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1.
Synthetic peptides for AIDS research 总被引:1,自引:0,他引:1
2.
Connell BJ Baleux F Coic YM Clayette P Bonnaffé D Lortat-Jacob H 《Chemistry & biology》2012,19(1):131-139
The HIV-1 envelope gp120, which features both the virus receptor (CD4) and coreceptor (CCR5/CXCR4) binding sites, offers multiple sites for therapeutic intervention. However, the latter becomes exposed, thus vulnerable to inhibition, only transiently when the virus has already bound cellular CD4. To pierce this defense mechanism, we engineered a series of heparan sulfate mimicking tridecapeptides and showed that one of them target the gp120 coreceptor binding site with μM affinity. Covalently linked to a CD4-mimetic that binds to gp120 and renders the coreceptor binding domain available to be targeted, the conjugated tridecapeptide now displays nanomolar affinity for its target. Using solubilized coreceptors captured on top of sensorchip we show that it inhibits gp120 binding to both CCR5 and CXCR4 and in peripheral blood mononuclear cells broadly inhibits HIV-1 replication with an IC(50) of 1 nM. 相似文献
3.
The interaction between the HIV gp120 protein and coreceptor CCR5 or CXCR4 of the host cell is critical in mediating the HIV entry process. A model for the CCR5-gp120 complex has been developed. In the model, the N-terminus of CCR5 binds to three discontinuous domains of gp120, including the fourth conserved (C4) region, β19/β20 connecting loop, and V3 loop. The second extra-cellular loop (ECL2) of CCR5 also interacts with the crown part of the gp120 V3 loop. The bindings of the three CCR5 antagonists, maraviroc, aplaviroc, and vicriviroc, to the trans-membrane domain of CCR5 have been modeled. The bindings are found to affect the conformation of the ECL2 domain, which in turn drives the N-terminus of CCR5 to an altered state. Aplaviroc is more hydrophilic than maraviroc and vicriviroc, and its binding is more interfered by solvent, resulting in a quite different effect to the structure of CCR5 compared with those of the other two molecules. The above results are in accord with experimental observations and provide a structural basis for further design of CCR5 antagonists. 相似文献
4.
Clark BE Auyeung K Fregolino E Parrilli M Lanzetta R De Castro C Pantophlet R 《Chemistry & biology》2012,19(2):254-263
The broadly neutralizing antibody 2G12 binds a fairly conserved cluster of oligomannose sugars on the HIV surface glycoprotein gp120, which has led to the hypothesis that these sugars pose potential vaccine targets. Here, we present the chemical analysis, antigenicity, and immunogenicity of?a bacterial lipooligosaccharide (LOS) comprised of?a manno-oligosaccharide sequence analogous to the 2G12 epitope. Antigenic similarity of the LOS to oligomannose was evidenced by 2G12 binding to the LOS and the inability of sera elicited against synthetic oligomannosides, but incapable of binding natural oligomannose, to bind the LOS. Immunization with heat-killed bacteria yielded epitope-specific serum antibodies with the capacity to bind soluble gp120. Although these sera did not exhibit specific anti-HIV activity, our data suggest that this LOS may find utility as a template for the design of glycoconjugates to target HIV. 相似文献
5.
Christine Hager-Braun Elisabeth O. Hochleitner Miroslaw K. Gorny Susan Zolla-Pazner Rachelle J. Bienstock Kenneth B. Tomer 《Journal of the American Society for Mass Spectrometry》2010,21(10):1687-1698
A subset of the neutralizing anti-HIV antibodies recognize epitopes on the envelope protein gp120 of the human immunodeficiency
virus. These epitopes are exposed during conformational changes when gp120 binds to its primary receptor CD4. Based on chemical
modification of lysine and arginine residues followed by mass spectrometric analysis, we determined the epitope on gp120 recognized
by the human monoclonal antibody 559/64-D, which was previously found to be specific for the CD4 binding domain. Twenty-four
lysine and arginine residues in recombinant full-length glycosylated gp120 were characterized; the relative reactivities of
two lysine residues and five arginine residues were affected by the binding of 559/64-D. The data show that the epitope is
discontinuous and is located in the proximity of the CD4-binding site. Additionally, the reactivities of a residue that is
located in the secondary receptor binding region and several residues distant from the CD4 binding site were also altered
by Ab binding. These data suggest that binding of 559/64-D induced conformational changes which result in altered surface
exposure of specific amino acids distant from the CD4-binding site. Consequently, binding of 559/64-D to gp120 affects not
only the CD4-binding site, which is recognized as the epitope, but appears to have a global effect on surface exposed residues
of the full-length glycosylated gp120. 相似文献
6.
