The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Mario Canki - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Potential Genotoxicity of HIV Entry Inhibitors Derived from Natural Sources
2016Co-Authors: Elena E Paskaleva, Yanze Liu, Manoj Arra, Hui-jun Guo, Glenn Swartz, Jeffrey S. Kennedy, Curt M. Breneman, Er Shekhtman, Mario CankiAbstract:AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy. We have used the structure-activity relationship (SAR) of 2-BP as a platform to identify new small chemical molecules that fit into the various identified active sites in an effort to identify more potent CD4 entry inhibitors. To validate further drug development, we tested the PA and 2-BP scaffold molecules for genotoxic potential. The FDA and International Conference on Harmonisation (ICH) recommends using a standardized 3-test battery for testing compound genotoxicity consisting of the bacterial reverse mutation assay, mouse lymphoma assay, and rat micronucleus assay. PA and 2-BP and their metabolites tested negative in all three genotoxicty tests. 2-BP is the first derivative of PA to undergo pre
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Evaluation of potential genotoxicity of HIV entry inhibitors derived from natural sources.
PloS one, 2014Co-Authors: Elena E Paskaleva, Yanze Liu, Alexander Shekhtman, Manoj Arra, Hui-jun Guo, Glenn Swartz, Jeffrey S. Kennedy, Curt M. Breneman, Mario CankiAbstract:AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy. We have used the structure-activity relationship (SAR) of 2-BP as a platform to identify new small chemical molecules that fit into the various identified active sites in an effort to identify more potent CD4 entry inhibitors. To validate further drug development, we tested the PA and 2-BP scaffold molecules for genotoxic potential. The FDA and International Conference on Harmonisation (ICH) recommends using a standardized 3-test battery for testing compound genotoxicity consisting of the bacterial reverse mutation assay, mouse lymphoma assay, and rat micronucleus assay. PA and 2-BP and their metabolites tested negative in all three genotoxicty tests. 2-BP is the first derivative of PA to undergo pre-clinical screening, which will enable us to now test multiple simultaneous small chemical structures based on activity in scaffold modeling across the dimension of pre-clinical testing to enable transition to human testing.
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palmitic acid is a novel cd4 fusion inhibitor that blocks hiv entry and infection
AIDS Research and Human Retroviruses, 2009Co-Authors: David Y W Lee, Xudong Lin, Elena E Paskaleva, Yanze Liu, Shadakshara S Puttamadappa, Carol S Thornber, James R Drake, Maja Habulin, Alexander Shekhtman, Mario CankiAbstract:The high rate of HIV-1 mutation and the frequent sexual transmission highlight the need for novel therapeutic modalities with broad activity against both CXCR4 (X4) and CCR5 (R5)-tropic viruses. We investigated a large number of natural products, and from Sargassum fusiforme we isolated and identified palmitic acid (PA) as a natural small bioactive molecule with activity against HIV-1 infection. Treatment with 100 microM PA inhibited both X4 and R5 independent infection in the T cell line up to 70%. Treatment with 22 microM PA inhibited X4 infection in primary peripheral blood lymphocytes (PBL) up to 95% and 100 microM PA inhibited R5 infection in primary macrophages by over 90%. Inhibition of infection was concentration dependent, and cell viability for all treatments tested remained above 80%, similar to treatment with 10(-6)M nucleoside analogue 2', 3'-dideoxycytidine (ddC). Micromolar PA concentrations also inhibited cell-to-cell fusion and specific virus-to-cell fusion up to 62%. PA treatment did not result in internalization of the cell surface CD4 receptor or lipid raft disruption, and it did not inhibit intracellular virus replication. PA directly inhibited gp120-CD4 complex formation in a dose-dependent manner. We used fluorescence spectroscopy to determine that PA binds to the CD4 receptor with K(d) approximately 1.5 +/- 0.2 microM, and we used one-dimensional saturation transfer difference NMR (STD-NMR) to determined that the PA binding epitope for CD4 consists of the hydrophobic methyl and methelene groups located away from the PA carboxyl terminal, which blocks efficient gp120-CD4 attachment. These findings introduce a novel class of antiviral compound that binds directly to the CD4 receptor, blocking HIV-1 entry and infection. Understanding the structure-affinity relationship (SAR) between PA and CD4 should lead to the development of PA analogs with greater potency against HIV-1 entry.
