Cell-Delivered Entry Inhibitors for HIV-1:CCR5Downregulation and Blocking Virus/Membrane Fusion in Defending the Host Cell Population

The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3. Comparisons between cryo-EM structures of Env trimer complexed with BG1 (6.2 Å resolution) and PG9 (11.5 Å resolution) revealed a new V1V2-targeting strategy by BG1. Analyses of the EM structures provided information relevant to vaccine design including molecular details for different modes of asymmetric recognition of Env trimer and a binding model for BG1 recognition of V1V2 involving glycan flexibility.

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Recent Progress in the Development of HIV-1 Entry Inhibitors: From Small Molecules to Potent Anti-HIV Agents

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190712204050 ◽

2019 ◽

Vol 19 (18) ◽

pp. 1599-1620 ◽

Cited By ~ 2

Author(s):

Khomson Suttisintong ◽

Narongpol Kaewchangwat ◽

Eknarin Thanayupong ◽

Chakkrapan Nerungsi ◽

Onsiri Srikun ◽

...

Keyword(s):

Host Cell ◽

Viral Entry ◽

Chemokine Receptors ◽

Recent Progress ◽

Viral Envelope ◽

Surface Glycoprotein ◽

Entry Inhibitors ◽

Transmembrane Glycoprotein ◽

Glycoprotein Gp120 ◽

Hiv 1

Viral entry, the first process in the reproduction of viruses, primarily involves attachment of the viral envelope proteins to membranes of the host cell. The crucial components that play an important role in viral entry include viral surface glycoprotein gp120, viral transmembrane glycoprotein gp41, host cell glycoprotein (CD4), and host cell chemokine receptors (CCR5 and CXCR4). Inhibition of the multiple molecular interactions of these components can restrain viruses, such as HIV-1, from fusion with the host cell, blocking them from reproducing. This review article specifically focuses on the recent progress in the development of small-molecule HIV-1 entry inhibitors and incorporates important aspects of their structural modification that lead to the discovery of new molecular scaffolds with more potency.

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Faculty Opinions recommendation of Viral protein U counteracts a human host cell restriction that inhibits HIV-1 particle production.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030738.368869 ◽

2006 ◽

Author(s):

Paul Bieniasz

Keyword(s):

Host Cell ◽

Viral Protein ◽

Particle Production ◽

Human Host ◽

Viral Protein U ◽

Hiv 1

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3D-QSAR and Molecular Docking Studies of HIV-1 Entry Inhibitors Targeting GP120-CD4 Binding Site

Anti-Infective Agents ◽

10.2174/2211352515666170809151958 ◽

2018 ◽

Vol 15 (2) ◽

Author(s):

Bhumika D. Patel ◽

Nidhi Choksi ◽

Kinjal Patel ◽

Qureshi Gulamnizami

Keyword(s):

Molecular Docking ◽

Binding Site ◽

3D Qsar ◽

Docking Studies ◽

Molecular Docking Studies ◽

Entry Inhibitors ◽

Cd4 Binding Site ◽

Hiv 1

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Design, Synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116000 ◽

2021 ◽

pp. 116000

Author(s):

Francesca Curreli ◽

Shahad Ahmed ◽

Sofia M. Benedict Victor ◽

Ildar R. Iusupov ◽

Evgeny A. Spiridonov ◽

...

Keyword(s):

Antiviral Activity ◽

Small Molecule ◽

Design Synthesis ◽

Entry Inhibitors ◽

Hiv 1

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HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽

10.3390/v13050852 ◽

2021 ◽

Vol 13 (5) ◽

pp. 852

Author(s):

Ashley Lauren Bennett ◽

Rory Henderson

Keyword(s):

Host Cell ◽

Conformational Changes ◽

Neutralizing Antibodies ◽

Critical Role ◽

Cell Receptor ◽

Broadly Neutralizing Antibodies ◽

Structural Mapping ◽

Host Cell Receptor ◽

Immunogen Design ◽

Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

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