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1.
Microorganisms ; 12(6)2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38930566

RESUMO

SARS-CoV-2, the pathogen causing COVID-19, continues to pose a significant threat to public health and has had major economic implications. Developing safe and effective vaccines and therapies offers a path forward for overcoming the COVID-19 pandemic. The presented study, performed by using the informational spectrum method (ISM), representing an electronic biology-based tool for analysis of protein-protein interactions, identified the highly conserved region of spike protein (SP) from SARS-CoV-2 virus, which is essential for recognition and targeting between the virus and its protein interactors on the target cells. This domain is suggested as a promising target for the drug therapy and vaccines, which could be effective against all currently circulating variants of SARS-CoV-2 viruses. The analysis of the virus/host interaction, performed by the ISM, also revealed OX-2 membrane glycoprotein (CD200) as a possible interactor of SP, which could serve as a novel therapeutic target for COVID-19 disease.

2.
Entropy (Basel) ; 25(10)2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37895584

RESUMO

The SARS-CoV-2 virus, the causative agent of COVID-19, is known for its genetic diversity. Virus variants of concern (VOCs) as well as variants of interest (VOIs) are classified by the World Health Organization (WHO) according to their potential risk to global health. This study seeks to enhance the identification and classification of such variants by developing a novel bioinformatics criterion centered on the virus's spike protein (SP1), a key player in host cell entry, immune response, and a mutational hotspot. To achieve this, we pioneered a unique phylogenetic algorithm which calculates EIIP-entropy as a distance measure based on the distribution of the electron-ion interaction potential (EIIP) of amino acids in SP1. This method offers a comprehensive, scalable, and rapid approach to analyze large genomic data sets and predict the impact of specific mutations. This innovative approach provides a robust tool for classifying emergent SARS-CoV-2 variants into potential VOCs or VOIs. It could significantly augment surveillance efforts and understanding of variant characteristics, while also offering potential applicability to the analysis and classification of other emerging viral pathogens and enhancing global readiness against emerging and re-emerging viral pathogens.

3.
Front Biosci (Landmark Ed) ; 27(5): 152, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35638419

RESUMO

BACKGROUND: A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the leading threat to global health. An effective antiviral could not only help those still vulnerable to the virus but could be a critical treatment if a virus emerges toward evading coronavirus disease 2019 (COVID-19) vaccines. Despite the significant efforts to test already-approved drugs for their potential to kill the virus, researchers found very few actually worked. METHODS: The present report uses the electronic molecular descriptors, the quasi-valence number (AQVN), and the electron-ion interaction potential (EIIP), for the analysis of natural compounds with proven therapeutic activity against the COVID-19. RESULTS: Based on the analysis of the electronic properties of natural compounds which are effective against SARS-CoV-2 virus the simple theoretical criterion for the selection of candidate compounds for the treatment of COVID-19 is proposed. CONCLUSIONS: The proposed theoretical criterion can be used for the identification and optimization of new lead compounds for the treatment of the COVID-19 disease and for the selection of the food and food supplements which could have a beneficial effect on COVID-19 patients.


Assuntos
Tratamento Farmacológico da COVID-19 , Antivirais/farmacologia , Antivirais/uso terapêutico , Vacinas contra COVID-19 , Humanos , SARS-CoV-2
4.
PLoS Pathog ; 18(5): e1010345, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35576232

RESUMO

Ehrlichia chaffeensis (E. chaffeensis) has evolved eukaryotic ligand mimicry to repurpose multiple cellular signaling pathways for immune evasion. In this investigation, we demonstrate that TRP120 has a novel repetitive short linear motif (SLiM) that activates the evolutionarily conserved Hedgehog (Hh) signaling pathway to inhibit apoptosis. In silico analysis revealed that TRP120 has sequence and functional similarity with Hh ligands and a candidate Hh ligand SLiM was identified. siRNA knockdown of Hh signaling and transcriptional components significantly reduced infection. Co-immunoprecipitation and surface plasmon resonance demonstrated that rTRP120-TR interacted directly with Hh receptor Patched-2 (PTCH2). E. chaffeensis infection resulted in early upregulation of Hh transcription factor GLI-1 and regulation of Hh target genes. Moreover, soluble recombinant TRP120 (rTRP120) activated Hh and induced gene expression consistent with the eukaryotic Hh ligand. The TRP120-Hh-SLiM (NPEVLIKD) induced nuclear translocation of GLI-1 in THP-1 cells and primary human monocytes and induced a rapid and expansive activation of Hh pathway target genes. Furthermore, Hh activation was blocked by an α-TRP120-Hh-SLiM antibody. TRP120-Hh-SLiM significantly increased levels of Hh target, anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and siRNA knockdown of BCL-2 dramatically inhibited infection. Blocking Hh signaling with the inhibitor Vismodegib, induced a pro-apoptotic cellular program defined by decreased mitochondria membrane potential, significant reductions in BCL-2, activation of caspase 3 and 9, and increased apoptotic cells. This study reveals a novel E. chaffeensis SLiM ligand mimetic that activates Hh signaling to maintain E. chaffeensis infection by engaging a BCL-2 anti-apoptotic cellular program.


