Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide

Münch, Jan; Ständker, Ludger; Adermann, Knut; Schulz, Axel; Schindler, Michael; Chinnadurai, Raghavan; Pöhlmann, Stefan; Chaipan, Chawaree; Biet, Thorsten; Peters, Thomas; Meyer, Bernd; Wilhelm, Dennis; Liang, Hong; Jing, Weiguo; Jiang, Shibo; Forssmann, Wolf‐Georg; Kirchhoff, Frank

doi:10.1016/j.cell.2007.02.042

Cited by 236 publications

(299 citation statements)

References 46 publications

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“…AAT reduces TNF-a production and release [64], increases IL-10 levels 65 and protects the insulin-producing beta cells in the pancreatic islets against immune attack [64]. In a screen of all human plasma proteins, AAT was the only naturally occurring protein that inhibits HIV-1 [66], confirming a previous observation that AAT prevented HIV-1 replication induced by IL-18 [67]. "…”

Section: Endogenous Inhibitors Limit the Biological Impact Of Cytokinessupporting

confidence: 69%

Historical insights into cytokines

2007

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Cytokines affect nearly every biological process; these include embryonic development, disease pathogenesis, non-specific response to infection, specific response to antigen, changes in cognitive functions and progression of the degenerative processes of aging. In addition, cytokines are part of stem cell differentiation, vaccine efficacy and allograft rejection. This short insight focuses on the milestones in cytokine biology and how the various and often contradictory activities of these small, non-structural proteins affected the fields of inflammation and immunology. Multiple biological properties or pleiotropism is the hallmark of a cytokine. Today, the term "cytokine" encompasses interferons, the interleukins, the chemokine family, mesenchymal growth factors, the tumor necrosis factor family and adipokines. As of this writing, 33 cytokines are called interleukins, but many are part of families of related but distinct gene products. There are certainly over 100 separate genes coding for cytokine-like activities, many with overlapping functions and many still unexplored. Also discussed in this overview are the failures and successes of cytokines as therapeutic targets. A recent advance in the field has been that of differential cytokine production, which can be used to classify human disease as being "autoimmune" or "autoinflammatory" thus impacting on therapeutic interventions.

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Section: Endogenous Inhibitors Limit the Biological Impact Of Cytokinessupporting

confidence: 69%

Historical insights into cytokines

2007

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“…CHR is the target for NHR peptides, e.g. N36 (44) and 5-helix (45), whereas the fusion peptide is the target for a novel peptidic fusion inhibitor identified from human body liquid, VIRIP (46). We believe that the gp41 CT region, particularly the LLP2 domain, may also serve as an attractive target for development of HIV-1 fusion and entry inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Surface Exposure of the HIV-1 Env Cytoplasmic Tail LLP2 Domain during the Membrane Fusion Process

Zhu

Huang

et al. 2008

Journal of Biological Chemistry

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HIV-1 gp41 cytoplasmic tail (CT) is highly conserved among HIV-1 isolates, particularly the region designated lentivirus lytic peptide (LLP1-2), which includes two ␣-helical domains LLP1 and LLP2. Although the gp41 CT is recognized as a modulator of viral fusogenicity, little is known about the regulatory mechanism of this region in the viral fusion process. Here we report that anti-LLP1-2 and anti-LLP2 antibodies (IgG) inhibited HIV-1 Env-mediated cell fusion and bound to the interface between effector and target cells at a suboptimal temperature (31.5°C), which slows down the fusion process and prolongs the fusion intermediate state. This suggests that LLP1-2, especially the LLP2 region located inside the viral membrane, is transiently exposed on the membrane surface during the fusion process. Synthetic LLP2 peptide could bind to the gp41 six-helix bundle core with high binding affinity. These results suggest that the gp41 CT may interact with the gp41 core, via the surface-exposed LLP2 domain, to regulate Env-mediated membrane fusion.

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“…Drugs targeting viral glycoproteins or their receptors block the first events in the viral replication cycle and are less constrained by intracellular delivery or metabolism (6,8,9). Unfortunately, these drugs share the limitations of other drugs targeting viral proteins (2,10,11), such as prompt selection for resistance (12,13).…”

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confidence: 99%

Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses

St.Vincent¹,

Colpitts

Устинов

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

139

130

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Antiviral drugs targeting viral proteins often result in prompt selection for resistance. Moreover, the number of viral targets is limited. Novel antiviral targets are therefore needed. The unique characteristics of fusion between virion envelopes and cell membranes may provide such targets. Like all fusing bilayers, viral envelopes locally adopt hourglass-shaped stalks during the initial stages of fusion, a process that requires local negative membrane curvature. Unlike cellular vesicles, however, viral envelopes do not redistribute lipids between leaflets, can only use the energy released by virion proteins, and fuse to the extracellular leaflets of cell membranes. Enrichment in phospholipids with hydrophilic heads larger than their hydrophobic tails in the convex outer leaflet of vesicles favors positive curvature, therefore increasing the activation energy barrier for fusion. Such phospholipids can increase the activation barrier beyond the energy provided by virion proteins, thereby inhibiting viral fusion. However, phospholipids are not pharmacologically useful. We show here that a family of synthetic rigid amphiphiles of shape similar to such phospholipids, RAFIs (rigid amphipathic fusion inhibitors), inhibit the infectivity of several otherwise unrelated enveloped viruses, including hepatitis C and HSV-1 and -2 (lowest apparent IC 50 48 nM), with no cytotoxic or cytostatic effects (selectivity index > 3,000) by inhibiting the increased negative curvature required for the initial stages of fusion.lipid bilayer fusion | DNA virus | RNA virus | Sindbis virus | nucleosides

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Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide

Cited by 236 publications

References 46 publications

Historical insights into cytokines

Historical insights into cytokines

Surface Exposure of the HIV-1 Env Cytoplasmic Tail LLP2 Domain during the Membrane Fusion Process

Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses

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