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Sargassum fusiforme fraction is a potent and specific inhibitor of hiv 1 fusion and reverse transcriptase
Virology Journal, 2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, Carol S Thornber, Karen M Duus, James J Mcsharry, Jeanclaude Veille, David Yuwei Lee, Mario CankiAbstract:Sargassum fusiforme (Harvey) Setchell has been shown to be a highly effective inhibitor of HIV-1 infection. To identify its mechanism of action, we performed bioactivity-guided fractionation on Sargassum fusiforme mixture. Here, we report isolation of a bioactive fraction SP4-2 (S. fusiforme), which at 8 μg/ml inhibited HIV-1 infection by 86.9%, with IC50 value of 3.7 μg. That represents 230-fold enhancement of antiretroviral potency as compared to the whole extract. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5) tropic HIV-1. Specifically, 10 μg/ml SP4-2 blocked HIV-1 fusion and entry by 53%. This effect was reversed by interaction of SP4-2 with sCD4, suggesting that S. fusiforme inhibits HIV-1 infection by blocking CD4 receptor, which also explained observed inhibition of both X4 and R5-tropic HIV-1. SP4-2 also inhibited HIV-1 replication after virus entry, by directly inhibiting HIV-1 reverse transcriptase (RT) in a dose dependent manner by up to 79%. We conclude that the SP4-2 fraction contains at least two distinct and biologically active molecules, one that inhibits HIV-1 fusion by interacting with CD4 receptor, and another that directly inhibits HIV-1 RT. We propose that S. fusiforme is a lead candidate for anti-HIV-1 drug development.
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Virology Journal BioMed Central
2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, James J Mcsharry, David Yuwei Lee, Karen Duus, Claude L Veille, Carol Thornber, Mario CankiAbstract:Sargassum fusiforme fraction is a potent and specific inhibitor of HIV-1 fusion and reverse transcriptas
Delin Duan - One of the best experts on this subject based on the ideXlab platform.
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hidden diversity and phylogeographic history provide conservation insights for the edible seaweed Sargassum fusiforme in the northwest pacific
Evolutionary Applications, 2017Co-Authors: Zhongmin Sun, Xu Gao, Jian Ting Yao, Han Gil Choi, Hikaru Endo, Delin DuanAbstract:Understanding the evolutionary processes that have created diversity and the genetic potential of species to adapt to environmental change is an important premise for biodiversity conservation. Herein, we used mitochondrial trnW-L and cox3 and plastid rbcL-S data sets to analyze population genetic variation and phylogeographic history of the brown alga Sargassum fusiforme, whose natural resource has been largely exterminated in the Asia-Northwest Pacific in the past decades. Phylogenetic trees and network analysis consistently revealed three major haplotype groups (A, B, and C) in S. fusiforme, with A and B distributed in the Japan-Pacific coast. Group C consisted of three subgroups (C1, C2, and C3) which were distributed in the Sea of Japan, the Yellow-Bohai Sea, and East China Sea, respectively. Isolation-with-migration (IM a) analysis revealed that the three groups diverged approximately during the mid-Pleistocene (c. 756-1,224 ka). Extended Bayesian skyline plots (EBSP) showed that groups A and B underwent relatively long-term stable population size despite a subsequent rapid demographic expansion, while subgroups C2 and C3 underwent a sudden expansion at c. 260 ka. FST and AMOVA detected low population-level genetic variation and high degrees of divergence between groups. The cryptic diversity and phylogeographic patterns found in S. fusiforme not only are essential to understand how environmental shifts and evolutionary processes shaped diversity and distribution of coastal seaweeds but also provide additional insights for conserving and managing seaweed resources and facilitate predictions of their responses to future climate change and habitat loss.
