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

2019 ◽  
Vol 19 (18) ◽  
pp. 1599-1620 ◽  
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.

scholarly journals Imaging Viral Infection by Fluorescence Microscopy: Focus on HIV-1 Early Stage

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 213
Author(s):  
Soumajit Mukherjee ◽  
Emmanuel Boutant ◽  
Eleonore Réal ◽  
Yves Mély ◽  
Halina Anton
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Integration Site ◽  
Viral Envelope ◽  
Integration Step ◽  
Imaging Studies ◽  
Cytoplasmic Transport ◽  
Capsid Shell ◽  
Wide Range ◽  
Hiv 1

During the last two decades, progresses in bioimaging and the development of various strategies to fluorescently label the viral components opened a wide range of possibilities to visualize the early phase of Human Immunodeficiency Virus 1 (HIV-1) life cycle directly in infected cells. After fusion of the viral envelope with the cell membrane, the viral core is released into the cytoplasm and the viral RNA (vRNA) is retro-transcribed into DNA by the reverse transcriptase. During this process, the RNA-based viral complex transforms into a pre-integration complex (PIC), composed of the viral genomic DNA (vDNA) coated with viral and host cellular proteins. The protective capsid shell disassembles during a process called uncoating. The viral genome is transported into the cell nucleus and integrates into the host cell chromatin. Unlike biochemical approaches that provide global data about the whole population of viral particles, imaging techniques enable following individual viruses on a single particle level. In this context, quantitative microscopy has brought original data shedding light on the dynamics of the viral entry into the host cell, the cytoplasmic transport, the nuclear import, and the selection of the integration site. In parallel, multi-color imaging studies have elucidated the mechanism of action of host cell factors implicated in HIV-1 viral cycle progression. In this review, we describe the labeling strategies used for HIV-1 fluorescence imaging and report on the main advancements that imaging studies have brought in the understanding of the infection mechanisms from the viral entry into the host cell until the provirus integration step.

scholarly journals Antiviral Breadth and Combination Potential of Peptide Triazole HIV-1 Entry Inhibitors

2011 ◽  
Vol 56 (2) ◽  
pp. 1073-1080 ◽  
Author(s):  
Karyn McFadden ◽  
Patricia Fletcher ◽  
Fiorella Rossi ◽  
Kantharaju ◽  
Muddagowda Umashankara ◽  
...  
Keyword(s):  
Transcriptase Inhibitor ◽  
Viral Envelope ◽  
Cell Infection ◽  
Entry Inhibitors ◽  
Antiviral Compounds ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Glycoprotein Gp120 ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACTThe first stage of human immunodeficiency virus type 1 (HIV-1) infection involves the fusion of viral and host cellular membranes mediated by viral envelope glycoprotein gp120. Inhibitors that specifically target gp120 are gaining increased attention as therapeutics or preventatives to prevent the spread of HIV-1. One promising new group of inhibitors is the peptide triazoles, which bind to gp120 and simultaneously block its interaction with both CD4 and the coreceptor. In this study, we assessed the most potent peptide triazole, HNG-156, for inhibitory breadth, cytotoxicity, and efficacy, both alone and in combination with other antiviral compounds, against HIV-1. HNG-156 inhibited a panel of 16 subtype B and C isolates of HIV-1 in a single-round infection assay. Inhibition of cell infection by replication-competent clinical isolates of HIV-1 was also observed with HNG-156. We found that HNG-156 had a greater than predicted effect when combined with several other entry inhibitors or the reverse transcriptase inhibitor tenofovir. Overall, we find that HNG-156 is noncytotoxic, has a broad inhibition profile, and provides a positive combination with several inhibitors of the HIV-1 life cycle. These results support the pursuit of efficacy and toxicity analyses in more advanced cell and animal models to develop peptide triazole family inhibitors of HIV-1 into antagonists of HIV-1 infection.

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

2019 ◽  
Vol 19 (18) ◽  
pp. 1650-1675 ◽  
Author(s):  
Damoder Reddy Motati ◽  
Dilipkumar Uredi ◽  
E. Blake Watkins
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Biological Evaluation ◽  
New Drugs ◽  
Design Synthesis ◽  
Mortality And Morbidity ◽  
Glycoprotein Gp120 ◽  
Hiv Entry ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

scholarly journals HIV Cell Fusion Assay

2013 ◽  
Vol 19 (1) ◽  
pp. 108-118 ◽  
Author(s):  
Elizabeth B. Smith ◽  
Robert A. Ogert ◽  
David Pechter ◽  
Artjohn Villafania ◽  
Susan J. Abbondanzo ◽  
...  
Keyword(s):  
Host Cell ◽  
Cell Fusion ◽  
Chemokine Receptor ◽  
Viral Entry ◽  
Envelope Glycoprotein ◽  
Laser Scanning ◽  
Viral Envelope ◽  
Fusion Event ◽  
Cxcr4 Signaling ◽  
Hiv Entry

