The Experts below are selected from a list of 4914 Experts worldwide ranked by ideXlab platform
Shibo Jiang - One of the best experts on this subject based on the ideXlab platform.
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Development of Protein- and Peptide-Based HIV Entry Inhibitors Targeting gp120 or gp41
Viruses, 2019Co-Authors: Qian Wang, Shibo JiangAbstract:Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple drug-resistant strains has led to the increased failure of ARDs, thus calling for the development of anti-HIV drugs with targets or mechanisms of action different from those of the current ARDs. The first peptide-based HIV Entry Inhibitor, enfuvirtide, was approved by the U.S. FDA in 2003 for treatment of HIV/AIDS patients who have failed to respond to the current ARDs, which has stimulated the development of several series of protein- and peptide-based HIV Entry Inhibitors in preclinical and clinical studies. In this review, we highlighted the properties and mechanisms of action for those promising protein- and peptide-based HIV Entry Inhibitors targeting the HIV-1 gp120 or gp41 and discussed their advantages and disadvantages, compared with the current ARDs.
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a ccr5 antagonist based hiv Entry Inhibitor exhibited potent spermicidal activity potential application for contraception and prevention of hiv sexual transmission
European Journal of Pharmaceutical Sciences, 2018Co-Authors: Mingjun Yang, Shibo Jiang, Ruina Zhi, Mingxin Dong, Yuzhu Wang, Fang Tian, Minjie Xia, Qiuyun DaiAbstract:Abstract B07 is a small-molecule CCR5 antagonist-based HIV-1 Entry Inhibitor that is being developed as an anti-HIV microbicide for preventing sexual transmission of HIV. Here we evaluated its spermicidal and contraceptive potential, including sperm motility, plasma membrane integrity, and contraceptive efficacy tested in rabbits. We found that B07 inhibited sperm motility and movement patterns in a concentration- and time-dependent manner. Within 30 min, B07 induced sperm immobilization with the minimum 100% effective concentration and median effective concentration of 640.0 and 64.4 μg/mL, respectively. The hypo-osmotic swelling test showed that plasma membranes of B07-treated sperms exhibited slight disruption, as verified by electron micrographs. In both B07 gel and N-9 gel groups, not a single implantation site or embryo was observed based on the contraceptive efficacy test in rabbits, indicating that B07 could effectively block the potential of sperm to reach and/or fertilize oocytes. The safety profile of B07 in vivo was evaluated by use of an optimized rabbit vaginal irritation test. While the pathological scores of the N-9 gel group was 14.67 ± 1.21, those of the blank control and B07 gel groups were 2.17 ± 0.76 and 4.00 ± 0.89, respectively, which were within the clinically acceptable range (
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co delivery of hiv 1 Entry Inhibitor and nonnucleoside reverse transcriptase Inhibitor shuttled by nanoparticles cocktail therapeutic strategy for antiviral therapy
AIDS, 2016Co-Authors: Qian Wang, Lan Xie, Shibo JiangAbstract:Objectives: Traditionally, the antiviral efficacy of classic cocktail therapy is significantly limited by the distinct pharmacokinetic profiles of partner therapeutics that lead to inconsistent in-vivo biodistribution. Here we developed a new cocktail-like drug delivery vehicle using biodegradable polymeric nanoparticles (NP) encapsulating nonnucleoside reverse transcriptase Inhibitor (NNRTI) DAAN-14f (14f), surface-conjugated with HIV-1 fusion Inhibitor T1144, designated T1144-NP-DAAN-14f (T1144-NP-14f), and aiming to achieve enhanced cellular uptake, improved antiviral activity and prolonged blood circulation time. Methods: T1144-NP-14f was prepared through the emulsion/solvent evaporation technique and a maleimide-thiol coupling reaction. Particle size and morphology were determined by dynamic light scattering detection and transmission electron microscopy. Anti-HIV-1 activity was assessed by HIV-1 Env-mediated cell–cell fusion and infection by laboratory-adapted, primary, and resistant HIV-1 isolates, respectively. The in-vitro release of 14f was investigated using the equilibrium dialysis method, and the pharmacokinetic study of T1144-NP-14f was performed on Sprague-Dawley rats. Results: T1144-NP-14f displayed a spherical shape under transmission electron microscopy observation and had a size of 117 ± 19 nm. T1144-NP-14f exhibited the strongest antiviral activity against a broad spectrum of HIV-1 strains, including NNRTI-, T1144-, or T20-resistant isolates, respectively. Both in-vitro release and in-vivo pharmacokinetic profile showed that T1144-NP-14f exhibited a sustained controlled release behavior. Conclusion: Our results demonstrated that the combination of Entry Inhibitor with NNRTI encapsulated in nanoparticles (T1144-NP-14f) was highly effective in inhibiting HIV-1 infection. This new cocktail-like drug delivery platform could serve as an effective anti-HIV-1 regimen by taking advantage of the extrinsic and intrinsic antiviral activity of individual drugs.
