STAT3 protein level. LGTV inhibited JAK1 activation and reduced gp130 protein expression in infected cells, with the viral NS5 protein mediating this effect. TBEV infection also reduces gp130 level. On the other hand, pretreatment of Vero cells with OSM significantly reduces LGTV replication, and STAT1/STAT2 knockdown had little effect on OSM-mediated antiviral effect, which suggests it is independent of STAT1/STAT2 and, instead, it is potentially mediated by STAT3 signlaing. These findings shed light on the LGTV and TBEV-cell interactions, offering insights for the future development of antiviral therapeutics and improved vaccines.


Assuntos
Fenômenos Biológicos , Vírus da Encefalite Transmitidos por Carrapatos , Animais , Chlorocebus aethiops , Humanos , Janus Quinases/metabolismo , Células Vero , Receptor gp130 de Citocina/metabolismo , Antivirais/metabolismo
14.
Biomed Pharmacother ; 173: 116423, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38493593

RESUMO

Corona Virus Disease 2019 (COVID-19) is a global pandemic epidemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which poses a serious threat to human health worldwide and results in significant economic losses. With the continuous emergence of new virus strains, small molecule drugs remain the most effective treatment for COVID-19. The traditional drug development process usually requires several years; however, the development of computer-aided drug design (CADD) offers the opportunity to develop innovative drugs quickly and efficiently. The literature review describes the general process of CADD, the viral proteins that play essential roles in the life cycle of SARS-CoV-2 and can serve as therapeutic targets, and examples of drug screening of viral target proteins by applying CADD methods. Finally, the potential of CADD in COVID-19 therapy, the deficiency, and the possible future development direction are discussed.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Descoberta de Drogas , Desenho de Fármacos , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/metabolismo
15.
Sci Rep ; 14(1): 4287, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383655

RESUMO

The SARS-CoV-2 virus, belonging to the Coronavirus genus, which poses a threat to human health worldwide. Current therapies focus on inhibiting viral replication or using anti-inflammatory/immunomodulatory compounds to enhance host immunity. This makes the active ingredients of traditional Chinese medicine compounds ideal therapies due to their proven safety and minimal toxicity. Previous research suggests that andrographolide and baicalin inhibit coronaviruses; however, their synergistic effects remain unclear. Here, we studied the antiviral mechanisms of their synergistic use in vitro and in vivo. We selected the SARS-CoV-2 pseudovirus for viral studies and found that synergistic andrographolide and baicalein significantly reduced angiotensin-converting enzyme 2 protein level and viral entry of SARS-CoV-2 into cells compared to singal compound individually and inhibited the major protease activity of SARS-CoV-2. This mechanism is essential to reduce the pathogenesis of SARS-CoV-2. In addition, their synergistic use in vivo also inhibited the elevation of pro-inflammatory cytokines, including IL-6 and TNF-α-the primary cytokines in the development of acute respiratory distress syndrome (the main cause of COVID-19 deaths). In conclusion, this study shows that synergistic andrographolide and baicalein treatment acts as potent inhibitors of coronavirus mechanisms in vitro and in vivo-and is more effective together than in isolation.


Assuntos
Enzima de Conversão de Angiotensina 2 , Diterpenos , Flavonoides , SARS-CoV-2 , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Regulação para Baixo , SARS-CoV-2/fisiologia , Citocinas/metabolismo , Antivirais/farmacologia , Antivirais/metabolismo
16.
Int J Mol Sci ; 25(3)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38338708

RESUMO

Establishing a drug-screening platform is critical for the discovery of potential antiviral agents against SARS-CoV-2. In this study, we developed a platform based on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to investigate SARS-CoV-2 infectivity, with the aim of evaluating potential antiviral agents for anti-SARS-CoV-2 activity and cardiotoxicity. Cultured myocytes of iPSC-CMs and immortalized human cardiomyocyte cell line (AC-16) were primarily characterized for the expression of cardiac markers and host receptors of SARS-CoV-2. An infectivity model for the wild-type SARS-CoV-2 strain was then established. Infection modeling involved inoculating cells with SARS-CoV-2 at varying multiplicities of infection (MOIs) and then quantifying infection using immunofluorescence and plaque assays. Only iPSC-CMs, not AC16 cells, expressed angiotensin-converting enzyme 2 (ACE-2), and quantitative assays confirmed the dose-dependent infection of iPSC-CMs by SARS-CoV-2, unlike the uninfectable AC16 cells lacking the expression of ACE2. Cytotoxicity was evaluated using MTT assays across a concentration range. An assessment of the plant-derived compound panduratin A (panA) showed cytotoxicity at higher doses (50% cytotoxic concentration (CC50) 10.09 µM) but promising antiviral activity against SARS-CoV-2 (50% inhibition concentration (IC50) 0.8-1.6 µM), suppressing infection at concentrations 10 times lower than its CC50. Plaque assays also showed decreased viral production following panA treatment. Overall, by modeling cardiac-specific infectivity, this iPSC-cardiomyocyte platform enables the reliable quantitative screening of compound cytotoxicity alongside antiviral efficacy. By combining disease pathogenesis and pharmacology, this system can facilitate the evaluation of potential novel therapeutics, such as panA, for drug discovery applications.


