The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Luciano Polonelli - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection
'Italian Society of Sivilculture and Forest Ecology (SISEF)', 2009Co-Authors: G. Conti, Walter Magliani, S. Conti, L. Nencioni, R. Sgarbanti, A. T. Palamara, Luciano PolonelliAbstract:58 Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection. Giorgio Conti,1 Walter Magliani,1 Stefania Conti,1 Lucia Nencioni,2 Rossella Sgarbanti,2 Anna Teresa Palamara,2 and Luciano Polonelli1* Department of Pathology and Laboratory Medicine, Microbiology Section, University of Parma, Parma, Italy1, Department of Public Health Sciences, Pharmaceutical Microbiology Section, University of Rome La Sapienza, Rome, Italy2 The “in vitro” and “in vivo” activities of a killer decapeptide (KP) against influenza A virus is described, and the mechanisms of action are suggested. KP represents the functional internal image of a yeast killer toxin that proved to exert antimicrobial and anti-human immunodeficiency virus type 1 (HIV-1) activities. Treatment with KP demonstrated a significant inhibitory Activity on the replication of two strains of influenza A virus in different cell lines, as evaluated by hemagglutination, hemadsorption, and plaque assays. The complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular) were observed at a KP concentration of 4 μg/ml. Moreover, KP administered intraperitoneally at a dose of 100 μg/mice once a day for 10 days to influenza A/NWS/33 (H1N1) virus-infected mice improved the survival of the animals by 40% and significantly decreased the viral titers in their lungs. Overall, KP appears to be the first anti-idiotypic antibody-derived peptide that displays inhibitory Activity and that has a potential Therapeutic effect against pathogenic microorganisms. Even if the precise molecular mechanism by which KP can interferewith viral multiplication remains to be determined, our results suggest that adsorption and fusion are not affected, as reported from studies with monoclonal Ab HC63. According to the experimental conditions adopted, in the presence of KP, appreciable reductions in the levels of viral proteins, including glycosylated forms, have been observed. In particular, M1 and HA synthesis in the late phase of viral multiplication were mainly affected. These findings support the hypothesis that the marked reduction of M1 synthesis may be the major cause of the lack of production of mature viral particles, owing to the fundamental role played by this protein. On the basis of the immunoprecipitation and hemadsorption assay results, however, the possibility for the concomitant involvement of virus-coded HA may not be excluded due to its incorrect or defective association or insertion into cellular plasma membrane. 59 Inhibition of multiplication of RNA genome containing viruses performed by different concentrations ofMESNA. G. Conti 1, P.Portincasa 1, F. Piazza° and C. Zini° 1 Department of Pathology and Laboratory Medicine, Microbiology Section ° Department of Otorino-Odonto-Ophthalmology, University of Parma, Gramsci 14, Parma, Italy The antiviral Activity of MESNA, a thiol group compound, was evaluated in cellular monolayers infected by different strains of RNA viruses, other than Influenza virus. Furthermore, the action of the compound was preliminarly evaluated also in cells infected by DNA viruses. Whereas DNA viruses were not affected, the multiplication of RNA genome viruses was inhibited at different extent, depending on the virus strains. MESNA was able to inhibit viral multiplicaton in a dose-dependent fashion and virus yield was reduced at concentrations of MESNA which did not damage mock-infected cells. With respect to influenza virus, MESNA treatment determined a marked reduction of the normal synthesis of early and late virus-induced proteins suggesting an action on viral RNA transcriptase Activity. However, “in vitro” assay of viral RNA dependent-RNA polymerase Activity performed on purified virions showed negative results in that MESNA was not able to inhibit or block “in vitro” viral enzyme Activity. This evidence led us to hypothesise a possible role of a cellular factor (s) interacting with a function (s) expressed by the virus working during the early phase of infection. Data obtained with human influenza virus strain, A, NWS, H1N1, were reproducible and comparable with those obtained with avian influenza virus strain, A, Ulster 73, H7N1. Furthermore, data obtained in MDCK cells were comparable to those, above described, obtained in LLC-MK2 cells