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Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41.
Current topics in medicinal chemistry, 2015Co-Authors: Lifeng Cai, Asim K. Debnath, Shibo JiangAbstract:Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 Entry, thus serving as key targets for the development of HIV-1 Entry Inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV Entry Inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV Entry Inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV Entry Inhibitor candidates and further predicted the future trend of HIV Entry Inhibitor development.
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Identification of a D-amino acid decapeptide HIV-1 Entry Inhibitor
Biochemical and biophysical research communications, 2006Co-Authors: Cesar Boggiano, Shibo Jiang, Shuwen Liu, Qian Zhao, James M. Binley, Sylvie E. BlondelleAbstract:Entry of human immunodeficiency virus type 1 (HIV-1) virion into host cells involves three major steps, each being a potential target for the development of Entry Inhibitors: gp120 binding to CD4, gp120-CD4 complex interacting with a coreceptor, and gp41 refolding to form a six-helix bundle. Using a D-amino acid decapeptide combinatorial library, we identified peptide dC13 as having potent HIV-1 fusion Inhibitory activity, and effectively inhibiting infection by several laboratory-adapted and primary HIV-1 strains. While dC13 did not block binding of gp120 to CD4, nor disrupt the gp41 six-helix bundle formation, it effectively blocked the binding of an anti-CXCR4 monoclonal antibody and chemokine SDF-1alpha to CXCR4-expressing cells. However, because R5-using primary viruses were also neutralized, the antiviral activity of dC13 implies additional mode(s) of action. These results suggest that dC13 is a useful HIV-1 coreceptor antagonist for CXCR4 and, due to its biostability and simplicity, may be of value for developing a new class of HIV-1 Entry Inhibitors.
Asim Kumar Debnath - One of the best experts on this subject based on the ideXlab platform.
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punica granatum pomegranate juice provides an hiv 1 Entry Inhibitor and candidate topical microbicide
Annals of the New York Academy of Sciences, 2005Co-Authors: Robert A Neurath, Nathan Strick, Asim Kumar DebnathAbstract:For approximately 24 years the AIDS pandemic has claimed approximately 30 million lives, causing approximately 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be acceptable, accessible, affordable, and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients (inactive materials of drug dosage forms) or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. Therefore, fruit juices were screened for Inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor, and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. The results indicate that HIV-1 Entry Inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. Therefore, these results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored.
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punica granatum pomegranate juice provides an hiv 1 Entry Inhibitor and candidate topical microbicide
BMC Infectious Diseases, 2004Co-Authors: Robert A Neurath, Nathan Strick, Asim Kumar DebnathAbstract:Background For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option.
Sulong Xiao - One of the best experts on this subject based on the ideXlab platform.
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synthesis of a hexavalent betulinic acid derivative as a hemagglutinin targeted influenza virus Entry Inhibitor
Molecular Pharmaceutics, 2020Co-Authors: Yingying Chen, Sulong Xiao, Yongmin Zhang, Li-he Zhang, Demin Zhou, Xinchen Wang, Yinbiao Zhu, Bo ZhangAbstract:Naturally occurring pentacyclic triterpenes, such as betulinic acid (BA) and its derivatives, exhibit various pharmaceutical activities and have been the subject of great interest, in particular for their antiviral properties. Here, we found a new anti-influenza virus conjugate, hexakis 6-deoxy-6-[4-N-(3β-hydroxy-lup-20(29)-en-28-oate)aminomethyl-1H-1,2,3-triazol-1-yl]-2,3-di-O-acetyl-α-cyclodextrin (CYY1-11, 1), in a mini library of pentacyclic triterpene-cyclodextrin conjugates by performing a cell-based screening assay and then exploring the underlying mechanisms. Our results showed that conjugate 1 possessed a high-level activity against the influenza virus A/WSN/33 with an IC50 value of 5.20 μM (SI > 38.4). The study of the mechanism of action indicated that conjugate 1 inhibited viral replication by directly targeting the influenza hemagglutinin protein (KD = 1.50 μM), thus efficiently preventing the attachment of the virion to its receptors on host cells and subsequent infection. This study suggests that multivalent BA derivatives have possible use as a new class of influenza virus Entry Inhibitors.