Xinling Wang Miao Cao Yanling Wu Wei Xu Qian Wang Tianlei Ying Lu Lu Shibo Jiang 《Molecules (Basel, Switzerland)》2021,26(7)
Acquired immune deficiency syndrome (AIDS) has prevailed over the last 30 years. Although highly active antiretroviral therapy (HAART) has decreased mortality and efficiently controlled the progression of disease, no vaccine or curative drugs have been approved until now. A viral inactivator is expected to inactivate cell-free virions in the absence of target cells. Previously, we identified a gp120-binding protein, mD1.22, which can inactivate laboratory-adapted HIV-1. In this study, we have found that the gp41 N-terminal heptad repeat (NHR)-binding antibody D5 single-chain variable fragment (scFv) alone cannot inactivate HIV-1 at the high concentration tested. However, D5 scFv in the combination could enhance inactivation activity of mD1.22 against divergent HIV-1 strains, including HIV-1 laboratory-adapted strains, primary HIV-1 isolates, T20- and AZT-resistant strains, and LRA-reactivated virions. Combining mD1.22 and D5 scFv exhibited synergistic effect on inhibition of infection by divergent HIV-1 strains. These results suggest good potential to develop the strategy of combining a gp120-binding protein and a gp41-binding antibody for the treatment of HIV-1 infection. 相似文献
7.
Possible inhibitors preventing human immunodeficiency virus type 1 (HIV-1) entry into the cells are recognized as hopeful next-generation anti-HIV-1 drugs. It is highly desirable to develop a potent inhibitor blocking binding of glycoprotein CD4 of the cell with glycoprotein gp120 of HIV-1, because the gp120-CD4 binding is the initial step of HIV-1 entry into the cells. It has been recently reported that (-)-epigallocatechin gallate (EGCG) from green tea is an inhibitor blocking gp120-CD4 binding. But the inhibitory mechanism remains unknown. For understanding the inhibitory mechanism, extensive molecular docking, molecular dynamics simulations, and binding free-energy calculations have been performed in this study to predict the most favorable structures of CD4-EGCG, gp120-CD4, and gp120-CD4-EGCG binding complexes in water. The results reveal that EGCG binds with CD4 in such a way that the calculated binding affinity of gp120 with the CD4-EGCG complex is negligible. So, the favorable binding of EGCG with CD4 can effectively block gp120-CD4 binding. The calculated CD4-EGCG binding affinity (DeltaG(bind) = -5.5 kcal/mol, K(d) = 94 microM) is in excellent agreement with available experimental data suggesting IC(50) approximately 100 microM for EGCG-blocking CD4-gp120 binding. These results and insights provide a rational basis for future design of novel, more potent inhibitors to block gp120-CD4 binding. 相似文献
8.
Paul S Kalaga RS Gololobov G Brenneman D 《Applied biochemistry and biotechnology》2000,83(1-3):71-82; discussion 82-4, 145-53
The autoimmune repertoire is well known from previous studies to be capable of producing catalytic antibodies directed to self-antigens. In the present study, we explored the ability of 26 monoclonal light chains (L chains) from multiple myeloma patients to cleave radiolabeled gp120, a foreign protein. One L chain with this activity was identified. 125I-gp120 and unlabeled gp120 were cleaved at several sites by the L chain, as shown by SDS-polyacrylamide gel electrophoresis, autoradiography, and immunoblotting, respectively. The apparent dissociation constant of the L chain was 130-145 nM, indicating high-affinity gp120 recognition. 125I-albumin was not cleaved by the L chain, and various proteins and peptides did not inhibit gp120 cleavage by the L chain, suggesting that the activity is not a nonspecific phenomenon. The substrate recognition determinants may be conserved in different HIV-1 strains, because gp120 isolated from strains SF2, MN, and IIIB was found to be cleaved by the L chain. Micromolar concentrations of a synthetic peptide corresponding to residues 23-30 of gp120 inhibited the cleavage of 125I-gp120, suggesting that these residues are components of the epitope recognized by the L chain. The toxic effect of gp120 in neuronal cultures was reduced by about 100-fold by pretreatment of the protein with the L chain. These observations open the possibility of utilizing gp120-cleaving antibodies in the treatment of AIDS. 相似文献
9.