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Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection
'American Society for Microbiology', 2008Co-Authors: G. Conti, Walter Magliani, Palamara, Anna Teresa, Nencioni Lucia, S. Conti, Sgarbanti Rossella, Luciano PolonelliAbstract:The in vitro and in vivo activities of a killer decapeptide (KP) against influenza A virus is described, and the mechanisms of action are suggested. KP represents the functional internal image of a yeast killer toxin that proved to exert antimicrobial and anti-human immunodeficiency virus type 1 (HIV-1) activities. Treatment with KP demonstrated a significant inhibitory Activity on the replication of two strains of influenza A virus in different cell lines, as evaluated by hemagglutination, hemadsorption, and plaque assays. The complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular) were observed at a KP concentration of 4 mu g/ml. Moreover, KP administered intraperitoneally at a dose of 100 mu g/mice once a day for 10 days to influenza A/NWS/33 (H1N1) virus-infected mice improved the survival of the animals by 40% and significantly decreased the viral titers in their lungs. Overall, KP appears to be the first anti-idiotypic antibody-derived peptide that displays inhibitory Activity and that has a potential Therapeutic effect against pathogenic microorganisms, HIV-1, and influenza A virus by different mechanisms of action
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a killer mimotope with Therapeutic Activity against aids related opportunistic micro organisms inhibits ex vivo hiv 1 replication
AIDS, 2006Co-Authors: Claudio Casoli, Walter Magliani, Stefania Conti, Antonio Cassone, Elisabetta Pilotti, Carlo Federico Perno, Emanuela Balestra, Eugenia Polverini, Luciano PolonelliAbstract:Objective: To verify whether a synthetic Therapeutic killer decapeptide (KP), a functional mimotope of a yeast killer toxin with wide-spectrum microbicidal Activity, inclusive of AIDS-related opportunistic micro-organ isms, through interaction with P-glucan receptors, which has been found to possess sequence homology with critical segments in gp160 V1/V2 and V3 loops, may also be inhibiting HIV-1 replication. Methods: Primary peripheral blood mononuclear cells (PBMCs) cultures established from HIV-1-infected patients were treated with KP in comparison with zidovudine and supernatants and cells were harvested for analysis of HIV RNA and proviral contents, respectively. Virus production in exogenous in-vitro PBMCs infection with lymphocytotropic and monocytotropic HIV-1 strains was also assessed in presence of KP by enzyme-linked immunosorbent assay HIV p24 gag antigen detection. The binding affinity of KP to CD4, CCR5 and CXCR4 was evaluated on CD4-CCR5 or CD4-CXCR4 transfected astroglioma cell lines. Results: KP was shown to be devoid of cytotoxicity on PBMCs and to inhibit HIV-1 replication in PBMCs of a patient in the acute phase of infection. The antiretroviral Activity of KP, which proved to be more potent than zidovudine at micromolar concentrations, is abolished by beta 1,3-glucan but not by beta 1,6-glucan. Down-regulation of CCR5 co-receptor, and/or physical block of the gp120-receptor interaction are possible mechanisms of KP Activity. Conclusion: KP appears to be the first anti body-derived short peptide displaying an inhibitory Activity against HIV-1 and related opportunistic micro-organisms by different mechanisms of action. (c) 2006 Lippincott Williams & Wilkins.