Assuntos
Ehrlichia chaffeensis , Ehrlichiose , Proteínas de Bactérias/metabolismo , Ehrlichia chaffeensis/genética , Ehrlichiose/metabolismo , Proteínas Hedgehog/metabolismo , Interações Hospedeiro-Patógeno/genética , Humanos , Ligantes , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
5.
mBio ; 13(2): e0007622, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35357214

RESUMO

Ehrlichia chaffeensis evades innate host defenses by reprogramming the mononuclear phagocyte through mechanisms that involve the exploitation of multiple evolutionarily conserved cellular signaling pathways, including Notch. This immune evasion strategy is directed in part by tandem repeat protein (TRP) effectors. Specifically, the TRP120 effector activates and regulates Notch signaling through interactions with the Notch receptor and the negative regulator, F-Box and WD repeat domain-containing 7 (FBW7). However, the specific molecular interactions and motifs required for E. chaffeensis TRP120-Notch receptor interaction and activation have not been defined. To investigate the molecular basis of TRP120 Notch activation, we compared TRP120 with endogenous canonical/noncanonical Notch ligands and identified a short region of sequence homology within the tandem repeat (TR) domain. TRP120 was predicted to share biological function with Notch ligands, and a function-associated sequence in the TR domain was identified. To investigate TRP120-Notch receptor interactions, colocalization between TRP120 and endogenous Notch-1 was observed. Moreover, direct interactions between full-length TRP120, the TRP120 TR domain containing the putative Notch ligand sequence, and the Notch receptor LBR were demonstrated. To molecularly define the TRP120 Notch activation motif, peptide mapping was used to identify an 11-amino acid short linear motif (SLiM) located within the TRP120 TR that activated Notch signaling and downstream gene expression. Peptide mutants of the Notch SLiM or anti-Notch SLiM antibody reduced or eliminated Notch activation and NICD nuclear translocation. This investigation reveals a novel molecularly defined pathogen encoded Notch SLiM mimetic that activates Notch signaling consistent with endogenous ligands. IMPORTANCE E. chaffeensis infects and replicates in mononuclear phagocytes, but how it evades innate immune defenses of this indispensable primary innate immune cell is not well understood. This investigation revealed the molecular details of a ligand mimicry cellular reprogramming strategy that involved a short linear motif (SLiM), which enabled E. chaffeensis to exploit host cell signaling to establish and maintain infection. E. chaffeensis TRP120 is a moonlighting effector that has been associated with cellular activation and other functions, including ubiquitin ligase activity. Herein, we identified and demonstrated that a SLiM present within each tandem repeat of TRP120 activated Notch signaling. Notch is an evolutionarily conserved signaling pathway responsible for many cell functions, including cell fate, development, and innate immunity. This study is significant because it revealed the first molecularly defined pathogen encoded SLiM that appears to have evolved de novo to mimic endogenous Notch ligands. Understanding Notch activation during E. chaffeensis infection provides a model to study pathogen exploitation of signaling pathways and will be useful in developing molecularly targeted countermeasures for inhibiting infection by a multitude of disease-causing pathogens that exploit cell signaling through molecular mimicry.


