scholarly journals Virtual screening and identification of potential HIV-1 inhibitors based on the cross-reactive neutralizing antibody N6

2019 ◽  
Vol 63 (4) ◽  
pp. 445-456 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Gregory I. Nikolaev ◽  
Yuri V. Kornoushenko ◽  
Jinghe Huang ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Free Energy ◽  
Neutralizing Antibody ◽  
Positive Control ◽  
Effective Interactions ◽  
Gp120 Protein ◽  
Cd4 Binding Site ◽  
Screening And Identification ◽  
The Cross ◽  
Hiv 1

Six potential peptidomimetics of the cross-reactive neutralizing anti-HIV-1 antibody N6 that are able to mimic the pharmacophoric features of this immunoglobulin by specific and effective interactions with the CD4-binding site of the viral gp120 protein were identified by virtual screening and molecular modeling. The key role in the interaction of these compounds with gp120 is shown to play multiple van der Waals contacts with conserved residues of the gp120 Phe43 cavity critical for the HIV binding to cellular receptor CD4, as well as hydrogen bonds with Asp-368gp120 that increase the chemical affinity without activating unwanted allosteric effect. According to the data of molecular dynamics, the complexes of the identified ligands with gp120 are energetically stable and show the lower values of binding free energy compared with the HIV-1 inhibitors NBD-11021 and DMJ-II-121 used in the calculations as a positive control. The identified compounds may be involved in the design of novel antiviral drugs presenting HIV-1 inhibitors that block the early stages of the development of HIV infection.

scholarly journals In silico Identification of High-Affinity Ligands of the Hiv-1 Gp120 Protein, Potential Peptidomimetics of Neutralizing Antibody N6

2019 ◽  
Vol 14 (2) ◽  
pp. 430-449 ◽  
Author(s):  
A.M. Andrianov ◽  
G.I. Nikolaev ◽  
Y.V. Kornoushenko ◽  
J. Huang ◽  
S. Jiang ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Experimental Studies ◽  
Neutralizing Antibody ◽  
Positive Control ◽  
Effective Interactions ◽  
Affinity Ligands ◽  
Gp120 Protein ◽  
Cd4 Binding Site ◽  
Anti Hiv ◽  
Hiv 1

Six potential peptidomimetics of the cross-reactive neutralizing anti-HIV-1 antibody N6 that are able to mimic the pharmacophoric features of this immunoglobulin by specific and effective interactions with the CD4-binding site of the viral gp120 protein were identified by virtual screening and molecular modeling. The key role in the interaction of these compounds with gp120 is shown to play multiple van der Waals contacts with conserved residues of the gp120 Phe-43 cavity critical for the HIV binding to cellular receptor CD4, as well as hydrogen bond with Asp-368gp120 that increase the chemical affinity without activating unwanted allosteric effect. According to the data of molecular dynamics, the complexes of the identified ligands with gp120 are energetically stable and show the lower values of binding free energy compared with the HIV-1 inhibitors NBD-11021 and DMJ-II-121 used in the calculations as a positive control. Based on the data obtained, it was concluded that the identified compounds may be considered as promising candidates for detailed experimental studies to their further use in the design of novel antiviral drugs presenting HIV-1 inhibitors that block the early stages of the development of HIV infection.

scholarly journals Comparative Immunogenicity of Subtype A Human Immunodeficiency Virus Type 1 Envelope Exhibiting Differential Exposure of Conserved Neutralization Epitopes

2009 ◽  
Vol 84 (5) ◽  
pp. 2573-2584 ◽  
Author(s):  
Catherine A. Blish ◽  
D. Noah Sather ◽  
George Sellhorn ◽  
Leonidas Stamatatos ◽  
Yide Sun ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Variable Loops ◽  
Linear Epitopes ◽  
Subtype A ◽  
Hiv 1