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Therapeutic Activity of an engineered synthetic killer antiidiotypic antibody fragment against experimental mucosal and systemic candidiasis
Infection and Immunity, 2003Co-Authors: Luciano Polonelli, Walter Magliani, Stefania Conti, Luisa Bracci, Luisa Lozzi, Paolo Neri, Daniela Adriani, Flavia De Bernardis, Antonio CassoneAbstract:Peptides derived from the sequence of a single-chain, recombinant, antiidiotypic antibody (IdAb; KT-scFv) acting as a functional internal image of a microbicidal, wide-spectrum yeast killer toxin (KT) were synthesized and studied for their antimicrobial Activity by using the KT-susceptible Candida albicans as model organism. A decapeptide containing the first three amino acids (SAS) of the light chain CDR1 was selected and optimized by alanine replacement of a single residue. This peptide exerted a strong candidacidal Activity in vitro, with a 50% inhibitory concentration of 0.056 μM, and was therefore designated killer peptide (KP). Its Activity was neutralized by laminarin, a β1-3 glucan molecule, but not by pustulan, a β1-6 glucan molecule. KP also competed with the binding of a KT-like monoclonal IdAb to germinating cells of the fungus. In a rat model of vaginal candidiasis, local, postchallenge administration of KP was efficacious in rapidly abating infections caused by fluconazole-susceptible or -resistant C. albicans strains. In systemic infection of BALB/c or SCID mice preinfected intravenously with a lethal fungal load, KP caused a highly significant prolongation of the median survival time, with >80% of the animals still surviving after >60 days, whereas >90% of control mice died within 3 to 5 days. KP is therefore the first engineered peptide derived from a recombinant IdAb retaining KT microbicidal Activity, probably through the interaction with the β-glucan KT receptor on target microbial cells.
Antonio Cassone - One of the best experts on this subject based on the ideXlab platform.
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a killer mimotope with Therapeutic Activity against aids related opportunistic micro organisms inhibits ex vivo hiv 1 replication
AIDS, 2006Co-Authors: Claudio Casoli, Walter Magliani, Stefania Conti, Antonio Cassone, Elisabetta Pilotti, Carlo Federico Perno, Emanuela Balestra, Eugenia Polverini, Luciano PolonelliAbstract:Objective: To verify whether a synthetic Therapeutic killer decapeptide (KP), a functional mimotope of a yeast killer toxin with wide-spectrum microbicidal Activity, inclusive of AIDS-related opportunistic micro-organ isms, through interaction with P-glucan receptors, which has been found to possess sequence homology with critical segments in gp160 V1/V2 and V3 loops, may also be inhibiting HIV-1 replication. Methods: Primary peripheral blood mononuclear cells (PBMCs) cultures established from HIV-1-infected patients were treated with KP in comparison with zidovudine and supernatants and cells were harvested for analysis of HIV RNA and proviral contents, respectively. Virus production in exogenous in-vitro PBMCs infection with lymphocytotropic and monocytotropic HIV-1 strains was also assessed in presence of KP by enzyme-linked immunosorbent assay HIV p24 gag antigen detection. The binding affinity of KP to CD4, CCR5 and CXCR4 was evaluated on CD4-CCR5 or CD4-CXCR4 transfected astroglioma cell lines. Results: KP was shown to be devoid of cytotoxicity on PBMCs and to inhibit HIV-1 replication in PBMCs of a patient in the acute phase of infection. The antiretroviral Activity of KP, which proved to be more potent than zidovudine at micromolar concentrations, is abolished by beta 1,3-glucan but not by beta 1,6-glucan. Down-regulation of CCR5 co-receptor, and/or physical block of the gp120-receptor interaction are possible mechanisms of KP Activity. Conclusion: KP appears to be the first anti body-derived short peptide displaying an inhibitory Activity against HIV-1 and related opportunistic micro-organisms by different mechanisms of action. (c) 2006 Lippincott Williams & Wilkins.