Assuntos
Ehrlichia chaffeensis , Ehrlichiose , Proteínas de Bactérias/metabolismo , Ehrlichia chaffeensis/genética , Interações Hospedeiro-Patógeno , Humanos , Ligantes , Monócitos/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais
6.
ChemistryOpen ; 11(2): e202100248, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35103413

RESUMO

In the current pandemic, finding an effective drug to prevent or treat the infection is the highest priority. A rapid and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes viral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and therefore is an attractive drug target. In this study, we used a combined in silico virtual screening for candidates for SARS-CoV-2 PLpro protease inhibitors. We used the Informational spectrum method applied for Small Molecules for searching the Drugbank database followed by molecular docking. After in silico screening of drug space, we identified 44 drugs as potential SARS-CoV-2 PLpro inhibitors that we propose for further experimental testing.


Assuntos
Proteases Semelhantes à Papaína de Coronavírus/química , SARS-CoV-2/química , COVID-19 , Humanos , Simulação de Acoplamento Molecular
7.
mSphere ; 6(2)2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883266

RESUMO

Ehrlichia chaffeensis expresses the TRP120 multifunctional effector, which is known to play a role in phagocytic entry, on the surface of infectious dense-cored ehrlichiae, but a cognate host receptor has not been identified. We recently reported that E. chaffeensis activates canonical Wnt signaling in monocytes to promote bacterial uptake and intracellular survival and that TRP120 was involved in this activation event. To identify the specific mechanism of pathway activation, we hypothesized that TRP120 is a Wnt signaling ligand mimetic that initiates Wnt pathway activity through direct interaction with the Wnt pathway Frizzled family of receptors. In this study, we used confocal immunofluorescence microscopy to demonstrate very strong colocalization between E. chaffeensis and Fzd2, 4, 5, 7, and 9 as well as coreceptor LRP5 at 1 to 3 h postinfection. Direct binding between TRP120 and multiple Fzd receptors was further confirmed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR). Interfering RNA knockdown of Wnt receptors, coreceptors, and signaling pathway components significantly reduced E. chaffeensis infection, demonstrating that complex and redundant interactions are involved in Wnt pathway exploitation. We utilized in silico approaches to identify a repetitive short linear motif (SLiM) in TRP120 that is homologous to Wnt ligands and used mutant SLiM peptides and an α-TRP120-Wnt-SLiM antibody to demonstrate that the TRP120 Wnt SLiM activates the canonical Wnt pathway and promotes E. chaffeensis infection. This study reports the first example of bacterial mimicry of Wnt pathway ligands and highlights a pathogenic mechanism with potential for targeting by antimicrobial therapeutics.IMPORTANCE Upon infecting mammalian hosts, Ehrlichia chaffeensis establishes a replicative niche in microbe-eating immune system cells where it expertly orchestrates infection and spread. One of the ways Ehrlichia survives within these phagocytes is by activating evolutionarily conserved signaling pathways including the Wnt pathway; however, the molecular details of pathway hijacking have not been defined. This study is significant because it identifies an ehrlichial protein that directly interacts with components of the Wnt receptor complex, influencing pathway activity and promoting infection. Consequentially, Ehrlichia serves as a unique tool to investigate the intricacies of how pathogens repurpose human immune cell signaling and provides an opportunity to better understand many cellular processes in health and disease. Furthermore, understanding how this bacterium utilizes its small genome to survive within cells that evolved to destroy pathogens will facilitate the development of antibacterial therapeutics that could target Ehrlichia as well as other intracellular agents of human disease.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ehrlichia chaffeensis/genética , Ehrlichia chaffeensis/metabolismo , Interações Hospedeiro-Patógeno/genética , Receptores Wnt/metabolismo , Via de Sinalização Wnt/fisiologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Ligantes , Monócitos/microbiologia , Receptores Wnt/genética , Células THP-1 , Via de Sinalização Wnt/genética
8.
F1000Res ; 10: 28, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-36247800

RESUMO

A safe and effective vaccine is urgently needed to bring the current SARS-CoV-2 pandemic under control. The spike protein (SP) of SARS-CoV-2 represents the principal target for most vaccines currently under development. Despite the presence of a CoV proof-reading function in viral replication, SP protein from SARS-CoV still extensively mutates, which might have an impact on current and future vaccine development. Here, we present analysis of more than 1600 SP unique variants suggesting that vaccine candidates based on the Wuhan-Hu-1 reference strain would be effective against most of currently circulated SARS-CoV-2 viruses, but that further monitoring of the evolution of this virus is important for identification of other mutations, which could affect the effectiveness of vaccines.