ABSTRACT Development of broadly cross-reactive neutralizing antibodies (NAbs) remains a major goal of HIV-1 vaccine development, but most candidate envelope immunogens have had limited ability to cross-neutralize heterologous strains. To evaluate the immunogenicity of subtype A variants of HIV-1, rabbits were immunized with pairs of closely related subtype A envelopes from the same individual. In each immunogen pair, one variant was readily neutralized by a variety of monoclonal antibodies and plasma antibodies, while the other was neutralization resistant, suggesting differences in the exposures of key epitopes. The breadth of the antibody response was evaluated against subtype A, B, C, and D variants of HIV-1. The specificity of the immunogen-derived neutralizing antibody response was also compared to that of the infected individuals from whom these variants were cloned. None of the immunogens produced broad neutralizing antibodies in immunized animals, and most of the neutralizing antibodies were directed to the variable loops, particularly the V3 loop. No detectable antibodies to either of the potentially exposed conserved epitopes, the membrane proximal external region, or the CD4 binding site were found with immunized rabbits. In contrast, relatively little of the neutralizing activity within the plasma samples of the infected individuals was directed to linear epitopes within the variable loops. These data indicate that immunogens designed to expose conserved regions did not enhance generation of broadly neutralizing antibodies in comparison with the immunogens that failed to expose those regions using this immunization approach.

scholarly journals Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

2020 ◽  
Vol 117 (31) ◽  
pp. 18719-18728 ◽  
Author(s):  
Magnus A. G. Hoffmann ◽  
Yotam Bar-On ◽  
Zhi Yang ◽  
Harry B. Gristick ◽  
Priyanthi N. P. Gnanapragasam ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Neutralizing Antibody ◽  
Viral Fitness ◽  
Viral Escape ◽  
Target Cells ◽  
High Avidity ◽  
Viral Control ◽  
Cd4 Binding Site ◽  
Hiv 1

CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated CD4 (CD4-VLPs) to permit high-avidity binding of trimeric HIV-1 envelope spikes. In neutralization assays, CD4-VLPs were >12,000-fold more potent than sCD4 and CD4-Ig and >100-fold more potent than the broadly neutralizing antibody (bNAb) 3BNC117, with >12,000-fold improvements against strains poorly neutralized by 3BNC117. CD4-VLPs also neutralized patient-derived viral isolates that were resistant to 3BNC117 and other bNAbs. Intraperitoneal injections of CD4-CCR5-VLP produced only subneutralizing plasma concentrations in HIV-1–infected humanized mice but elicited CD4-binding site mutations that reduced viral fitness. All mutant viruses showed reduced sensitivity to sCD4 and CD4-Ig but remained sensitive to neutralization by CD4-VLPs in vitro. In vitro evolution studies demonstrated that CD4-VLPs effectively controlled HIV-1 replication at neutralizing concentrations, and viral escape was not observed. Moreover, CD4-VLPs potently neutralized viral swarms that were completely resistant to CD4-Ig, suggesting that escape pathways that confer resistance against conventional CD4-based inhibitors are ineffective against CD4-VLPs. These findings suggest that therapeutics that mimic HIV-1 target cells could prevent viral escape by exposing a universal vulnerability of HIV-1: the requirement to bind CD4 on a target cell. We propose that therapeutic and delivery strategies that ensure durable bioavailability need to be developed to translate this concept into a clinically feasible functional cure therapy.

scholarly journals In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 746 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Grigory I. Nikolaev ◽  
Yuri V. Kornoushenko ◽  
Wei Xu ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Cellular Receptor ◽  
Dynamic Simulations ◽  
Entry Inhibitors ◽  
Fusion Inhibitors ◽  
Gp120 Protein ◽  
Hiv 1

Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry. Complexes of the designed molecules bound to gp120 were then generated by molecular docking and optimized using semiempirical quantum chemical method PM7. Finally, the binding affinity analysis of these ligand/gp120 complexes was performed by molecular dynamic simulations and binding free energy calculations. As a result, five top-ranking compounds that mimic the key interactions of CD4 with gp120 and show the high binding affinity were identified as the most promising CD4-mimemic candidates. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics.

