Few interesting abstracts and links. Apologies if this has been discussed here already.
Disintegration of retroviruses by chelating agents
Exposurein vitro of various mammalian retroviruses to the chelating agents EDTA or EGTA in millimolar concentrations resulted in partial disintegration of viral membranes as measured by accessibility or even release of reverse transcriptase, an internal viral protein, without any other treatment usually required. Among the viruses responding to chelators were mammalian type C viruses, primate type D viruses and bovine leukemia virus. The effect was dose-dependent. The avian type C virus AMV, however, was found to be not susceptible to the agents. Rauscher mouse leukemia virus treatedin vitro with EDTA or EGTA showed reduced infectivity in mice. The results are considered as evidence for some association of divalent cations with membranes of mammalian retroviruses. The disintegrating activity of EGTA suggests that Ca2+ is an integral constituent of viruses but Mg2+ may also be involved. These cations seem to be responsible for maintaining integrity of retroviral membranes which, after chelation of ions, are either disrupted or become permeable for the exogenous template of reverse transcriptase. In addition, the distintegrating activity of trifluoperazine may indicate that a calmodulin-like protein occurs in retroviral membranes. V. Wunderlich1 and G. Sydow1(1)Central Institute for Cancer Research, Robert-Rssle-Institute, Academy of Sciences of the German Democratic Republic, Berlin, German Democratic Republic. Received: 1 March 1982 Accepted: 2 April 1982
Metal chelation underlies anti-HIV integrase activity of beta-diketo acids [no abstract] http://www.accessmylibrary.com/coms2/summary_0286-803606_ITM
Patent: DMPS as antiHIV treatment: http://www.freepatentsonline.com/5464869.html
Metal chelators as potential antiviral agents.
Metal-chelating compounds can inhibit virus-induced enzymes in infected cells by coordinating with metal ions at their active sites. Consideration of the coordinating properties of ligands can explain the antiviral activity of these compounds. The antiviral actions of a number of compounds (e.g., thiosemicarbazones, pyrophosphate analogues, beta-diketones, cyclic polyethers and flavanoids) are discussed in the light of their metal-chelating properties. Hutchinson DW.Antiviral Res. 1985 Aug;5(4):193-205
Inhibition of Tat-mediated HIV-1-LTR transactivation and virus replication by sulfhydryl compounds with chelating properties
D-Penicillamine, a structural analog of cysteine, has the ability to chelate metal ions and reacts with cysteine. We have shown earlier that D-Penicillamin is a potential inhibitor of tat-mediated transactivation of HIV-1-LTR (14) and posesses anti-HIV-1 activity (23). Following this approach, we evaluated the anti-tat and anti-HIV-1 activity of several sulfhydryl compounds with chelating properties. The tested compounds: N-(2-Mercapto-propionyl)-glycin (MPG), 2,3-Dimercapto-propanol (DMP) and 2,3-Dimercapto-propane-sulfonic acid (DMPS) exhibited an inhibitory effect on the tat-mediated transactivation in Jurkat cells, as well as in U937 cells. The highest inhibitory response was shown by DMP leading to about 50% inhibition of transactivation in Jurkat cels and an 80% inhibition in U937 cells. On the contrary, DMPS (30 pg/ml) had no inhibitory effect in U937 cells, but did exhibit a 50% inhibition of transactivation in Jurkat cells at 30 μg/ml. The antiviral activity of DMP and DMPS was evaluated in H9 cells. In the concentration range which is effective for antiviral effect, both the compounds were highly cytotoxic. Mercapto-propionyl-glycin, although a weak inhibitor of transactivation, was able to inhibit synctia formation to more than 90% and inhibit the viral antigene expression to about 70%. The concentration of MPG needed to achieve this antiviral effect was very high, but it had no cytotoxicity at this concentration. We suggest that a search for compounds using this approach may be useful in developing potential inhibitors of tat-mediated transactivation. DEMIRHAN Ilhan et al (2) Department of Biochemistry, The George Washington University Medical Center, Washington, D.C., ETATS-UNIS
Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin.
