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 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 Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein

2012 ◽  
Vol 209 (8) ◽  
pp. 1469-1479 ◽  
Author(s):  
Florian Klein ◽  
Christian Gaebler ◽  
Hugo Mouquet ◽  
D. Noah Sather ◽  
Clara Lehmann ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Protein ◽  
Neutralizing Antibodies ◽  
Conformational Epitope ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Capture Method ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Viral Isolates

Two to three years after infection, a fraction of HIV-1–infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti–HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti–HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti–HIV-1 serologic breadth and potency should not be limited to single epitopes.

scholarly journals Characterization of Co-Formulated High-Concentration Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies for Subcutaneous Administration

Antibodies ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 36
Author(s):  
Vaneet K. Sharma ◽  
Bijay Misra ◽  
Kevin T. McManus ◽  
Sreenivas Avula ◽  
Kaliappanadar Nellaiappan ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Clinical Investigation ◽  
Total Concentration ◽  
Subcutaneous Administration ◽  
Analytical Techniques ◽  
Neutralizing Antibody ◽  
High Concentration ◽  
Anti Hiv ◽  
Hiv 1

The discovery of numerous potent and broad neutralizing antibodies (bNAbs) against Human Immunodeficiency Virus type 1 (HIV-1) envelope glycoprotein has invigorated the potential of using them as an effective preventative and therapeutic agent. The majority of the anti-HIV-1 antibodies, currently under clinical investigation, are formulated singly for intra-venous (IV) infusion. However, due to the high degree of genetic variability in the case of HIV-1, a single broad neutralizing antibody will likely not be sufficient to protect against the broad range of viral isolates. To that end, delivery of two or more co-formulated bnAbs against HIV-1 in a single subcutaneous (SC) injection is highly desired. We, therefore, co-formulated two anti-HIV bnAbs, 3BNC117-LS and 10-1074-LS, to a total concentration of 150 mg/mL for SC administration and analyzed them using a panel of analytical techniques. Chromatographic based methods, such as RP-HPLC, CEX-HPLC, SEC-HPLC, were developed to ensure separation and detection of each antibody in the co-formulated sample. In addition, we used a panel of diverse pseudoviruses to detect the functionality of individual antibodies in the co-formulation. We also used these methods to test the stability of the co-formulated antibodies and believe that such an approach can support future efforts towards the formulation and characterization of multiple high-concentration antibodies for SC delivery.

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 Peripheral Membrane Interactions Boost the Engagement by an Anti-HIV-1 Broadly Neutralizing Antibody

2017 ◽  
Vol 292 (13) ◽  
pp. 5571-5583 ◽  
Author(s):  
Edurne Rujas ◽  
José M. M. Caaveiro ◽  
Sara Insausti ◽  
Miguel García-Porras ◽  
Kouhei Tsumoto ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Membrane Interactions ◽  
Broadly Neutralizing Antibody ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Molecular dynamics for structural complexes of potential HIV-1 inhibitors with the viral envelope gp120 protein

2018 ◽  
Vol 62 (5) ◽  
pp. 576-584
Author(s):  
I. A. Kashyn ◽  
G. I. Nikolaev ◽  
M. A. Tuzikov ◽  
A. M. Andrianov
Keyword(s):  
Molecular Dynamics ◽  
Viral Envelope ◽  
Amino Acid Residues ◽  
Free Energies ◽  
Gp120 Protein ◽  
Dynamics Simulations ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Envelope Gp120

Molecular dynamics simulations for the structural complexes of potential HIV-1 inhibitors with the viral envelope gp120 protein were carried out. Free energies of the formation of these supramolecular structures and contributions of individual amino-acid residues of gp120 to the enthalpy binding were calculated. The residues of gp120 critical for interactions with the ligands were identified. Based on the data obtained, five compounds promising for synthesis and testing for antiviral activity were selected. It is suggested that these compounds may be successfully used in the design of novel, potent and broad anti-HIV drugs.

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.

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