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Therapeutic Activity of an engineered synthetic killer antiidiotypic antibody fragment against experimental mucosal and systemic candidiasis
Infection and Immunity, 2003Co-Authors: Luciano Polonelli, Walter Magliani, Stefania Conti, Luisa Bracci, Luisa Lozzi, Paolo Neri, Daniela Adriani, Flavia De Bernardis, Antonio CassoneAbstract:Peptides derived from the sequence of a single-chain, recombinant, antiidiotypic antibody (IdAb; KT-scFv) acting as a functional internal image of a microbicidal, wide-spectrum yeast killer toxin (KT) were synthesized and studied for their antimicrobial Activity by using the KT-susceptible Candida albicans as model organism. A decapeptide containing the first three amino acids (SAS) of the light chain CDR1 was selected and optimized by alanine replacement of a single residue. This peptide exerted a strong candidacidal Activity in vitro, with a 50% inhibitory concentration of 0.056 μM, and was therefore designated killer peptide (KP). Its Activity was neutralized by laminarin, a β1-3 glucan molecule, but not by pustulan, a β1-6 glucan molecule. KP also competed with the binding of a KT-like monoclonal IdAb to germinating cells of the fungus. In a rat model of vaginal candidiasis, local, postchallenge administration of KP was efficacious in rapidly abating infections caused by fluconazole-susceptible or -resistant C. albicans strains. In systemic infection of BALB/c or SCID mice preinfected intravenously with a lethal fungal load, KP caused a highly significant prolongation of the median survival time, with >80% of the animals still surviving after >60 days, whereas >90% of control mice died within 3 to 5 days. KP is therefore the first engineered peptide derived from a recombinant IdAb retaining KT microbicidal Activity, probably through the interaction with the β-glucan KT receptor on target microbial cells.
Walter Magliani - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection
'Italian Society of Sivilculture and Forest Ecology (SISEF)', 2009Co-Authors: G. Conti, Walter Magliani, S. Conti, L. Nencioni, R. Sgarbanti, A. T. Palamara, Luciano PolonelliAbstract:58 Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection. Giorgio Conti,1 Walter Magliani,1 Stefania Conti,1 Lucia Nencioni,2 Rossella Sgarbanti,2 Anna Teresa Palamara,2 and Luciano Polonelli1* Department of Pathology and Laboratory Medicine, Microbiology Section, University of Parma, Parma, Italy1, Department of Public Health Sciences, Pharmaceutical Microbiology Section, University of Rome La Sapienza, Rome, Italy2 The “in vitro” and “in vivo” activities of a killer decapeptide (KP) against influenza A virus is described, and the mechanisms of action are suggested. KP represents the functional internal image of a yeast killer toxin that proved to exert antimicrobial and anti-human immunodeficiency virus type 1 (HIV-1) activities. Treatment with KP demonstrated a significant inhibitory Activity on the replication of two strains of influenza A virus in different cell lines, as evaluated by hemagglutination, hemadsorption, and plaque assays. The complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular) were observed at a KP concentration of 4 μg/ml. Moreover, KP administered intraperitoneally at a dose of 100 μg/mice once a day for 10 days to influenza A/NWS/33 (H1N1) virus-infected mice improved the survival of the animals by 40% and significantly decreased the viral titers in their lungs. Overall, KP appears to be the first anti-idiotypic antibody-derived peptide that displays inhibitory Activity and that has a potential Therapeutic effect against pathogenic microorganisms. Even if the precise molecular mechanism by which KP can interferewith viral multiplication remains to be determined, our results suggest that adsorption and fusion are not affected, as reported from studies with monoclonal Ab HC63. According to the experimental conditions adopted, in the presence of KP, appreciable reductions in the levels of viral proteins, including glycosylated forms, have been observed. In particular, M1 and HA synthesis in the late phase of viral multiplication were mainly affected. These findings support the hypothesis that the marked reduction of M1 synthesis may be the major cause of the lack of production of mature viral particles, owing to the fundamental role played by this protein. On the basis of the immunoprecipitation and hemadsorption assay results, however, the possibility for the concomitant involvement of virus-coded HA may not be excluded due to its incorrect or defective association or insertion into cellular plasma membrane. 