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extraction and identification of phlorotannins from the brown alga Sargassum fusiforme harvey setchell
Marine Drugs, 2017Co-Authors: Delin Duan, Xiaoyong Liu, Xin GaoAbstract:Phlorotannins are a group of complex polymers of phloroglucinol (1,3,5-trihydroxybenzene), which are unique compounds from marine brown algae. In our present study, a procedure for extraction and enrichment of phlorotannins from S. fusiforme with highly antioxidant potentials was established. After comparison of different extraction methods, the optimal extraction conditions were established as follows. The freeze-dried seaweed powder was extracted with 30% ethanol-water solvent with a solid/liquid ratio of 1:5 at temperature of 25 °C for 30 min. After extraction, the phlorotannins were fractioned by different solvents, among which the ethyl acetate fraction exhibited both the highest total phlorotannin content (88.48 ± 0.30 mg PGE/100 mg extract) and the highest antioxidant activities. The extracts obtained from these locations were further purified and characterized using a modified UHPLC-QQQ-MS method. Compounds with 42 different molecular weights were detected and tentatively identified, among which the fuhalol-type phlorotannins were the dominant compounds, followed by phlorethols and fucophlorethols with diverse degree of polymerization. Eckol-type phlorotannins including some newly discovered carmalol derivatives were detected in Sargassum species for the first time. Our study not only described the complex phlorotannins composition in S. fusiforme, but also highlighted the challenges involved in structural elucidation of these compounds.
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a study of neuroprotective and antioxidant activities of heteropolysaccharides from six Sargassum species
International Journal of Biological Macromolecules, 2014Co-Authors: Weihua Jin, Delin Duan, Jian Ting Yao, Wenjing Zhang, Jing Wang, Enyi Xie, Dongchao Liu, Quanbin ZhangAbstract:Heteropolysaccharides were extracted from Sargassum integerrimum (S.I), Sargassum maclurei (S.M), Sargassum naozhouense (S.N), Spiraea thunbergii (S.T), Sargassum hemiphyllum (S.H) and Sargassum fusiforme (S.F), and their neuroprotective effects and antioxidant activities were investigated. It showed that S.I, S.N, S.T and S.F exhibited neuroprotective activities, whereas S.H and S.M did not. For this reason, they were separated by anion-exchange chromatography. It was apparent that the fraction 2 represented the principal difference between the active and non-active compounds. However, it did not correlate with neuroprotective effect. In addition, the results on antioxidant activities showed that the hydroxyl-radical scavenging effect contribute to the neuroprotective effect of S.T and S.N, and the DPPH-radical scavenging effect and reducing power contribute to S.T, S.F and S.I. However, the superoxide-radical scavenging effect did not correlate with neuroprotective activity. The conclusion was that the neuroprotective activity of the family of compounds investigated depended on a variety of factors. (C) 2014 Elsevier B.V. All rights reserved.
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asymmetric genetic exchange in the brown seaweed Sargassum fusiforme phaeophyceae driven by oceanic currents
Marine Biology, 2013Co-Authors: Jie Zhang, Zimin Hu, Juan M Lopezbautista, Delin DuanAbstract:Geological phenomena (e.g. drastic sea level fluctuations during the Quaternary Ice Age in the Northern Hemisphere) have been demonstrated to intensively affect the biogeographic patterns and tempo-spatial compositions of genetic diversity of marine organisms. However, it is poorly understood whether contemporary factors such as oceanic surface currents have also shaped inter-regional population genetics of specific coastal marine flora, with or without limited dispersal capability. In this study, we determined mtDNA Cox1 gene sequences of the brown seaweed Sargassum fusiforme from nine populations along the Chinese coast and one population from the west coast of South Korea, in an effort to understand what factors are contributing to their current genetic structure and geographic distribution patterns. Genetic analyses indicated a deep genetic break between the Yellow-Bohai Sea (YBS) and the other two marginal seas, the East China Sea (ECS) and the South China Sea (SCS). In particular, the amount of genetic exchange from the SCS to each of the ECS and YBS was significantly higher than that from the opposite directions. Our analyses supports the hypothesis that biogeographic patterns of genetic variation in S. fusiforme are probably an interactive consequence of post-glacial colonization from two scattered refugia driven by the offshore Kuroshio Current and asymmetric gene flow among adjacent sea margins.