scholarly journals Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

2015 ◽  
Vol 112 (38) ◽  
pp. 11947-11952 ◽  
Author(s):  
Jean-Philippe Julien ◽  
Jeong Hyun Lee ◽  
Gabriel Ozorowski ◽  
Yuanzi Hua ◽  
Alba Torrents de la Peña ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Size Exclusion ◽  
Negative Stain ◽  
Clade C ◽  
Exclusion Chromatography ◽  
Cd4 Binding Site ◽  
Broadly Neutralizing Antibody ◽  
Negative Stain Electron Microscopy ◽  
Is Design ◽  
Hiv 1

A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4 °C and 62.7 °C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.

scholarly journals Recombinant HIV-1 vaccine candidates based on replication-defective flavivirus vector

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
M. Giel-Moloney ◽  
M. Esteban ◽  
B. H. Oakes ◽  
M. Vaine ◽  
B. Asbach ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Effective Vaccine ◽  
Cell Responses ◽  
Vaccination Strategies ◽  
Gp120 Protein ◽  
Clade C ◽  
Antibody Titers ◽  
Efficient Expression ◽  
Dna Vectors ◽  
Hiv 1

AbstractMultiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV. In this study, an alternative replication-defective flavivirus vector, RepliVax (RV), was evaluated for the delivery of HIV-1 immunogens. Recombinant RV-HIV viruses were engineered to stably express clade C virus Gag and Env (gp120TM) proteins and propagated in Vero helper cells. RV-based vectors enabled efficient expression and correct maturation of Gag and gp120TM proteins, were apathogenic in a sensitive suckling mouse neurovirulence test, and were similar in immunogenicity to recombinant poxvirus NYVAC-HIV vectors in homologous or heterologous prime-boost combinations in mice. In a pilot NHP study, immunogenicity of RV-HIV viruses used as a prime or boost for DNA or NYVAC candidates was compared to a DNA prime/NYVAC boost benchmark scheme when administered together with adjuvanted gp120 protein. Similar neutralizing antibody titers, binding IgG titers measured against a broad panel of Env and Gag antigens, and ADCC responses were observed in the groups throughout the course of the study, and T cell responses were elicited. The entire data demonstrate that RV vectors have the potential as novel HIV-1 vaccine components for use in combination with other promising candidates to develop new effective vaccination strategies.

scholarly journals Development of Potential HIV-1 Inhibitors by In Silico Click Chemistry And Molecular Modeling Methods

2018 ◽  
Vol 13 (2) ◽  
pp. 507-525 ◽  
Author(s):  
A.M. Andrianov ◽  
G.I. Nikolaev ◽  
I.A. Kashyn ◽  
A.V. Tuzikov
Keyword(s):  
Molecular Modeling ◽  
Click Chemistry ◽  
In Silico ◽  
Viral Neutralization ◽  
Drug Candidates ◽  
Modular Units ◽  
Gp120 Protein ◽  
Cd4 Binding Site ◽  
Hiv Drugs ◽  
Hiv 1

Design of novel potential HIV-1 inhibitors able to block CD4-binding site of the envelope gp120 protein was carried out based on click chemistryin silico, a methodology allowing one to generate a large number of drug candidates by assembly from small modular units and to study their properties. Using the methods of molecular modeling, the neutralizing activity of designed molecules was evaluated, as a result of which five leading compounds that are promising for synthesis and biological trials were identified. Their chemical formulas are C24H23N7O2, C23H20N6O2, C21H17F3N6, C22H20ClN9O and C19H15N9O. It has been shown that these compounds can be used as good scaffolds for the development of novel potent and broad anti-HIV drugs with extensive viral neutralization effect.

Sign in / Sign up

Export Citation Format

Share Document