9.
J Proteome Res ; 19(11): 4649-4654, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-32794723

RESUMO

The Bacillus Calmette-Guerin vaccine is still widely used in the developing world. The vaccination prevents infant death not only from tuberculosis but also from unrelated infectious agents, especially respiratory tract infections and neonatal sepsis. It is proposed that these off-target protective effects of the BCG vaccine are mediated by the general long-term boosting of innate immune mechanisms, also termed "trained innate immunity". Recent studies indicate that both COVID-19 incidence and total deaths are strongly associated with the presence or absence of national mandatory BCG vaccination programs and encourage the initiation of several clinical studies with the expectation that revaccination with BCG could reduce the incidence and severity of COVID-19. Here, presented results from the bioinformatics analysis of the Mycobacterium bovis (strain BCG/Pasteur 1173P2) proteome suggests four immunodominant antigens that could induce an immune response against SARS-CoV-2.


Assuntos
Vacina BCG , Proteínas de Bactérias , Betacoronavirus , Infecções por Coronavirus , Reposicionamento de Medicamentos , Pandemias , Pneumonia Viral , Vacina BCG/química , Vacina BCG/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Betacoronavirus/química , Betacoronavirus/imunologia , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Humanos , Mycobacterium bovis/química , Mycobacterium bovis/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Proteoma/química , Proteoma/imunologia , SARS-CoV-2 , Vacinas Virais/química , Vacinas Virais/imunologia
10.
F1000Res ; 9: 52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32419926

RESUMO

A novel coronavirus recently identified in Wuhan, China (SARS-CoV-2) has expanded the number of highly pathogenic coronaviruses affecting humans. The SARS-CoV-2 represents a potential epidemic or pandemic threat, which requires a quick response for preparedness against this infection. The present report uses the informational spectrum methodology to identify the possible origin and natural host of the new virus, as well as putative therapeutic and vaccine targets. The performed in silico analysis indicates that the newly emerging SARS-CoV-2 is closely related to severe acute respiratory syndrome (SARS)-CoV and, to a lesser degree, Middle East respiratory syndrome (MERS)-CoV. Moreover, the well-known SARS-CoV receptor (ACE2) might be a putative receptor for the novel virus as well. Actin protein was also suggested as a host factor that participates in cell entry and pathogenesis of SARS-CoV-2; therefore, drugs modulating biological activity of this protein (e.g. ibuprofen) were suggested as potential candidates for treatment of this viral infection. Additional results indicated that civets and poultry are potential candidates for the natural reservoir of the SARS-CoV-2, and that domain 288-330 of S1 protein from the SARS-CoV-2 represents promising therapeutic and/or vaccine target.


Assuntos
Vacinas contra COVID-19 , SARS-CoV-2/química , Tropismo Viral , Enzima de Conversão de Angiotensina 2/química , COVID-19 , China , Humanos , Receptores Virais/química , Glicoproteína da Espícula de Coronavírus/química
11.
Vaccine ; 38(3): 416-422, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31735501

RESUMO

The immunization of poultry where H5 and H7 influenza viruses (IVs) are endemic is one of the strategies to prevent unexpected zoonoses. Our group has been focused on conserved HA-epitopes as potential vaccine candidates to obtain multivalent immune responses against distinct IV subtypes. In this study, two conserved epitopes (NG-34 and CS-17) fused to flagellin were produced in a Baculovirus platform based on Trichoplusia ni larvae as living biofactories. Soluble extracts obtained from larvae expressing "flagellin-NG34/CS17 antigen" were used to immunize chickens and the efficacy of the vaccine was evaluated against a heterologous H7N1 HPAIV challenge in chickens. The flagellin-NG34/CS17 vaccine protected the vaccinated chickens and blocked viral shedding orally and cloacally. Furthermore, no apparent clinical signs were monitored in 10/12 vaccinated individuals. The mechanism of protection conferred is under investigation.