59 Inhibition of multiplication of RNA genome containing viruses performed by different concentrations ofMESNA. G. Conti 1, P.Portincasa 1, F. Piazza° and C. Zini° 1 Department of Pathology and Laboratory Medicine, Microbiology Section ° Department of Otorino-Odonto-Ophthalmology, University of Parma, Gramsci 14, Parma, Italy The antiviral Activity of MESNA, a thiol group compound, was evaluated in cellular monolayers infected by different strains of RNA viruses, other than Influenza virus. Furthermore, the action of the compound was preliminarly evaluated also in cells infected by DNA viruses. Whereas DNA viruses were not affected, the multiplication of RNA genome viruses was inhibited at different extent, depending on the virus strains. MESNA was able to inhibit viral multiplicaton in a dose-dependent fashion and virus yield was reduced at concentrations of MESNA which did not damage mock-infected cells. With respect to influenza virus, MESNA treatment determined a marked reduction of the normal synthesis of early and late virus-induced proteins suggesting an action on viral RNA transcriptase Activity. However, “in vitro” assay of viral RNA dependent-RNA polymerase Activity performed on purified virions showed negative results in that MESNA was not able to inhibit or block “in vitro” viral enzyme Activity. This evidence led us to hypothesise a possible role of a cellular factor (s) interacting with a function (s) expressed by the virus working during the early phase of infection. Data obtained with human influenza virus strain, A, NWS, H1N1, were reproducible and comparable with those obtained with avian influenza virus strain, A, Ulster 73, H7N1. Furthermore, data obtained in MDCK cells were comparable to those, above described, obtained in LLC-MK2 cells
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Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection
'American Society for Microbiology', 2008Co-Authors: G. Conti, Walter Magliani, Palamara, Anna Teresa, Nencioni Lucia, S. Conti, Sgarbanti Rossella, Luciano PolonelliAbstract:The in vitro and in vivo activities of a killer decapeptide (KP) against influenza A virus is described, and the mechanisms of action are suggested. KP represents the functional internal image of a yeast killer toxin that proved to exert antimicrobial and anti-human immunodeficiency virus type 1 (HIV-1) activities. Treatment with KP demonstrated a significant inhibitory Activity on the replication of two strains of influenza A virus in different cell lines, as evaluated by hemagglutination, hemadsorption, and plaque assays. The complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular) were observed at a KP concentration of 4 mu g/ml. Moreover, KP administered intraperitoneally at a dose of 100 mu g/mice once a day for 10 days to influenza A/NWS/33 (H1N1) virus-infected mice improved the survival of the animals by 40% and significantly decreased the viral titers in their lungs. Overall, KP appears to be the first anti-idiotypic antibody-derived peptide that displays inhibitory Activity and that has a potential Therapeutic effect against pathogenic microorganisms, HIV-1, and influenza A virus by different mechanisms of action
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a killer mimotope with Therapeutic Activity against aids related opportunistic micro organisms inhibits ex vivo hiv 1 replication
AIDS, 2006Co-Authors: Claudio Casoli, Walter Magliani, Stefania Conti, Antonio Cassone, Elisabetta Pilotti, Carlo Federico Perno, Emanuela Balestra, Eugenia Polverini, Luciano PolonelliAbstract:Objective: To verify whether a synthetic Therapeutic killer decapeptide (KP), a functional mimotope of a yeast killer toxin with wide-spectrum microbicidal Activity, inclusive of AIDS-related opportunistic micro-organ isms, through interaction with P-glucan receptors, which has been found to possess sequence homology with critical segments in gp160 V1/V2 and V3 loops, may also be inhibiting HIV-1 replication. Methods: Primary peripheral blood mononuclear cells (PBMCs) cultures established from HIV-1-infected patients were treated with KP in comparison with zidovudine and supernatants and cells were harvested for analysis of HIV RNA and proviral contents, respectively. Virus production in exogenous in-vitro PBMCs infection with lymphocytotropic and monocytotropic HIV-1 strains was also assessed in presence of KP by enzyme-linked immunosorbent assay HIV p24 gag antigen detection. The binding affinity of KP to CD4, CCR5 and CXCR4 was evaluated on CD4-CCR5 or CD4-CXCR4 transfected astroglioma cell lines. Results: KP was shown to be devoid of cytotoxicity on PBMCs and to inhibit HIV-1 replication in PBMCs of a patient in the acute phase of infection. The antiretroviral Activity of KP, which proved to be more potent than zidovudine at micromolar concentrations, is abolished by beta 1,3-glucan but not by beta 1,6-glucan. Down-regulation of CCR5 co-receptor, and/or physical block of the gp120-receptor interaction are possible mechanisms of KP Activity. Conclusion: KP appears to be the first anti body-derived short peptide displaying an inhibitory Activity against HIV-1 and related opportunistic micro-organisms by different mechanisms of action. (c) 2006 Lippincott Williams & Wilkins.