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Development of bivalent oleanane-type triterpenes as potent HCV Entry Inhibitors.
European journal of medicinal chemistry, 2014Co-Authors: Yiyun Peng, Qi Wang, Yongying Shi, Han Wang, Yongxiang Zheng, Emily M. Lee, Sulong XiaoAbstract:The development of Entry Inhibitors is an emerging approach to the prevention and reduction of HCV infection. Starting from echinocystic acid (EA), a μM HCV Entry Inhibitor, we have developed a series of bivalent oleanane-type triterpenes which, upon optimization of the length, rigidity and hydrophobicity of the linker, exert dramatically potent enhancement of inhibition with IC50 values extending into the nM level. This study establishes the importance of triterpene natural products as new leads in the development of potential HCV Entry Inhibitors.
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Conjugation of cyclodextrin with fullerene as a new class of HCV Entry Inhibitors
Bioorganic & medicinal chemistry, 2012Co-Authors: Sulong Xiao, Yiyun Peng, Qi Wang, Ming Yang, Matthieu Sollogoub, Pierre Sinaÿ, Yongmin Zhang, Li-he Zhang, Demin ZhouAbstract:An α-cyclodextrin-[60]fullerene conjugate with a flexible linker at the secondary face of α-cyclodextrin has been prepared, which displays significant water solubility and, more importantly, acts as a new class of HCV Entry Inhibitor with IC(50) at 0.17 μM level.
Judith M. Lalonde - One of the best experts on this subject based on the ideXlab platform.
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a model of peptide triazole Entry Inhibitor binding to hiv 1 gp120 and the mechanism of bridging sheet disruption
Biochemistry, 2013Co-Authors: Ali Emileh, Judith M. Lalonde, Ferit Tuzer, Diogo Rodrigo Magalhaes Moreira, Carole A Bewley, Cameron F Abrams, M Umashankara, Herman Yeh, Irwin M ChaikenAbstract:Peptide triazole (PT) Entry Inhibitors prevent HIV-1 infection by blocking the binding of viral gp120 to both the HIV-1 receptor and the coreceptor on target cells. Here, we used all-atom explicit solvent molecular dynamics (MD) to propose a model for the encounter complex of the peptide triazoles with gp120. Saturation transfer difference nuclear magnetic resonance (STD NMR) and single-site mutagenesis experiments were performed to test the simulation results. We found that docking of the peptide to a conserved patch of residues lining the “F43 pocket” of gp120 in a bridging sheet naive gp120 conformation of the glycoprotein led to a stable complex. This pose prevents formation of the bridging sheet minidomain, which is required for receptor–coreceptor binding, providing a mechanistic basis for dual-site antagonism of this class of Inhibitors. Burial of the peptide triazole at the gp120 inner domain–outer domain interface significantly contributed to complex stability and rationalizes the significant con...
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structure based design and synthesis of an hiv 1 Entry Inhibitor exploiting x ray and thermodynamic characterization
ACS Medicinal Chemistry Letters, 2013Co-Authors: Judith M. Lalonde, David M. Jones, Joel R. Courter, Jongwoo Park, Arne Schön, Amy M. Princiotto, John R. Mascola, Ernesto Freire, Matthew Lekhac, Joseph SodroskiAbstract:The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 Entry Inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral Entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral Entry. The thermodynamic signatures indicate a binding preference for the (R,R)- over the (S,S)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4–gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 Entry Inhibitors.
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Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-Ray and Thermodynamic Characterization.
ACS medicinal chemistry letters, 2013Co-Authors: Judith M. Lalonde, Matthew Le-khac, David M. Jones, Joel R. Courter, Jongwoo Park, Arne Schön, Amy M. Princiotto, John R. Mascola, Ernesto FreireAbstract:The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 Entry Inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a sub-micromolar binding affinity (110 nM) and inhibits viral Entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral Entry. thermodynamic signatures indicate a binding preference for the (R,R)-over the (S,S)-enantiomer. The crystal structure of the small molecule-gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4:gp120 interface is an effective tactic to enhance the neutralization potency of small molecule HIV-1 Entry Inhibitors.