Assuntos
Flagelina/administração & dosagem , Granulovirus , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Vírus da Influenza A Subtipo H7N1 , Influenza Aviária/prevenção & controle , Administração Intranasal , Sequência de Aminoácidos , Animais , Galinhas , Cães , Flagelina/imunologia , Granulovirus/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunização/métodos , Vírus da Influenza A Subtipo H7N1/fisiologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Aviária/imunologia , Larva/imunologia , Células Madin Darby de Rim Canino , Zoonoses/imunologia , Zoonoses/prevenção & controle
12.
Pathogens ; 8(4)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703251

RESUMO

Highly pathogenic avian influenza viruses (HPAIV) of the H5-subtype have circulated continuously in Egypt since 2006, resulting in numerous poultry outbreaks and considerable sporadic human infections. The extensive circulation and wide spread of these viruses in domestic poultry have resulted in various evolutionary changes with a dramatic impact on viral transmission ability to contact mammals including humans. The transmitted viruses are either (1) adapted well enough in their avian hosts to readily infect mammals, or (2) adapted in the new mammalian hosts to improve their fitness. In both cases, avian influenza viruses (AIVs) acquire various host-specific adaptations. These adaptive variations are not all well-known or thoroughly characterized. In this study, a phylogenetic algorithm based on the informational spectrum method, designated hereafter as ISM, was applied to analyze the affinity of H5-type HA proteins of Egyptian AIV isolates (2006-2015) towards human-type cell receptors. To characterize AIV H5-HA proteins displaying high ISM values reflecting an increased tendency of the HA towards human-type receptors, recombinant IV expressing monobasic, low pathogenic (LP) H5-HA versions in the background of the human influenza virus A/PR/8/1934(H1N1) (LP 7+1), were generated. These viruses were compared with a LP 7+1 expressing a monobasic H5-HA from a human origin virus isolate (human LP-7271), for their receptor binding specificity (ISM), in vitro replication efficiency and in vivo pathogenicity in mammals. Interestingly, using ISM analysis, we identified a LP 7+1 virus (LP-S10739C) expressing the monobasic H5-HA of AIV A/Chicken/Egypt/S10739C/2015(H5N1) that showed high affinity towards human-type receptors. This in silico prediction was reflected by a higher in vitro replication efficiency in mammalian cell cultures and a higher virulence in mice as compared with LP-7271. Sequence comparison between the LP-S10739C and the LP-7271 H5-HA, revealed distinct amino acid changes. Their contribution to the increased mammalian receptor propensity of LP-S10739C demands further investigation to better deduce the molecular determinant behind the reported high morbidity of 2014 to 2015 HPAI H5N1 virus in humans in Egypt. This study provides insights into the evolution of Egyptian H5 HPAIVs and highlights the need to identify the viral evolution in order to recognize emerging AIV with the potential to threaten human and animal populations.

13.
PLoS One ; 14(9): e0222201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553755

RESUMO

Swine influenza virus (SIVs) infections cause a significant economic impact to the pork industry. Moreover, pigs may act as mixing vessel favoring genome reassortment of diverse influenza viruses. Such an example is the pandemic H1N1 (pH1N1) virus that appeared in 2009, harboring a combination of gene segments from avian, pig and human lineages, which rapidly reached pandemic proportions. In order to confront and prevent these possible emergences as well as antigenic drift phenomena, vaccination remains of vital importance. The present work aimed to evaluate a new DNA influenza vaccine based on distinct conserved HA-peptides fused with flagellin and applied together with Diluvac Forte as adjuvant using a needle-free device (IntraDermal Application of Liquids, IDAL®). Two experimental pig studies were performed to test DNA-vaccine efficacy against SIVs in pigs. In the first experiment, SIV-seronegative pigs were vaccinated with VC4-flagellin DNA and intranasally challenged with a pH1N1. In the second study, VC4-flagellin DNA vaccine was employed in SIV-seropositive animals and challenged intranasally with an H3N2 SIV-isolate. Both experiments demonstrated a reduction in the viral shedding after challenge, suggesting vaccine efficacy against both the H1 and H3 influenza virus subtypes. In addition, the results proved that maternally derived antibodies (MDA) did not constitute an obstacle to the vaccine approach used. Moreover, elevated titers in antibodies both against H1 and H3 proteins in serum and in bronchoalveolar lavage fluids (BALFs) was detected in the vaccinated animals along with a markedly increased mucosal IgA response. Additionally, vaccinated animals developed stronger neutralizing antibodies in BALFs and higher inhibiting hemagglutination titers in sera against both the pH1N1 and H3N2 influenza viruses compared to unvaccinated, challenged-pigs. It is proposed that the described DNA-vaccine formulation could potentially be used as a multivalent vaccine against SIV infections.


