Virtual Screening of Novel Hiv-1 Entry Inhibitors Blocking Cd4-Binding Site of the Virus Envelope Gp120 Protein

2014 ◽  
Vol 9 (2) ◽  
pp. 359-372 ◽  
Author(s):  
И.А. Кашин ◽  
I.A. Kashyn
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Virus Envelope ◽  
Entry Inhibitors ◽  
Gp120 Protein ◽  
Cd4 Binding Site ◽  
Hiv 1 ◽  
Envelope Gp120

scholarly journals Changes in the Immunogenic Properties of Soluble gp140 Human Immunodeficiency Virus Envelope Constructs upon Partial Deletion of the Second Hypervariable Region

2003 ◽  
Vol 77 (4) ◽  
pp. 2310-2320 ◽  
Author(s):  
Indresh K. Srivastava ◽  
Keating VanDorsten ◽  
Lucia Vojtech ◽  
Susan W. Barnett ◽  
Leonidas Stamatatos
Keyword(s):  
Human Immunodeficiency Virus ◽  
Binding Site ◽  
Hypervariable Region ◽  
V3 Loop ◽  
Virus Envelope ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Hiv Envelope ◽  
Immunogenic Properties ◽  
Hiv 1

ABSTRACT Immunization of macaques with the soluble oligomeric gp140 form of the SF162 envelope (SF162gp140) or with an SF162gp140-derived construct lacking the central region of the V2 loop (ΔV2gp140) results in the generation of high titers of antibodies capable of neutralizing the homologous human immunodeficiency virus type 1 (HIV-1), SF162 virus (Barnett et al. J. Virol. 75 :5526-5540, 2001). However, the ΔV2gp140 immunogen is more effective than the SF162gp140 immunogen in eliciting the generation of antibodies capable of neutralizing heterologous HIV-1 isolates. This indicates that deletion of the V2 loop alters the immunogenicity of the SF162gp140 protein. The present studies were aimed at identifying the envelope regions whose immunogenicity is altered following V2 loop deletion. We report that the antibodies elicited by the SF162gp140 immunogen recognize elements of the V1, V2, and V3 loops, the CD4-binding site, and the C1 and C2 regions on the homologous SF162 gp120. With the exception of the V1 and V2 loops, the same regions are recognized on heterologous gp120 proteins. Surprisingly, although a minority of the SF162gp140-elicited antibodies target the V3 loop on the homologous gp120, the majority of the antibodies elicited by this immunogen that are capable of binding to the heterologous gp120s tested recognize their V3 loops. Deletion of the V2 loop has two effects. First, it alters the immunogenicity of the V3 and V1 loops, and second, it renders the C5 region immunogenic. Although deletion of the V2 loop does not result in an increase in the immunogenicity of the CD4-binding site per se, the relative ratio of anti-CD4-binding site to anti-V3 loop antibodies that bind to the heterologous gp120s tested is higher in sera collected from the ΔV2gp140-immunized animals than in the SF162gp140-immunized animals. Overall, our studies indicate that it is possible to alter the immunogenic structure of the HIV envelope by introducing specific modifications.

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 Computer-aided design of novel HIV-1 entry inhibitors blocking the virus envelope gp120 V3 loop

2012 ◽  
Vol 28 (6) ◽  
pp. 468-476 ◽  
Author(s):  
A. M. Andrianov ◽  
I. V. Anishchenko ◽  
M. A. Kisel ◽  
Yu. V. Kornoushenko ◽  
V. A. Nikolayevich ◽  
...  
Keyword(s):  
Computer Aided Design ◽  
V3 Loop ◽  
Virus Envelope ◽  
Entry Inhibitors ◽  
Computer Aided ◽  
Aided Design ◽  
Hiv 1 ◽  
Envelope Gp120

scholarly journals Design, Synthesis, and Antiviral Activity of Entry Inhibitors That Target the CD4-Binding Site of HIV-1

2012 ◽  
Vol 55 (10) ◽  
pp. 4764-4775 ◽  
Author(s):  
Francesca Curreli ◽  
Spreeha Choudhury ◽  
Ilya Pyatkin ◽  
Victor P. Zagorodnikov ◽  
Anna Khulianova Bulay ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Binding Site ◽  
Design Synthesis ◽  
Entry Inhibitors ◽  
Cd4 Binding Site ◽  
Hiv 1

scholarly journals Mutation at a Single Position in the V2 Domain of the HIV-1 Envelope Protein Confers Neutralization Sensitivity to a Highly Neutralization-Resistant Virus

2010 ◽  
Vol 84 (21) ◽  
pp. 11200-11209 ◽  
Author(s):  
Sara M. O'Rourke ◽  
Becky Schweighardt ◽  
Pham Phung ◽  
Dora P. A. J. Fonseca ◽  
Karianne Terry ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Protein ◽  
Neutralization Sensitivity ◽  
Receptor Binding Site ◽  
Entry Inhibitors ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Protein Variants ◽  
Hiv 1

ABSTRACT Understanding the determinants of neutralization sensitivity and resistance is important for the development of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. In these studies, we have made use of the swarm of closely related envelope protein variants (quasispecies) from an extremely neutralization-resistant clinical isolate in order to identify mutations that conferred neutralization sensitivity to antibodies in sera from HIV-1-infected individuals. Here, we describe a virus with a rare mutation at position 179 in the V2 domain of gp120, where replacement of aspartic acid (D) by asparagine (N) converts a virus that is highly resistant to neutralization by multiple polyclonal and monoclonal antibodies, as well as antiviral entry inhibitors, to one that is sensitive to neutralization. Although the V2 domain sequence is highly variable, D at position 179 is highly conserved in HIV-1 and simian immunodeficiency virus (SIV) and is located within the LDI/V recognition motif of the recently described α4β7 receptor binding site. Our results suggest that the D179N mutation induces a conformational change that exposes epitopes in both the gp120 and the gp41 portions of the envelope protein, such as the CD4 binding site and the MPER, that are normally concealed by conformational masking. Our results suggest that D179 plays a central role in maintaining the conformation and infectivity of HIV-1 as well as mediating binding to α4β7.

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