Elena E Paskaleva - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Potential Genotoxicity of HIV Entry Inhibitors Derived from Natural Sources
2016Co-Authors: Elena E Paskaleva, Yanze Liu, Manoj Arra, Hui-jun Guo, Glenn Swartz, Jeffrey S. Kennedy, Curt M. Breneman, Er Shekhtman, Mario CankiAbstract:AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy. We have used the structure-activity relationship (SAR) of 2-BP as a platform to identify new small chemical molecules that fit into the various identified active sites in an effort to identify more potent CD4 entry inhibitors. To validate further drug development, we tested the PA and 2-BP scaffold molecules for genotoxic potential. The FDA and International Conference on Harmonisation (ICH) recommends using a standardized 3-test battery for testing compound genotoxicity consisting of the bacterial reverse mutation assay, mouse lymphoma assay, and rat micronucleus assay. PA and 2-BP and their metabolites tested negative in all three genotoxicty tests. 2-BP is the first derivative of PA to undergo pre
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Evaluation of potential genotoxicity of HIV entry inhibitors derived from natural sources.
PloS one, 2014Co-Authors: Elena E Paskaleva, Yanze Liu, Alexander Shekhtman, Manoj Arra, Hui-jun Guo, Glenn Swartz, Jeffrey S. Kennedy, Curt M. Breneman, Mario CankiAbstract:AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy. We have used the structure-activity relationship (SAR) of 2-BP as a platform to identify new small chemical molecules that fit into the various identified active sites in an effort to identify more potent CD4 entry inhibitors. To validate further drug development, we tested the PA and 2-BP scaffold molecules for genotoxic potential. The FDA and International Conference on Harmonisation (ICH) recommends using a standardized 3-test battery for testing compound genotoxicity consisting of the bacterial reverse mutation assay, mouse lymphoma assay, and rat micronucleus assay. PA and 2-BP and their metabolites tested negative in all three genotoxicty tests. 2-BP is the first derivative of PA to undergo pre-clinical screening, which will enable us to now test multiple simultaneous small chemical structures based on activity in scaffold modeling across the dimension of pre-clinical testing to enable transition to human testing.
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palmitic acid is a novel cd4 fusion inhibitor that blocks hiv entry and infection
AIDS Research and Human Retroviruses, 2009Co-Authors: David Y W Lee, Xudong Lin, Elena E Paskaleva, Yanze Liu, Shadakshara S Puttamadappa, Carol S Thornber, James R Drake, Maja Habulin, Alexander Shekhtman, Mario CankiAbstract:The high rate of HIV-1 mutation and the frequent sexual transmission highlight the need for novel therapeutic modalities with broad activity against both CXCR4 (X4) and CCR5 (R5)-tropic viruses. We investigated a large number of natural products, and from Sargassum fusiforme we isolated and identified palmitic acid (PA) as a natural small bioactive molecule with activity against HIV-1 infection. Treatment with 100 microM PA inhibited both X4 and R5 independent infection in the T cell line up to 70%. Treatment with 22 microM PA inhibited X4 infection in primary peripheral blood lymphocytes (PBL) up to 95% and 100 microM PA inhibited R5 infection in primary macrophages by over 90%. Inhibition of infection was concentration dependent, and cell viability for all treatments tested remained above 80%, similar to treatment with 10(-6)M nucleoside analogue 2', 3'-dideoxycytidine (ddC). Micromolar PA concentrations also inhibited cell-to-cell fusion and specific virus-to-cell fusion up to 62%. PA treatment did not result in internalization of the cell surface CD4 receptor or lipid raft disruption, and it did not inhibit intracellular virus replication. PA directly inhibited gp120-CD4 complex formation in a dose-dependent manner. We used fluorescence spectroscopy to determine that PA binds to the CD4 receptor with K(d) approximately 1.5 +/- 0.2 microM, and we used one-dimensional saturation transfer difference NMR (STD-NMR) to determined that the PA binding epitope for CD4 consists of the hydrophobic methyl and methelene groups located away from the PA carboxyl terminal, which blocks efficient gp120-CD4 attachment. These findings introduce a novel class of antiviral compound that binds directly to the CD4 receptor, blocking HIV-1 entry and infection. Understanding the structure-affinity relationship (SAR) between PA and CD4 should lead to the development of PA analogs with greater potency against HIV-1 entry.
