The NMR structure of a cyclic V3 loop peptide that binds tightly to a monoclonal antibody that potently neutralizes HIV-1

AbstractThe host protein SERINC5 inhibits the infectivity of HIV-1 virions in an Env-dependent manner and is counteracted by Nef. The conformation of the Env trimer reportedly correlates with sensitivity to SERINC5. Here, we tested the hypothesis that the “open” conformation of the Env trimer revealed by sensitivity to the V3-loop specific antibody 447-52D directly correlates with sensitivity to SERINC5. Of five Envs tested, SF162 was the most sensitive to neutralization by 447-52D, but it was not the most sensitive to SERINC5; instead the Env of LAI was substantially more sensitive to SERINC5 than all the other Envs. Mutational opening of the trimer by substitution of two tyrosines that mediate interaction between the V2 and V3 loops sensitized the Envs of JRFL and LAI to 447-52D as previously reported, but only BaL was sensitized to SERINC5. These data suggest that trimer “openness” is not sufficient for sensitivity to SERINC5.

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Dual specificity of a human neutralizing monoclonal antibody, specific for the V3 loop of GP120 (HIV-1)

Immunology Letters ◽

10.1016/s0165-2478(99)00010-3 ◽

1999 ◽

Vol 67 (3) ◽

pp. 185-192 ◽

Cited By ~ 4

Author(s):

Isabelle L Laisney ◽

A.Donny Strosberg

Keyword(s):

Monoclonal Antibody ◽

V3 Loop ◽

Dual Specificity ◽

Neutralizing Monoclonal Antibody ◽

Hiv 1

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Structure of Simian Immunodeficiency Virus Envelope Spikes Bound with CD4 and Monoclonal Antibody 36D5

Journal of Virology ◽

10.1128/jvi.00134-17 ◽

2017 ◽

Vol 91 (16) ◽

Cited By ~ 5

Author(s):

Guiqing Hu ◽

Jun Liu ◽

Kenneth H. Roux ◽

Kenneth A. Taylor

Keyword(s):

Monoclonal Antibody ◽

Immune System ◽

Binding Site ◽

Simian Immunodeficiency Virus ◽

Conformational Dynamics ◽

V3 Loop ◽

Coreceptor Binding ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Coreceptor Binding Site

ABSTRACT The human immunodeficiency virus type 1 (HIV-1)/simian immunodeficiency virus (SIV) envelope spike (Env) mediates viral entry into host cells. The V3 loop of the gp120 component of the Env trimer contributes to the coreceptor binding site and is a target for neutralizing antibodies. We used cryo-electron tomography to visualize the binding of CD4 and the V3 loop monoclonal antibody (MAb) 36D5 to gp120 of the SIV Env trimer. Our results show that 36D5 binds gp120 at the base of the V3 loop and suggest that the antibody exerts its neutralization effect by blocking the coreceptor binding site. The antibody does this without altering the dynamics of the spike motion between closed and open states when CD4 is bound. The interaction between 36D5 and SIV gp120 is similar to the interaction between some broadly neutralizing anti-V3 loop antibodies and HIV-1 gp120. Two conformations of gp120 bound with CD4 are revealed, suggesting an intrinsic dynamic nature of the liganded Env trimer. CD4 binding substantially increases the binding of 36D5 to gp120 in the intact Env trimer, consistent with CD4-induced changes in the conformation of gp120 and the antibody binding site. Binding by MAb 36D5 does not substantially alter the proportions of the two CD4-bound conformations. The position of MAb 36D5 at the V3 base changes little between conformations, indicating that the V3 base serves as a pivot point during the transition between these two states. IMPORTANCE Glycoprotein spikes on the surfaces of SIV and HIV are the sole targets available to the immune system for antibody neutralization. Spikes evade the immune system by a combination of a thick layer of polysaccharide on the surface (the glycan shield) and movement between spike domains that masks the epitope conformation. Using SIV virions whose spikes were “decorated” with the primary cellular receptor (CD4) and an antibody (36D5) at part of the coreceptor binding site, we visualized multiple conformations trapped by the rapid freezing step, which were separated using statistical analysis. Our results show that the CD4-induced conformational dynamics of the spike enhances binding of the antibody.

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Elucidating the Disparate Inhibitory Mechanisms of Novel 1-Heteroaryl1,3-Propanediamine Derivatives and Maraviroc towards C-C Chemokine Receptor 5: Insights for Structural Modifications in HIV-1 Drug Discovery

Medicinal Chemistry ◽

10.2174/1573406417666201208122110 ◽

2020 ◽

Vol 17 ◽

Author(s):

Patrick Appiah-Kubi ◽

Fisayo Andrew Olotu ◽

Mahmoud E. S. Soliman

Keyword(s):

Drug Discovery ◽

Chemokine Receptor ◽

Competitive Inhibition ◽

Dynamic Effect ◽

Triazole Ring ◽

Internal Dynamic ◽

V3 Loop ◽

Structural Modifications ◽

Hiv 1 ◽

Chemokine Receptor 5

Introduction: Blocking Human Immunodeficiency Virus type 1 (HIV-1) entry via C-C chemokine receptor 5 (CCR5) inhibition has remained an essential strategy in HIV drug discovery. This underlies the development of CCR5 blockers, such as Maraviroc, which, however, elicits undesirable side effects despite its potency. Background: Recent lead optimization efforts led to the discovery of novel 1-heteroaryl-1,3-propanediamine derivatives; Compd-21 and -34, which were ~3 times more potent than Maraviroc, with improved pharmacokinetics. However, atomistic molecular interaction mechanism of how slight structural variance between these inhibitors significantly affects their binding profiles have not been elucidated. Method: This study employed explicit lipid bilayer molecular dynamics (MD) simulations, and advance analyses to explore these inhibitory discrepancies. Results: Findings revealed that the thiophene moiety substitution common to Compd-21 and -34 enhanced their CCR5- inhibitory activities due to complementary high-affinity interactions with Trp862.60, Tyr1083.32, Tyr2516.51, Glu2837.39. These cumulatively accounted for their ΔGbind which were higher than Maraviroc. Binding dynamics further revealed that the compounds mediated direct competitive inhibition at CCR5 by blocking the gp120 V3 loop. Furthermore, constituent tropane and triazole moieties in the compounds commonly engaged in interactions with Glu2837.39 and Trp862.60, respectively. Structural analyses also revealed that both Compd-21 and -34 elicited distinct internal dynamic effect on CCR5 relative to Maraviroc. Conclusion: Structural modifications at the thiophene substituent and the addition of new functional groups to the triazole ring may enhance inhibitor competition with gp120 V3-loop. Findings herein highlighted would contribute to future structure-based design of inhibitors of HIV-1 CCR5 with improved potencies.

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