The health and disease-related biology of the CXCR4 chemokine receptor presents the challenge of finding a small molecule that can bind CXCR4 and block T-cell tropic human immunodeficiency virus type 1 (HIV-1) cell entry, while preserving the ability of CXCR4 to respond to its native ligand, CXCL12. HIV entry into the host cell involves the interaction of the viral envelope glycoprotein gp120 binding to CD4, followed by a rearrangement in gp120, and subsequent interaction with the chemokine receptor CXCR4 or CCR5. These initial events can be re-created in a cell fusion assay that represents a surrogate system, mimicking the early stages of viral entry via these host cell receptors. In the current study, a T-tropic HIV cell fusion assay was established using U2OS cells expressing the envelope glycoprotein gp160 from the T-tropic HIV NL4-3 and HeLa cells expressing CD4 and CXCR4. Detection of the cell fusion event was based on a Gal4/VP16-activated β-lactamase signal and was measured by automated microscopy or laser scanning plate cytometry. Changes in morphology associated with cell fusion were combined with β-lactamase activity to generate results with robust assay statistics in both 384-well and 1536-well plates. Compounds were subsequently characterized by CXCR4 signaling assays to eliminate functional antagonists and allow the identification of a function-sparing HIV entry inhibitor.

scholarly journals The leukotriene B4receptor functions as a novel type of coreceptor mediating entry of primary HIV-1 isolates into CD4-positive cells

1998 ◽  
Vol 95 (16) ◽  
pp. 9530-9534 ◽  
Author(s):  
Christer Owman ◽  
Alfredo Garzino-Demo ◽  
Fiorenza Cocchi ◽  
Mikulas Popovic ◽  
Alan Sabirsh ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Viral Entry ◽  
Chemokine Receptors ◽  
Structural Similarity ◽  
Target Cells ◽  
Natural Ligand ◽  
Hiv 1 ◽  
Entry Efficiency ◽  
Receptor Family

The recently cloned human chemoattractant receptor-like (CMKRL)1, which is expressedin vivoin CD4-positive immune cells, has structural homology with the two chemokine receptors C-C chemokine receptor (CCR)5 and C-X-C chemokine receptor (CXCR)4, which serve as the major coreceptors necessary for fusion of the HIV-1 envelope with target cells. In view of the structural similarity, CMKRL1 was tested for its possible function as another HIV-1 coreceptor after stable expression in murine fibroblasts bearing the human CD4 receptor. The cells were infected with 10 primary clinical isolates of HIV-1, and entry was monitored by semiquantitative PCR of viral DNA. The efficiency of the entry was compared with the entry taking place in CD4-positive cells expressing either CCR5 or CXCR4. Seven of the isolates used CMKRL1 for viral entry; they were mainly of the syncytium-inducing phenotype and also used CXCR4. Entry efficiency was higher with CMKRL1 than with CXCR4 for more than half of these isolates. Three of the ten isolates did not use CMKRL1; instead, entry was mediated by both CCR5 and CXCR4. The experiments thus indicate that CMKRL1 functions as a coreceptor for the entry of HIV-1 into CD4-positive cells. In the course of this study, leukotriene B4was shown to be the natural ligand for this receptor (now designated BLTR), which therefore represents a novel type of HIV-1 coreceptor along with the previously identified chemokine receptors. BLTR belongs to the same general chemoattractant receptor family as the chemokine receptors but is structurally more distant from them than are any of the previously described HIV-1 coreceptors.

Human CD38 interferes with HIV‐1 fusion through a sequence homologous to the V3 loop of the viral envelope glycoprotein gp120.

2003 ◽  
Vol 17 (3) ◽  
pp. 1-20 ◽  
Author(s):  
Andrea Savarino ◽  
Thea Bensi ◽  
Annalisa Chiocchetti ◽  
Flavia Bottarel ◽  
Riccardo Mesturini ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
Viral Envelope ◽  
V3 Loop ◽  
Viral Envelope Glycoprotein ◽  
Envelope Glycoprotein Gp120 ◽  
Glycoprotein Gp120 ◽  
Hiv 1

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

2016 ◽  
Vol 30 (12) ◽  
pp. 545-550 ◽  
Author(s):  
Geoff Symonds ◽  
Jeffrey S. Bartlett ◽  
Hans-Peter Kiem ◽  
Marlene Tsie ◽  
Louis Breton
Keyword(s):  
Membrane Fusion ◽  
Host Cell ◽  
Cell Population ◽  
Entry Inhibitors ◽  
Hiv 1

scholarly journals Design and Identification of Potential HIV-1 Entry Inhibitors Using In Silico Click Chemistry and Molecular Modeling Methods

2021 ◽  
Vol 16 (2) ◽  
pp. 317-334
Author(s):  
A.M. Andrianov ◽  
A.M. Yushkevich ◽  
I.P. Bosko ◽  
A.D. Karpenko ◽  
Yu.V. Kornoushenko ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Click Chemistry ◽  
Computer Aided Design ◽  
Integrated Approach ◽  
Viral Envelope ◽  
Entry Inhibitors ◽  
Fusion Inhibitors ◽  
Host Cell Membranes ◽  
Aided Design ◽  
Hiv 1

An integrated approach including the click chemistry methodology, molecular docking, quantum mechanics, and molecular dynamics was used to computer-aided design of potential HIV-1 inhibitors able to block the membrane-proximal external region (MPER) of HIV-1 gp41, which plays an important role in the fusion of the viral and host cell membranes. Evaluation of the binding efficiency of the designed compounds to the HIV-1 MPER peptide was performed using the methods of molecular modeling, resulting in nine chemical compounds exhibiting high-affinity binding to this functionally important site of the trimeric “spike” of the viral envelope. The data obtained indicate that the identified compounds are promising for the development of novel antiviral drugs, HIV fusion inhibitors blocking the early stages of HIV infection.

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