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Sargassum fusiforme fraction is a potent and specific inhibitor of hiv 1 fusion and reverse transcriptase
Virology Journal, 2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, Carol S Thornber, Karen M Duus, James J Mcsharry, Jeanclaude Veille, David Yuwei Lee, Mario CankiAbstract:Sargassum fusiforme (Harvey) Setchell has been shown to be a highly effective inhibitor of HIV-1 infection. To identify its mechanism of action, we performed bioactivity-guided fractionation on Sargassum fusiforme mixture. Here, we report isolation of a bioactive fraction SP4-2 (S. fusiforme), which at 8 μg/ml inhibited HIV-1 infection by 86.9%, with IC50 value of 3.7 μg. That represents 230-fold enhancement of antiretroviral potency as compared to the whole extract. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5) tropic HIV-1. Specifically, 10 μg/ml SP4-2 blocked HIV-1 fusion and entry by 53%. This effect was reversed by interaction of SP4-2 with sCD4, suggesting that S. fusiforme inhibits HIV-1 infection by blocking CD4 receptor, which also explained observed inhibition of both X4 and R5-tropic HIV-1. SP4-2 also inhibited HIV-1 replication after virus entry, by directly inhibiting HIV-1 reverse transcriptase (RT) in a dose dependent manner by up to 79%. We conclude that the SP4-2 fraction contains at least two distinct and biologically active molecules, one that inhibits HIV-1 fusion by interacting with CD4 receptor, and another that directly inhibits HIV-1 RT. We propose that S. fusiforme is a lead candidate for anti-HIV-1 drug development.
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Virology Journal BioMed Central
2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, James J Mcsharry, David Yuwei Lee, Karen Duus, Claude L Veille, Carol Thornber, Mario CankiAbstract:Sargassum fusiforme fraction is a potent and specific inhibitor of HIV-1 fusion and reverse transcriptas
Yanze Liu - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Potential Genotoxicity of HIV Entry Inhibitors Derived from Natural Sources
2016Co-Authors: Elena E Paskaleva, Yanze Liu, Manoj Arra, Hui-jun Guo, Glenn Swartz, Jeffrey S. Kennedy, Curt M. Breneman, Er Shekhtman, Mario CankiAbstract:AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy. We have used the structure-activity relationship (SAR) of 2-BP as a platform to identify new small chemical molecules that fit into the various identified active sites in an effort to identify more potent CD4 entry inhibitors. To validate further drug development, we tested the PA and 2-BP scaffold molecules for genotoxic potential. The FDA and International Conference on Harmonisation (ICH) recommends using a standardized 3-test battery for testing compound genotoxicity consisting of the bacterial reverse mutation assay, mouse lymphoma assay, and rat micronucleus assay. PA and 2-BP and their metabolites tested negative in all three genotoxicty tests. 2-BP is the first derivative of PA to undergo pre
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Evaluation of potential genotoxicity of HIV entry inhibitors derived from natural sources.