Replication of human immunodeficiency virus type 1 (HIV-1) can be influenced by iron. Hence, decreasing the availability of iron may inhibit HIV-1 replication. Deferoxamine and deferiprone, both forming catalytically inactive iron-chelator complexes, and bleomycin, by use of which iron catalyzes oxidative nucleic acid destruction, were investigated. Expression of p24 antigen in human monocyte-derived macrophages and peripheral blood lymphocytes (PBL) was reduced by all 3 iron chelators. In PBL, p24 reduction was mirrored by a decrease in proliferation after incubation with deferoxamine or deferiprone, suggesting that viral inhibition is closely linked to a decrease in cellular proliferation. In contrast, clinically relevant bleomycin concentrations reduced p24 levels by approximately 50% without affecting proliferation. When deferoxamine and the nucleoside analogue dideoxyinosine were used in combination, they acted synergistically in inhibiting HIV-1 replication. These observations suggest that iron chelators with different mechanisms of action could be of additional benefit in antiretroviral combination therapy. Georgiou NA, et al Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. n.georgiou@lab.azu.nl J Infect Dis. 2000 Feb;181(2):484-90. PMID: 10669330
Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection.
BACKGROUND: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHOD: One day after liver transplantation, PVG (RT1c) into BN(RT1n), the rats were infected with rat CMV (RCMV, Maastricht strain; 10(5) plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-alpha and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.PMID: 10609953 [PubMed - indexed for MEDLINE] Martelius T, et al. Department of Surgery, Helsinki University Hospital, Finland. Transplantation. 1999 Dec 15;68(11):1753-61
Effect of desferrioxamine B, a metal chelating agent, on rhabdovirus multiplication.
It has been suggested that the antiviral activity shown by chelating agents towards different viruses is probably related to the action on viral nucleic acid polymerases which require metal ions as essential cofactors. Desferrioxamine B, a metabolite from Streptomyces pilosus which chelates ions (Fe3+, Al3+, Cu2+, Zn2+, Co2+) from intracellular and external compartments, has been tested for its activity on the multiplication of VSV and rabies virus in CER cells. While desferrioxamine B was ineffective on rabies virus multiplication, it was shown to reduce plaque formation, cytopathic effect and viral yield by VSV at both low and high multiplicity of infection. The activity of the drug was not due to a direct action on virions outside the cells, but was probably related to an alteration in the delicate balance of intracellular ions which could in turn be critical for VSV multiplication. Conti C,et al Istituto di Microbiologia, Facolt di Medicina e Chirurgia, Universit di Roma La Sapienza. Boll Ist Sieroter Milan. 1990 Jun;69(2):431-6
Disintegration of retroviruses by chelating agents
Exposurein vitro of various mammalian retroviruses to the chelating agents EDTA or EGTA in millimolar concentrations resulted in partial disintegration of viral membranes as measured by accessibility or even release of reverse transcriptase, an internal viral protein, without any other treatment usually required. Among the viruses responding to chelators were mammalian type C viruses, primate type D viruses and bovine leukemia virus. The effect was dose-dependent. The avian type C virus AMV, however, was found to be not susceptible to the agents. Rauscher mouse leukemia virus treatedin vitro with EDTA or EGTA showed reduced infectivity in mice. The results are considered as evidence for some association of divalent cations with membranes of mammalian retroviruses. The disintegrating activity of EGTA suggests that Ca2+ is an integral constituent of viruses but Mg2+ may also be involved. These cations seem to be responsible for maintaining integrity of retroviral membranes which, after chelation of ions, are either disrupted or become permeable for the exogenous template of reverse transcriptase. In addition, the distintegrating activity of trifluoperazine may indicate that a calmodulin-like protein occurs in retroviral membranes. V. Wunderlich1 and G. Sydow1(1)Central Institute for Cancer Research, Robert-Rssle-Institute, Academy of Sciences of the German Democratic Republic, Berlin, German Democratic Republic. Received: 1 March 1982 Accepted: 2 April 1982
Metal chelation underlies anti-HIV integrase activity of beta-diketo acids [no abstract] http://www.accessmylibrary.com/coms2/summary_0286-803606_ITM
Patent: DMPS as antiHIV treatment: http://www.freepatentsonline.com/5464869.html
Metal chelators as potential antiviral agents.