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Therapeutic Activity of an engineered synthetic killer antiidiotypic antibody fragment against experimental mucosal and systemic candidiasis
Infection and Immunity, 2003Co-Authors: Luciano Polonelli, Walter Magliani, Stefania Conti, Luisa Bracci, Luisa Lozzi, Paolo Neri, Daniela Adriani, Flavia De Bernardis, Antonio CassoneAbstract:Peptides derived from the sequence of a single-chain, recombinant, antiidiotypic antibody (IdAb; KT-scFv) acting as a functional internal image of a microbicidal, wide-spectrum yeast killer toxin (KT) were synthesized and studied for their antimicrobial Activity by using the KT-susceptible Candida albicans as model organism. A decapeptide containing the first three amino acids (SAS) of the light chain CDR1 was selected and optimized by alanine replacement of a single residue. This peptide exerted a strong candidacidal Activity in vitro, with a 50% inhibitory concentration of 0.056 μM, and was therefore designated killer peptide (KP). Its Activity was neutralized by laminarin, a β1-3 glucan molecule, but not by pustulan, a β1-6 glucan molecule. KP also competed with the binding of a KT-like monoclonal IdAb to germinating cells of the fungus. In a rat model of vaginal candidiasis, local, postchallenge administration of KP was efficacious in rapidly abating infections caused by fluconazole-susceptible or -resistant C. albicans strains. In systemic infection of BALB/c or SCID mice preinfected intravenously with a lethal fungal load, KP caused a highly significant prolongation of the median survival time, with >80% of the animals still surviving after >60 days, whereas >90% of control mice died within 3 to 5 days. KP is therefore the first engineered peptide derived from a recombinant IdAb retaining KT microbicidal Activity, probably through the interaction with the β-glucan KT receptor on target microbial cells.
Stefania Conti - One of the best experts on this subject based on the ideXlab platform.
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a killer mimotope with Therapeutic Activity against aids related opportunistic micro organisms inhibits ex vivo hiv 1 replication
AIDS, 2006Co-Authors: Claudio Casoli, Walter Magliani, Stefania Conti, Antonio Cassone, Elisabetta Pilotti, Carlo Federico Perno, Emanuela Balestra, Eugenia Polverini, Luciano PolonelliAbstract:Objective: To verify whether a synthetic Therapeutic killer decapeptide (KP), a functional mimotope of a yeast killer toxin with wide-spectrum microbicidal Activity, inclusive of AIDS-related opportunistic micro-organ isms, through interaction with P-glucan receptors, which has been found to possess sequence homology with critical segments in gp160 V1/V2 and V3 loops, may also be inhibiting HIV-1 replication. Methods: Primary peripheral blood mononuclear cells (PBMCs) cultures established from HIV-1-infected patients were treated with KP in comparison with zidovudine and supernatants and cells were harvested for analysis of HIV RNA and proviral contents, respectively. Virus production in exogenous in-vitro PBMCs infection with lymphocytotropic and monocytotropic HIV-1 strains was also assessed in presence of KP by enzyme-linked immunosorbent assay HIV p24 gag antigen detection. The binding affinity of KP to CD4, CCR5 and CXCR4 was evaluated on CD4-CCR5 or CD4-CXCR4 transfected astroglioma cell lines. Results: KP was shown to be devoid of cytotoxicity on PBMCs and to inhibit HIV-1 replication in PBMCs of a patient in the acute phase of infection. The antiretroviral Activity of KP, which proved to be more potent than zidovudine at micromolar concentrations, is abolished by beta 1,3-glucan but not by beta 1,6-glucan. Down-regulation of CCR5 co-receptor, and/or physical block of the gp120-receptor interaction are possible mechanisms of KP Activity. Conclusion: KP appears to be the first anti body-derived short peptide displaying an inhibitory Activity against HIV-1 and related opportunistic micro-organisms by different mechanisms of action. (c) 2006 Lippincott Williams & Wilkins.