PloS one, 2014Co-Authors: Elena E Paskaleva, Yanze Liu, Alexander Shekhtman, Manoj Arra, Hui-jun Guo, Glenn Swartz, Jeffrey S. Kennedy, Curt M. Breneman, Mario CankiAbstract:AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy. We have used the structure-activity relationship (SAR) of 2-BP as a platform to identify new small chemical molecules that fit into the various identified active sites in an effort to identify more potent CD4 entry inhibitors. To validate further drug development, we tested the PA and 2-BP scaffold molecules for genotoxic potential. The FDA and International Conference on Harmonisation (ICH) recommends using a standardized 3-test battery for testing compound genotoxicity consisting of the bacterial reverse mutation assay, mouse lymphoma assay, and rat micronucleus assay. PA and 2-BP and their metabolites tested negative in all three genotoxicty tests. 2-BP is the first derivative of PA to undergo pre-clinical screening, which will enable us to now test multiple simultaneous small chemical structures based on activity in scaffold modeling across the dimension of pre-clinical testing to enable transition to human testing.
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palmitic acid is a novel cd4 fusion inhibitor that blocks hiv entry and infection
AIDS Research and Human Retroviruses, 2009Co-Authors: David Y W Lee, Xudong Lin, Elena E Paskaleva, Yanze Liu, Shadakshara S Puttamadappa, Carol S Thornber, James R Drake, Maja Habulin, Alexander Shekhtman, Mario CankiAbstract:The high rate of HIV-1 mutation and the frequent sexual transmission highlight the need for novel therapeutic modalities with broad activity against both CXCR4 (X4) and CCR5 (R5)-tropic viruses. We investigated a large number of natural products, and from Sargassum fusiforme we isolated and identified palmitic acid (PA) as a natural small bioactive molecule with activity against HIV-1 infection. Treatment with 100 microM PA inhibited both X4 and R5 independent infection in the T cell line up to 70%. Treatment with 22 microM PA inhibited X4 infection in primary peripheral blood lymphocytes (PBL) up to 95% and 100 microM PA inhibited R5 infection in primary macrophages by over 90%. Inhibition of infection was concentration dependent, and cell viability for all treatments tested remained above 80%, similar to treatment with 10(-6)M nucleoside analogue 2', 3'-dideoxycytidine (ddC). Micromolar PA concentrations also inhibited cell-to-cell fusion and specific virus-to-cell fusion up to 62%. PA treatment did not result in internalization of the cell surface CD4 receptor or lipid raft disruption, and it did not inhibit intracellular virus replication. PA directly inhibited gp120-CD4 complex formation in a dose-dependent manner. We used fluorescence spectroscopy to determine that PA binds to the CD4 receptor with K(d) approximately 1.5 +/- 0.2 microM, and we used one-dimensional saturation transfer difference NMR (STD-NMR) to determined that the PA binding epitope for CD4 consists of the hydrophobic methyl and methelene groups located away from the PA carboxyl terminal, which blocks efficient gp120-CD4 attachment. These findings introduce a novel class of antiviral compound that binds directly to the CD4 receptor, blocking HIV-1 entry and infection. Understanding the structure-affinity relationship (SAR) between PA and CD4 should lead to the development of PA analogs with greater potency against HIV-1 entry.