Metal-chelating compounds can inhibit virus-induced enzymes in infected cells by coordinating with metal ions at their active sites. Consideration of the coordinating properties of ligands can explain the antiviral activity of these compounds. The antiviral actions of a number of compounds (e.g., thiosemicarbazones, pyrophosphate analogues, beta-diketones, cyclic polyethers and flavanoids) are discussed in the light of their metal-chelating properties. Hutchinson DW.Antiviral Res. 1985 Aug;5(4):193-205
Inhibition of Tat-mediated HIV-1-LTR transactivation and virus replication by sulfhydryl compounds with chelating properties
D-Penicillamine, a structural analog of cysteine, has the ability to chelate metal ions and reacts with cysteine. We have shown earlier that D-Penicillamin is a potential inhibitor of tat-mediated transactivation of HIV-1-LTR (14) and posesses anti-HIV-1 activity (23). Following this approach, we evaluated the anti-tat and anti-HIV-1 activity of several sulfhydryl compounds with chelating properties. The tested compounds: N-(2-Mercapto-propionyl)-glycin (MPG), 2,3-Dimercapto-propanol (DMP) and 2,3-Dimercapto-propane-sulfonic acid (DMPS) exhibited an inhibitory effect on the tat-mediated transactivation in Jurkat cells, as well as in U937 cells. The highest inhibitory response was shown by DMP leading to about 50% inhibition of transactivation in Jurkat cels and an 80% inhibition in U937 cells. On the contrary, DMPS (30 pg/ml) had no inhibitory effect in U937 cells, but did exhibit a 50% inhibition of transactivation in Jurkat cells at 30 μg/ml. The antiviral activity of DMP and DMPS was evaluated in H9 cells. In the concentration range which is effective for antiviral effect, both the compounds were highly cytotoxic. Mercapto-propionyl-glycin, although a weak inhibitor of transactivation, was able to inhibit synctia formation to more than 90% and inhibit the viral antigene expression to about 70%. The concentration of MPG needed to achieve this antiviral effect was very high, but it had no cytotoxicity at this concentration. We suggest that a search for compounds using this approach may be useful in developing potential inhibitors of tat-mediated transactivation. DEMIRHAN Ilhan et al (2) Department of Biochemistry, The George Washington University Medical Center, Washington, D.C., ETATS-UNIS
Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin.
Replication of human immunodeficiency virus type 1 (HIV-1) can be influenced by iron. Hence, decreasing the availability of iron may inhibit HIV-1 replication. Deferoxamine and deferiprone, both forming catalytically inactive iron-chelator complexes, and bleomycin, by use of which iron catalyzes oxidative nucleic acid destruction, were investigated. Expression of p24 antigen in human monocyte-derived macrophages and peripheral blood lymphocytes (PBL) was reduced by all 3 iron chelators. In PBL, p24 reduction was mirrored by a decrease in proliferation after incubation with deferoxamine or deferiprone, suggesting that viral inhibition is closely linked to a decrease in cellular proliferation. In contrast, clinically relevant bleomycin concentrations reduced p24 levels by approximately 50% without affecting proliferation. When deferoxamine and the nucleoside analogue dideoxyinosine were used in combination, they acted synergistically in inhibiting HIV-1 replication. These observations suggest that iron chelators with different mechanisms of action could be of additional benefit in antiretroviral combination therapy. Georgiou NA, et al Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. n.georgiou@lab.azu.nl J Infect Dis. 2000 Feb;181(2):484-90. PMID: 10669330
Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection.
BACKGROUND: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHOD: One day after liver transplantation, PVG (RT1c) into BN(RT1n), the rats were infected with rat CMV (RCMV, Maastricht strain; 10(5) plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-alpha and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.PMID: 10609953 [PubMed - indexed for MEDLINE] Martelius T, et al. Department of Surgery, Helsinki University Hospital, Finland. Transplantation. 1999 Dec 15;68(11):1753-61
Effect of desferrioxamine B, a metal chelating agent, on rhabdovirus multiplication.
It has been suggested that the antiviral activity shown by chelating agents towards different viruses is probably related to the action on viral nucleic acid polymerases which require metal ions as essential cofactors. Desferrioxamine B, a metabolite from Streptomyces pilosus which chelates ions (Fe3+, Al3+, Cu2+, Zn2+, Co2+) from intracellular and external compartments, has been tested for its activity on the multiplication of VSV and rabies virus in CER cells. While desferrioxamine B was ineffective on rabies virus multiplication, it was shown to reduce plaque formation, cytopathic effect and viral yield by VSV at both low and high multiplicity of infection. The activity of the drug was not due to a direct action on virions outside the cells, but was probably related to an alteration in the delicate balance of intracellular ions which could in turn be critical for VSV multiplication. Conti C,et al Istituto di Microbiologia, Facolt di Medicina e Chirurgia, Universit di Roma La Sapienza. Boll Ist Sieroter Milan. 1990 Jun;69(2):431-6