Sudhir Paul Ravi S. Kalaga G. Gololobov Douglas Brenneman 《Applied biochemistry and biotechnology》2000,83(1-3):71-84
The autoimmune repertoire is well known from previous studies to be capable of producing catalytic antibodies directed to
self-antigens. In the present study, we explored the ability of 26 monoclonal light chains (Lchains) from multiple myeloma
patients to cleave radiolabeled gp 120, a foreign protein. One L chain with this activity was identified. 125I-gp120 and unlabeled gp 120 were cleaved at several sites by the L chain, as shown by SDS-polyacrylamide gel electrophoresis,
autoradiography, and immunoblotting, respectively. The apparent dissociation constant of the L chain was 130–145 nM, indicating high-affinity gp 120 recognition. 125I-albumin was not cleaved by the L chain, and various proteins and peptides did not inhibit gp 120 cleavage by the L chain,
suggesting that the activity is not a nonspecific phenomenon. The substrate recognition determinants may be conserved in different
HIV-1 strains, because gp 120 isolated from strains SF2, MN, and IIIB was found to be cleaved by the L chain. Micromolar concentrations
of a synthetic peptide corresponding to residues 23–30 of gp 120 inhibited the cleavage of 125I-gp 120, suggesting that these residues are components of the epitope recognized by the L chain. The toxic effect of gp120
in neuronal cultures was reduced by about 100-fold by pretreatment of the protein with the L chain. These observations open
the possibility of utilizing gp120-cleaving antibodies in the treatment of AIDS. 相似文献
10.
Oligosaccharide and glycoprotein microarrays as tools in HIV glycobiology; glycan-dependent gp120/protein interactions. 总被引:11,自引:0,他引:11
Eddie W Adams Daniel M Ratner Heidi R Bokesch James B McMahon Barry R O'Keefe Peter H Seeberger 《Chemistry & biology》2004,11(6):875-881
Defining HIV envelope glycoprotein interactions with host factors or binding partners advances our understanding of the infectious process and provides a basis for the design of vaccines and agents that interfere with HIV entry. Here we employ carbohydrate and glycoprotein microarrays to analyze glycan-dependent gp120-protein interactions. In concert with new linking chemistries and synthetic methods, the carbohydrate arrays combine the advantages of microarray technology with the flexibility and precision afforded by organic synthesis. With these microarrays, we individually and competitively determined the binding profiles of five gp120 binding proteins, established the carbohydrate structural requirements for these interactions, and identified a potential strategy for HIV vaccine development. 相似文献
11.
A series of broadly neutralizing antibodies called PGT have been shown to be bound directly to human immunodeficiency virus type-1 via high mannose glycans on glycoprotein gp120. Despite the sequence similarities of amino acids of the antibodies, their affinities to the glycan differ. Glycan–antibody interactions among these antibodies are systematically compared with quantum chemical fragment molecular orbital calculations and molecular dynamics simulations. The differences among structural stability of the glycan in the active site of the complexes and total interaction energies as well as binding free energies between the glycan and antibodies agree well with the experimentally shown affinities of the glycan to the antibodies. The terminal saccharide, Man D3, is structurally stable and responsible for the glycan–antibody binding through electrostatic and dispersion interactions. The structural stability of nonterminal saccharides such as Man 4 or Man C plays substantial roles in the interaction via direct hydrogen bonds. © 2019 Wiley Periodicals, Inc. 相似文献
12.