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Sargassum fusiforme fraction is a potent and specific inhibitor of hiv 1 fusion and reverse transcriptase
Virology Journal, 2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, Carol S Thornber, Karen M Duus, James J Mcsharry, Jeanclaude Veille, David Yuwei Lee, Mario CankiAbstract:Sargassum fusiforme (Harvey) Setchell has been shown to be a highly effective inhibitor of HIV-1 infection. To identify its mechanism of action, we performed bioactivity-guided fractionation on Sargassum fusiforme mixture. Here, we report isolation of a bioactive fraction SP4-2 (S. fusiforme), which at 8 μg/ml inhibited HIV-1 infection by 86.9%, with IC50 value of 3.7 μg. That represents 230-fold enhancement of antiretroviral potency as compared to the whole extract. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5) tropic HIV-1. Specifically, 10 μg/ml SP4-2 blocked HIV-1 fusion and entry by 53%. This effect was reversed by interaction of SP4-2 with sCD4, suggesting that S. fusiforme inhibits HIV-1 infection by blocking CD4 receptor, which also explained observed inhibition of both X4 and R5-tropic HIV-1. SP4-2 also inhibited HIV-1 replication after virus entry, by directly inhibiting HIV-1 reverse transcriptase (RT) in a dose dependent manner by up to 79%. We conclude that the SP4-2 fraction contains at least two distinct and biologically active molecules, one that inhibits HIV-1 fusion by interacting with CD4 receptor, and another that directly inhibits HIV-1 RT. We propose that S. fusiforme is a lead candidate for anti-HIV-1 drug development.
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Virology Journal BioMed Central
2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, James J Mcsharry, David Yuwei Lee, Karen Duus, Claude L Veille, Carol Thornber, Mario CankiAbstract:Sargassum fusiforme fraction is a potent and specific inhibitor of HIV-1 fusion and reverse transcriptas
Xudong Lin - One of the best experts on this subject based on the ideXlab platform.
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palmitic acid is a novel cd4 fusion inhibitor that blocks hiv entry and infection
AIDS Research and Human Retroviruses, 2009Co-Authors: David Y W Lee, Xudong Lin, Elena E Paskaleva, Yanze Liu, Shadakshara S Puttamadappa, Carol S Thornber, James R Drake, Maja Habulin, Alexander Shekhtman, Mario CankiAbstract:The high rate of HIV-1 mutation and the frequent sexual transmission highlight the need for novel therapeutic modalities with broad activity against both CXCR4 (X4) and CCR5 (R5)-tropic viruses. We investigated a large number of natural products, and from Sargassum fusiforme we isolated and identified palmitic acid (PA) as a natural small bioactive molecule with activity against HIV-1 infection. Treatment with 100 microM PA inhibited both X4 and R5 independent infection in the T cell line up to 70%. Treatment with 22 microM PA inhibited X4 infection in primary peripheral blood lymphocytes (PBL) up to 95% and 100 microM PA inhibited R5 infection in primary macrophages by over 90%. Inhibition of infection was concentration dependent, and cell viability for all treatments tested remained above 80%, similar to treatment with 10(-6)M nucleoside analogue 2', 3'-dideoxycytidine (ddC). Micromolar PA concentrations also inhibited cell-to-cell fusion and specific virus-to-cell fusion up to 62%. PA treatment did not result in internalization of the cell surface CD4 receptor or lipid raft disruption, and it did not inhibit intracellular virus replication. PA directly inhibited gp120-CD4 complex formation in a dose-dependent manner. We used fluorescence spectroscopy to determine that PA binds to the CD4 receptor with K(d) approximately 1.5 +/- 0.2 microM, and we used one-dimensional saturation transfer difference NMR (STD-NMR) to determined that the PA binding epitope for CD4 consists of the hydrophobic methyl and methelene groups located away from the PA carboxyl terminal, which blocks efficient gp120-CD4 attachment. These findings introduce a novel class of antiviral compound that binds directly to the CD4 receptor, blocking HIV-1 entry and infection. Understanding the structure-affinity relationship (SAR) between PA and CD4 should lead to the development of PA analogs with greater potency against HIV-1 entry.