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a molecular dynamics simulation of peptide triazole hiv Entry Inhibitor binding to gp120 hydrophobic core
Biophysical Journal, 2012Co-Authors: Ali Emileh, Judith M. Lalonde, Ferit Tuzer, Diogo Rodrigo Magalhaes Moreira, Carole A Bewley, Irwin M Chaiken, Cameron F AbramsAbstract:The envelope spike on HIV surface is a non-covalent trimer of gp120 and gp41 dimers; with gp120 responsible for binding to the CD4 receptor and the mandatory coreceptor, CCR5 or CXCR4. Blocking the gp120-CD4 or gp120-coreceptor interaction can block viral Entry and infection. The HNG family of peptides (sequence RINNIXWSEAMM, X= derivatized azidoproline) is a promising class of dual-site Entry Inhibitors thought to allosterically inhibit the binding process and trap the flexible gp120 molecule in an inactive state. To date, there have been no reports on the structure of the peptide or the peptide/gp120 complex. Here we have used Molecular Dynamics to develop a docking model in which the peptide binds in a tripartite fashion, preventing the formation of the bridging sheet in gp120, which is necessary for coreceptor attachment and initiation of Entry. The protein undergoes significant induced fit conformational changes involving movement of large loops which allows the peptide to bind tightly. Our model is consistent with experimental observations on the peptide footprint on gp120, pointing to a hydrophobic core underneath the bridging sheet and close to the F43 pocket as the putative binding site. Our results provide an explanation for why the stereochemistry of the triazole moiety on the proline is important for peptide function, in addition to explaining the inactivity of D-tryptophan in the sequence. Furthermore, saturation transfer difference (STD) NMR experiments point to the I-X-P hydrophobic center on the peptide as the central contact point in the complex, which is consistent with the peptide pose proposed in MD studies. Our model may provide a unique basis for rational design of allosteric Entry Inhibitors of HIV and ultimately small molecule Inhibitors of viral Entry.
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structural determinants for affinity enhancement of a dual antagonist peptide Entry Inhibitor of human immunodeficiency virus type 1
Journal of Medicinal Chemistry, 2008Co-Authors: Hosahudya N Gopi, Simon Cocklin, Sabine Baxter, Judith M. Lalonde, Ferit Tuzer, M Umashankara, Vanessa Pirrone, Navid Madani, Isaac Zentner, Navneet JawandaAbstract:Structure–activity correlations were investigated for substituted peptide conjugates that function as dual receptor site antagonists of HIV-1 gp120. A series of peptide conjugates were constructed via click reaction of both aryl and alkyl acetylenes with an internally incorporated azidoproline 6 derived from the parent peptide 1 (12p1, RINNIPWSEAMM). Compared to 1, many of these conjugates were found to exhibit several orders of magnitude increase in both affinity for HIV-1 gp120 and inhibition potencies at both the CD4 and coreceptor binding sites of gp120. We sought to determine structural factors in the added triazole grouping responsible for the increased binding affinity and antiviral activity of the dual Inhibitor conjugates. We measured peptide conjugate potencies in both kinetic and cell infection assays. High affinity was sterically specific, being exhibited by the cis- but not the trans-triazole. The results demonstrate that aromatic, hydrophobic, and steric features in the residue 6 side-chain ...
Robert A Neurath - One of the best experts on this subject based on the ideXlab platform.
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punica granatum pomegranate juice provides an hiv 1 Entry Inhibitor and candidate topical microbicide
Annals of the New York Academy of Sciences, 2005Co-Authors: Robert A Neurath, Nathan Strick, Asim Kumar DebnathAbstract:For approximately 24 years the AIDS pandemic has claimed approximately 30 million lives, causing approximately 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be acceptable, accessible, affordable, and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients (inactive materials of drug dosage forms) or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. Therefore, fruit juices were screened for Inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor, and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. The results indicate that HIV-1 Entry Inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. Therefore, these results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored.
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punica granatum pomegranate juice provides an hiv 1 Entry Inhibitor and candidate topical microbicide
BMC Infectious Diseases, 2004Co-Authors: Robert A Neurath, Nathan Strick, Asim Kumar DebnathAbstract:Background For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option.