Assuntos
COVID-19 , Chalconas , Cardiopatias , Células-Tronco Pluripotentes Induzidas , Humanos , COVID-19/patologia , SARS-CoV-2 , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Cardiopatias/metabolismo , Antivirais/farmacologia , Antivirais/metabolismo
17.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339085

RESUMO

Systemic acquired resistance (SAR) is a plant defense mechanism that provides protection against a broad spectrum of pathogens in distal tissues. Recent studies have revealed a concerted function of salicylic acid (SA) and N-hydroxypipecolic acid (NHP) in the establishment of SAR against bacterial pathogens, but it remains unknown whether NHP is also involved in SAR against viruses. We found that the local application of acibenzolar-S-methyl (ASM), a synthetic analog of SA, suppressed plantago asiatica mosaic virus (PlAMV) infection in the distal leaves of Arabidopsis thaliana. This suppression of infection in untreated distal leaves was observed at 1 day, but not at 3 days, after application. ASM application significantly increased the expression of SAR-related genes, including PR1, SID2, and ALD1 after 1 day of application. Viral suppression in distal leaves after local ASM application was not observed in the sid2-2 mutant, which is defective in isochorismate synthase 1 (ICS1), which is involved in salicylic acid synthesis; or in the fmo1 mutant, which is defective in the synthesis of NHP; or in the SA receptor npr1-1 mutant. Finally, we found that the local application of NHP suppressed PlAMV infection in the distal leaves. These results indicate that the local application of ASM induces antiviral SAR against PlAMV through a mechanism involving NHP.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Tiadiazóis , Arabidopsis/metabolismo , Tiadiazóis/farmacologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Ácido Salicílico/farmacologia , Ácido Salicílico/metabolismo , Antivirais/farmacologia , Antivirais/metabolismo , Regulação da Expressão Gênica de Plantas , Doenças das Plantas/genética , Doenças das Plantas/microbiologia
18.
Org Biomol Chem ; 22(11): 2218-2225, 2024 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-38358380

RESUMO

Chronic infection with hepatitis B virus (HBV) is a major cause of cirrhosis and liver cancer. Capsid assembly modulators can induce error-prone assembly of HBV core proteins to prevent the formation of infectious virions, representing promising candidates for treating chronic HBV infections. To explore novel capsid assembly modulators from unexplored mirror-image libraries of natural products, we have investigated the synthetic process of the HBV core protein for preparing the mirror-image target protein. In this report, the chemical synthesis of full-length HBV core protein (Cp183) containing an arginine-rich nucleic acid-binding domain at the C-terminus is presented. Sequential ligations using four peptide segments enabled the synthesis of Cp183 via convergent and C-to-N direction approaches. After refolding under appropriate conditions, followed by the addition of nucleic acid, the synthetic Cp183 assembled into capsid-like particles.


Assuntos
Hepatite B , Ácidos Nucleicos , Humanos , Capsídeo/química , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B , Hepatite B/metabolismo , Proteínas do Core Viral/análise , Proteínas do Core Viral/química , Proteínas do Core Viral/metabolismo , Replicação Viral , Antivirais/metabolismo
19.
Nat Commun ; 15(1): 1745, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409141

RESUMO

Human cytomegalovirus (HCMV) is a widespread pathogen that in immunocompromised hosts can cause life-threatening disease. Studying HCMV-exposed monocyte-derived dendritic cells by single-cell RNA sequencing, we observe that most cells are entered by the virus, whereas less than 30% of them initiate viral gene expression. Increased viral gene expression is associated with activation of the stimulator of interferon genes (STING) that usually induces anti-viral interferon responses, and with the induction of several pro- (RHOB, HSP1A1, DNAJB1) and anti-viral (RNF213, TNFSF10, IFI16) genes. Upon progression of infection, interferon-beta but not interferon-lambda transcription is inhibited. Similarly, interferon-stimulated gene expression is initially induced and then shut off, thus further promoting productive infection. Monocyte-derived dendritic cells are composed of 3 subsets, with one being especially susceptible to HCMV. In conclusion, HCMV permissiveness of monocyte-derived dendritic cells depends on complex interactions between virus sensing, regulation of the interferon response, and viral gene expression.


Assuntos
Citomegalovirus , Interferons , Humanos , Citomegalovirus/fisiologia , Transdução de Sinais/genética , Antivirais/metabolismo , Células Dendríticas/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Adenosina Trifosfatases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
Viruses ; 16(2)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38399995

RESUMO

Most plants have developed unique mechanisms to cope with harsh environmental conditions to compensate for their lack of mobility. A key part of their coping mechanisms is the synthesis of secondary metabolites. In addition to their role in plants' defense against pathogens, they also possess therapeutic properties against diseases, and their use by humans predates written history. Viruses are a unique class of submicroscopic agents, incapable of independent existence outside a living host. Pathogenic viruses continue to pose a significant threat to global health, leading to innumerable fatalities on a yearly basis. The use of medicinal plants as a natural source of antiviral agents has been widely reported in literature in the past decades. Metabolomics is a powerful research tool for the identification of plant metabolites with antiviral potentials. It can be used to isolate compounds with antiviral capacities in plants and study the biosynthetic pathways involved in viral disease progression. This review discusses the use of medicinal plants as antiviral agents, with a special focus on the metabolomics evidence supporting their efficacy. Suggestions are made for the optimization of various metabolomics methods of characterizing the bioactive compounds in plants and subsequently understanding the mechanisms of their operation.


Assuntos
Plantas Medicinais , Viroses , Vírus , Humanos , Viroses/tratamento farmacológico , Metabolômica , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/metabolismo
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