Zouali M 《Applied biochemistry and biotechnology》2000,83(1-3):13-28; discussion 28-9, 145-53
B-cell superantigens (SAgs) interact with normal human nonimmune immunoglobulins (Igs) independently of the light-chain isotype, and activate a large proportion of the B-cell repertoire. Recently, the major envelope protein of human immunodeficiency virus 1 (HIV-1), gp120, was found to exhibit SAg-like properties for B cells with potential pathological consequences for the infected host, including accelerated apoptosis and progressive loss of B cells. This unconventional mode of interaction contrasts with its binding to immunization-induced antibodies, which requires the tertiary structure of the heavy- and light-chain variable regions. Examining the temporal development of V(H)3+ antibodies in HIV-1-infected subjects over a 7-yr period showed that V(H)3+ antibodies specific for the gp120 SAg-binding site are deficient. Quantification of V(H)3+ antibodies, which impart protective responses to infectious agents, in serum samples from HIV-seropositive slow progressors and from patients who progressed to AIDS-related manifestations reveals that paucity in V(H)3+ antibodies is a marker of rapid clinical decline. Remarkably, anti-gp160 V(H)3+ antibodies show a gradual decrease in progressors and vary with time, depending on the viral load. Thus, V(H)3+ antibodies could play an important role in protection, and their underexpression may accelerate disease progression. Investigation of the structural basis of the interaction between human Igs and gp120 shows that the viral gp120 SAg can interact only with a subset of human V(H)3+ Igs. A number of amino acid-positions present primarily in the first and third framework regions of the Ig heavy-chain variable regions correlate with gp120 binding. These residues partially overlap with the Staphylococcus aureus protein A-binding site for V(H)3+ Igs. Overall, these interactions could represent a novel mechanism of humoral deficiency resulting from the capacity of a viral SAg to impact an important subset of the B-cell repertoire and to induce B-cell death by apoptosis. 相似文献
13.
Dettin M Scarinci C Pasquato A Di Bello C 《Applied biochemistry and biotechnology》2002,102(1-6):41-47
The formation of a complex among gp120, CD4, and CCR5/CXCR4 represents a key step in human immunodeficiency virus (HIV) infection.
The use of synthetic peptides reproducing sequences of these surface proteins has increased knowledge about the interactions
that determine the penetration of HIV viruses into target cells. The final aim of such investigations is the design of molecules
able to inhibit the initial step of infection and the development of high-sensitivity in vitro assays for detection of HIV.
In particular, the studies presented herein concern the role of the gp120 V3 loop in the CD4 binding, the importance of the
N-terminal sequence of HIV-coreceptor CCR5, the sequences patterned on CXCR4 natural ligand (stromal-derived factor 1 [SDF-1])
as inhibitory peptides, and the importance of substrate secondary structure in determining the enzymatic processing of gp120
precursor (gp160). 相似文献
14.
Andrianov AM Anishchenko IV Tuzikov AV 《Journal of chemical information and modeling》2011,51(10):2760-2767
The V3 loop on gp120 from HIV-1 is a focus of many research groups involved in anti-AIDS drug studies, because this region of the protein determines the preference of the virus for T-lymphocytes or primary macrophages. Although the V3 loop governs cell tropism and, for this reason, exhibits one of the most attractive targets for anti-HIV-1 drug developments, its high sequence variability is a major complicating factor. Nevertheless, the data on the spatial arrangement of V3 obtained here for different HIV-1 subtypes by computer modeling clearly show that, despite a wide range of 3D folds, this functionally important site of gp120 forms at least three structurally invariant segments, which contain residues critical for cell tropism. It is evident that these conserved V3 segments represent potential HIV-1 vulnerable spots and, therefore, provide a blueprint for the design of novel, potent and broad antiviral agents able to stop the HIV's spread. 相似文献
15.
Design,Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines
Agnieszka Sulima Fuying Li Jeffrey Brian Morgan Phong Truong Joshua F. G. Antoline Therese Oertel Rodell C. Barrientos Oscar B. Torres Zoltan Beck Gregory H. Imler Jeffrey R. Deschamps Gary R. Matyas Arthur E. Jacobson Kenner C. Rice 《Molecules (Basel, Switzerland)》2022,27(5)
In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)–hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT–hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT–hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness. 相似文献
16.
Combatting Synthetic Designer Opioids: A Conjugate Vaccine Ablates Lethal Doses of Fentanyl Class Drugs 下载免费PDF全文
Paul T. Bremer Dr. Atsushi Kimishima Dr. Joel E. Schlosburg Dr. Bin Zhou Dr. Karen C. Collins Prof.Dr. Kim D. Janda 《Angewandte Chemie (International ed. in English)》2016,55(11):3772-3775
17.