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Therapeutic Activity of an engineered synthetic killer antiidiotypic antibody fragment against experimental mucosal and systemic candidiasis
Infection and Immunity, 2003Co-Authors: Luciano Polonelli, Walter Magliani, Stefania Conti, Luisa Bracci, Luisa Lozzi, Paolo Neri, Daniela Adriani, Flavia De Bernardis, Antonio CassoneAbstract:Peptides derived from the sequence of a single-chain, recombinant, antiidiotypic antibody (IdAb; KT-scFv) acting as a functional internal image of a microbicidal, wide-spectrum yeast killer toxin (KT) were synthesized and studied for their antimicrobial Activity by using the KT-susceptible Candida albicans as model organism. A decapeptide containing the first three amino acids (SAS) of the light chain CDR1 was selected and optimized by alanine replacement of a single residue. This peptide exerted a strong candidacidal Activity in vitro, with a 50% inhibitory concentration of 0.056 μM, and was therefore designated killer peptide (KP). Its Activity was neutralized by laminarin, a β1-3 glucan molecule, but not by pustulan, a β1-6 glucan molecule. KP also competed with the binding of a KT-like monoclonal IdAb to germinating cells of the fungus. In a rat model of vaginal candidiasis, local, postchallenge administration of KP was efficacious in rapidly abating infections caused by fluconazole-susceptible or -resistant C. albicans strains. In systemic infection of BALB/c or SCID mice preinfected intravenously with a lethal fungal load, KP caused a highly significant prolongation of the median survival time, with >80% of the animals still surviving after >60 days, whereas >90% of control mice died within 3 to 5 days. KP is therefore the first engineered peptide derived from a recombinant IdAb retaining KT microbicidal Activity, probably through the interaction with the β-glucan KT receptor on target microbial cells.
John H Griffin - One of the best experts on this subject based on the ideXlab platform.
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the tlr4 par1 axis regulates bone marrow mesenchymal stromal cell survival and Therapeutic capacity in experimental bacterial pneumonia
Stem Cells, 2018Co-Authors: Naveen Gupta, Ranjeet Kumar Sinha, Anna Krasnodembskaya, Victor Nizet, Michael A Matthay, John H GriffinAbstract:Bone marrow derived mesenchymal stromal cells have been shown to have significant Therapeutic effects in experimental models of pneumonia and lung injury. The current study examined the roles of the toll like receptor 4 (TLR4) and protease activated receptor 1 (PAR1) pathways on mesenchymal stromal cell (MSC) survival and Therapeutic Activity in a murine model of pneumonia. MSCs from TLR4 -/- and R41Q-PAR1 mutated mice were isolated to test the effect of mutating these specific pathways on MSC survival when exposed to cytotoxic stimuli in vitro. An Escherichia coli pneumonia model was used to assess the effect of these specific pathways on MSC Therapeutic Activity in vivo. Our results showed that mutation of either the TLR4 or PAR1 pathways in MSCs impaired cell survival under conditions of inflammatory stress in vitro, and eliminated their Therapeutic efficacy in vivo. Also, stimulation of the TLR4 pathway on MSCs led to secretion of low levels of prothrombin by MSCs, while disrupting the TLR4 pathway impaired canonical signaling through PAR1 in response to thrombin. Therefore, this study demonstrates that both TLR4 and PAR1 are required for MSC survival under inflammatory conditions in vitro and Therapeutic capacity in vivo, and that the TLR4 pathway regulates signaling through PAR1 on MSCs. Stem Cells 2018;36:796-806.