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Sargassum fusiforme fraction is a potent and specific inhibitor of hiv 1 fusion and reverse transcriptase
Virology Journal, 2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, Carol S Thornber, Karen M Duus, James J Mcsharry, Jeanclaude Veille, David Yuwei Lee, Mario CankiAbstract:Sargassum fusiforme (Harvey) Setchell has been shown to be a highly effective inhibitor of HIV-1 infection. To identify its mechanism of action, we performed bioactivity-guided fractionation on Sargassum fusiforme mixture. Here, we report isolation of a bioactive fraction SP4-2 (S. fusiforme), which at 8 μg/ml inhibited HIV-1 infection by 86.9%, with IC50 value of 3.7 μg. That represents 230-fold enhancement of antiretroviral potency as compared to the whole extract. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5) tropic HIV-1. Specifically, 10 μg/ml SP4-2 blocked HIV-1 fusion and entry by 53%. This effect was reversed by interaction of SP4-2 with sCD4, suggesting that S. fusiforme inhibits HIV-1 infection by blocking CD4 receptor, which also explained observed inhibition of both X4 and R5-tropic HIV-1. SP4-2 also inhibited HIV-1 replication after virus entry, by directly inhibiting HIV-1 reverse transcriptase (RT) in a dose dependent manner by up to 79%. We conclude that the SP4-2 fraction contains at least two distinct and biologically active molecules, one that inhibits HIV-1 fusion by interacting with CD4 receptor, and another that directly inhibits HIV-1 RT. We propose that S. fusiforme is a lead candidate for anti-HIV-1 drug development.
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Virology Journal BioMed Central
2008Co-Authors: Elena E Paskaleva, Xudong Lin, Yanze Liu, James J Mcsharry, David Yuwei Lee, Karen Duus, Claude L Veille, Carol Thornber, Mario CankiAbstract:Sargassum fusiforme fraction is a potent and specific inhibitor of HIV-1 fusion and reverse transcriptas
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Inhibition of highly productive HIV-1 infection in T cells, primary human macrophages, microglia, and astrocytes by Sargassum fusiforme
AIDS Research and Therapy, 2006Co-Authors: Elena E Paskaleva, David Y W Lee, Xudong Lin, Yanze Liu, Jeanclaude Veille, Robin Cotter, Michael T Klein, Emily Roberge, Bruce Clark, Mario CankiAbstract:Background The high rate of HIV-1 mutation and increasing resistance to currently available antiretroviral (ART) therapies highlight the need for new antiviral agents. Products derived from natural sources have been shown to inhibit HIV-1 replication during various stages of the virus life cycle, and therefore represent a potential source of novel therapeutic agents. To expand our arsenal of therapeutics against HIV-1 infection, we investigated aqueous extract from Sargassum fusiforme ( S. fusiforme ) for ability to inhibit HIV-1 infection in the periphery, in T cells and human macrophages, and for ability to inhibit in the central nervous system (CNS), in microglia and astrocytes. Results S. fusiforme extract blocked HIV-1 infection and replication by over 90% in T cells, human macrophages and microglia, and it also inhibited pseudotyped HIV-1 (VSV/NL4-3) infection in human astrocytes by over 70%. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5)-tropic HIV-1, was dose dependant and long lasting, did not inhibit cell growth or viability, was not toxic to cells, and was comparable to inhibition by the nucleoside analogue 2', 3'-didoxycytidine (ddC). S. fusiforme treatment blocked direct cell-to-cell infection spread. To investigate at which point of the virus life cycle this inhibition occurs, we infected T cells and CD4-negative primary human astrocytes with HIV-1 pseudotyped with envelope glycoprotein of vesicular stomatitis virus (VSV), which bypasses the HIV receptor requirements. Infection by pseudotyped HIV-1 (VSV/NL4-3) was also inhibited in a dose dependant manner, although up to 57% less, as compared to inhibition of native NL4-3, indicating post-entry interferences. Conclusion This is the first report demonstrating S. fusiforme to be a potent inhibitor of highly productive HIV-1 infection and replication in T cells, in primary human macrophages, microglia, and astrocytes. Results with VSV/NL4-3 infection, suggest inhibition of both entry and post-entry events of the virus life cycle. Absence of cytotoxicity and high viability of treated cells also suggest that S. fusiforme is a potential source of novel naturally occurring antiretroviral compounds that inhibit HIV-1 infection and replication at more than one site of the virus life cycle.