Assuntos
Vacinas contra Influenza/uso terapêutico , Infecções por Orthomyxoviridae/prevenção & controle , Doenças dos Suínos/prevenção & controle , Vacinas de DNA/uso terapêutico , Animais , Sequência Conservada , Feminino , Hemaglutininas/genética , Hemaglutininas/imunologia , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/imunologia , Masculino , Infecções por Orthomyxoviridae/imunologia , Suínos/imunologia , Suínos/virologia , Doenças dos Suínos/imunologia , Doenças dos Suínos/virologia , Vacinas de DNA/imunologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-30972303

RESUMO

Influenza A virus (IAV) matrix protein 2 (M2), an ion channel, is crucial for virus infection, and therefore, an important anti-influenza drug target. Adamantanes, also known as M2 channel blockers, are one of the two classes of Food and Drug Administration-approved anti-influenza drugs, although their use was discontinued due to prevalent drug resistance. Fast emergence of resistance to current anti-influenza drugs have raised an urgent need for developing new anti-influenza drugs against resistant forms of circulating viruses. Here we propose a simple theoretical criterion for fast virtual screening of molecular libraries for candidate anti-influenza ion channel inhibitors both for wild type and adamantane-resistant influenza A viruses. After in silico screening of drug space using the EIIP/AQVN filter and further filtering of drugs by ligand based virtual screening and molecular docking we propose the best candidate drugs as potential dual inhibitors of wild type and adamantane-resistant influenza A viruses. Finally, guanethidine, the best ranked drug selected from ligand-based virtual screening, was experimentally tested. The experimental results show measurable anti-influenza activity of guanethidine in cell culture.


Assuntos
Antivirais/isolamento & purificação , Biologia Computacional/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Proteínas da Matriz Viral/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas da Matriz Viral/química
15.
PLoS One ; 14(3): e0212431, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30822308

RESUMO

Swine influenza viruses (SIVs), the causal agents of swine influenza, are not only important to control due to the economic losses in the swine industry, but also can be pandemic pathogens. Vaccination is one of the most relevant strategies to control and prevent influenza infection. Current human vaccines against influenza induce strain-specific immunity and annual update is required due to the virus antigenic shift phenomena. Previously, our group has reported the use of conserved hemagglutinin peptides (HA-peptides) derived from H1-influenza virus as a potential multivalent vaccine candidate. Immunization of swine with these HA-peptides elicited antibodies that recognized and neutralized heterologous influenza viruses in vitro and demonstrated strong hemagglutination-inhibiting activity. In the present work, we cloned one HA-peptide (named NG34) into a plasmid fused with cytotoxic T lymphocyte-associated antigen (CTLA4) which is a molecule that modifies T cell activation and with an adjuvant activity interfering with the adaptive immune response. The resulting plasmid, named pCMV-CTLA4-Ig-NG34, was administered twice to animals employing a needle-free delivery approach. Two studies were carried out to test the efficacy of pCMV-CTLA4-Ig-NG34 as a potential swine influenza vaccine, one in seronegative and another in seropositive pigs against SIV. The second one was aimed to evaluate whether pCMV-CTLA4-Ig-NG34 vaccination would overcome maternally derived antibodies (MDA). After immunization, all animals were intranasally challenged with an H3N2 influenza strain. A complete elimination or significant reduction in the viral shedding was observed within the first week after the challenge in the vaccinated animals from both studies. In addition, no challenged heterologous virus load was detected in the airways of vaccinated pigs. Overall, it is suggested that the pCMV-CTLA4-Ig-NG34 vaccine formulation could potentially be used as a multivalent vaccine against influenza viruses.