G. V. Gololobov S. V. Mikhalap A. V. Starov A. F. Kolesnikov A. G. Gabibov 《Applied biochemistry and biotechnology》1994,47(2-3):305-315
Sera of patients with different types of leukemia and acquired immune deficiency syndrome (AIDS) have been examined for the
presence of the anti-DNA antibodies. DNA-hydrolyzing activity of antibodies was detected in the sera of patients with chronic
lymphoid leukemia (CLL), pre-B-cell acute lymphoid leukemia (pre-B-All), acute myeloleukosis (AML), and AIDS in stages III
and IV of the disease. In immunofluorescence tests, the DNA-hydrolyzing antibodies reacted preferentially with proliferating
cell nuclei compared with resting cells. A 35-kDa factor was identified as the target for the DNA antibodies in the cell nuclei.
The DNA-hydrolyzing antibody fraction from the serum of an AIDS patient crossreacted with HIV I virus proteins gp160, gp120,
and p65. 相似文献
18.
Manetti F Tintori C Armand-Ugón M Clotet-Codina I Massa S Ragno R Esté JA Botta M 《Journal of chemical information and modeling》2006,46(3):1344-1351
The HIV-1 entry process is an important target for the design of new pharmaceuticals for the multidrug therapy of AIDS. A lot of polyanionic compounds, such as polysulfonated and polysulfated, are reported in the literature for their ability to block early stages of HIV-1 replication. Several studies have been performed to elucidate the mechanism of the anti-HIV-1 activity of sulfated polysaccharides and polyanions in general, including binding to cell surface CD4 and interfering with the gp120-coreceptor interaction. Here, we show molecular modeling investigations on ADS-J1, a polyanionic compound with anti-HIV activity that is able to interfere with gp120-coreceptor interactions. Agreeing with experimental data, computer simulations suggested that the V3 loop of gp120 was the preferential binding site for ADS-J1 onto HIV-1. Moreover, mutations induced by the inhibitor significantly changed the stereoelectronic properties of the gp120 surface, justifying a marked drop in the affinity of ADS-J1 toward an ADS-J1-resistant HIV-1 strain. 相似文献
19.
The application of dendrimeric constructs in medical diagnostics and therapeutics is increasing. Dendrimers have attracted attention due to their compact, spherical three-dimensional structures with surfaces that can be modified by the attachment of various drugs, hydrophilic or hydrophobic groups, or reporter molecules. In the literature, many modified dendrimer systems with various applications have been reported, including drug and gene delivery systems, biosensors, bioimaging contrast agents, tissue engineering, and therapeutic agents. Dendrimers are used for the delivery of macromolecules, miRNAs, siRNAs, and many other various biomedical applications, and they are ideal carriers for bioactive molecules. In addition, the conjugation of dendrimers with antibodies, proteins, and peptides allows for the design of vaccines with highly specific and predictable properties, and the role of dendrimers as carrier systems for vaccine antigens is increasing. In this work, we will focus on a review of the use of dendrimers in cancer diagnostics and therapy. Dendrimer-based nanosystems for drug delivery are commonly based on polyamidoamine dendrimers (PAMAM) that can be modified with drugs and contrast agents. Moreover, dendrimers can be successfully used as conjugates that deliver several substances simultaneously. The potential to develop dendrimers with multifunctional abilities has served as an impetus for the design of new molecular platforms for medical diagnostics and therapeutics. 相似文献
20.
Joseph Jagur‐Grodzinski 《先进技术聚合物》2009,20(7):595-606
Recent advances in the use of polymers for passive targeting of drugs attached or incorporated into polymeric species (enhanced permeability and retention, EPR) as well as active targeting of drugs by ligands or antibodies of receptors overexpressed on the surface of the targeted cells, is discussed in the present review. Examples of sustained, slow release of a drug incorporated into a polymeric matrix are cited. Drugs used for passive modes of targeting have been described in the context of polymer‐drug conjugates, drugs in the polymer coated liposomes, and drugs inserted into polymeric micelles. Active targeting of the drugs and their internalization by receptors, on the surface of the targeted cells, was also discussed. Release of the drugs inside cells, after are broken the environmentally sensitive links attaching them to polymeric platforms was described. Examples illustrate targeting drug by local heat generated by ultrasound, or by photodynamic treatment. Delivery modes of drugs incorporated into other nanoparticles and the concept of prodrugs have been investigated. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献