Assuntos
Abatacepte , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Peptídeos , Doenças dos Suínos , Vacinas de DNA , Eliminação de Partículas Virais , Abatacepte/genética , Abatacepte/imunologia , Abatacepte/farmacologia , Animais , Cães , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/farmacologia , Vírus da Influenza A Subtipo H3N2/genética , Vacinas contra Influenza/genética , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/farmacologia , Células Madin Darby de Rim Canino , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/farmacologia , Plasmídeos/genética , Plasmídeos/imunologia , Plasmídeos/farmacologia , Suínos , Doenças dos Suínos/genética , Doenças dos Suínos/imunologia , Doenças dos Suínos/prevenção & controle , Vacinação , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/farmacologia , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/genética , Eliminação de Partículas Virais/imunologia
16.
Antivir Ther ; 24(8): 589-593, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32108589

RESUMO

BACKGROUND: Due to the limitations of current antiviral therapies because of drug resistance and the emergence of new circulating viral strains, novel effective antivirals are urgently needed. Results of the previous drug repurposing by virtual screening of DrugBank revealed the anticholinergic drug cycrimine as a possible inhibitor of the influenza virus infection. METHODS: In this study we examined the potential antiviral activity of cycrimine in vitro. RESULTS: The experimental results showed the anti-influenza activity of cycrimine against two different influenza A subtypes in cell culture. CONCLUSIONS: The findings of this study suggest cycrimine as a potential therapeutic agent for influenza.


Assuntos
Simulação por Computador , Reposicionamento de Medicamentos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cães
17.
F1000Res ; 7: 298, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29636902

RESUMO

Flu epidemics and potential pandemics pose great challenges to public health institutions, scientists and vaccine producers. Creating right vaccine composition for different parts of the world is not trivial and has been historically very problematic. This often resulted in decrease in vaccinations and reduced trust in public health officials. To improve future protection of population against flu we urgently need new methods for vaccine efficacy prediction and vaccine virus selection.

18.
Sci Rep ; 8(1): 1882, 2018 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-29382894

RESUMO

Zika virus (ZIKV) causes mostly asymptomatic infection or mild febrile illness. However, with an increasing number of patients, various clinical features such as microcephaly, Guillain-Barré syndrome and thrombocytopenia have also been reported. To determine which host factors are related to pathogenesis, the E protein of ZIKV was analyzed with the Informational Spectrum Method, which identifies common information encoded by primary structures of the virus and the respective host protein. The data showed that the ZIKV E protein and the complement component C1q cross-spectra are characterized by a single dominant peak at the frequency F = 0.338, suggesting similar biological properties. Indeed, C1q-specific antibodies were detected in sera obtained from mice and monkeys infected with ZIKV. As C1q has been known to be involved not only in immunity, but also in synaptic organization and different autoimmune diseases, a ZIKV-induced anti-C1q antibody response may contribute to the neurological complications. These findings might also be exploited for the design of safe and efficacious vaccines in the future.


Assuntos
Anticorpos Antivirais/imunologia , Autoanticorpos/imunologia , Complemento C1q/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/virologia , Macaca fascicularis , Camundongos , Microcefalia/imunologia , Microcefalia/virologia
19.
F1000Res ; 6: 13, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28529693

RESUMO

Background: Healthy nutrition is vital for good health and well-being. Despite the important role of a healthy nutritional diet, recommendations for healthy eating remain elusive and are mainly based on general properties of nutrients. The present study proposes an improved characterization of the molecular characteristics of nutrients, which are important for biological functions and can be useful in describing a healthy diet. Methods: We investigated the electronic properties of some known nutrient ingredients. In this analysis, we used the average quasi valence number (AQVN) and the electron-ion interaction potential (EIIP), which are molecular descriptors that represent the basic electronic properties of organic molecules.   Results: Our results show that most nutrients can be represented by specific groups of organic compounds according to their basic electronic properties, and these differ from the vast majority of known chemicals. Based on this finding, we have proposed a simple criterion for the selection of food components for healthy nutrition. Discussion: Further studies on the electronic properties of nutrients could serve as a basis for better understanding of their biological functions.

20.
F1000Res ; 6: 2067, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29535862

RESUMO

Vaccination against seasonal influenza viruses is the most effective way to prevent infection. A key factor in the effectiveness of the seasonal influenza vaccine is its immunological compatibility with the circulating viruses during the season. The high evolutionary rate, antigenic shift and antigenic drift of influenza viruses, represents the main obstacle for correct prediction of the vaccine effectiveness for an upcoming flu season. Conventional structural and phylogenetic approaches for assessment of vaccine effectiveness have had a limited success in prediction of vaccine efficacy in the past. Recently, a novel bioinformatics approach for assessment of effectiveness of seasonal influenza vaccine was proposed. Here, this approach was used for prediction of the vaccine effectiveness for the influenza season 2017/18 in US.

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