HIV envelope: challenges and opportunities for development of entry inhibitors

Caffrey, Michael

doi:10.1016/j.tim.2011.02.001

Cited by 74 publications

(71 citation statements)

References 91 publications

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“…For example, there is structural information for the gp120 core in the free state and in complex with CD4 receptor domains and various monoclonal antibodies (6 -8), and there are numerous structures of the gp41 extracellular domain in the fusion state (9 -12). However, all gp120 structures to date are missing significant regions of gp120 and, perhaps more importantly, domains of gp41 (5). As a consequence, there exists the possibility that the gp120 structure in complex with gp41, the state present on virus and HIVinfected cells, is structurally different than those characterized previously.…”

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confidence: 96%

“…Importantly, conformational changes of gp120 and gp41 are thought to be intrinsic to the entry process (2)(3)(4). Due to their critical role in HIV entry, gp120 and gp41 have been intensively studied by x-ray crystallography and NMR spectroscopy (5). For example, there is structural information for the gp120 core in the free state and in complex with CD4 receptor domains and various monoclonal antibodies (6 -8), and there are numerous structures of the gp41 extracellular domain in the fusion state (9 -12).…”

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confidence: 99%

“…The critical role of gp120 has led to efforts to find molecules that bind to gp120 and inhibit its interaction with receptors (5). For example, the peptide 12p1 (sequence, RINNIPWSEAMM), which was discovered by phage display against recombinant HIV-1 HXB2 gp120, binds to gp120 and blocks its interaction with CD4 with an IC 50 ranging from 0.3 to 25 M for different strains (13).…”

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confidence: 99%

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Probing the HIV gp120 Envelope Glycoprotein Conformation by NMR

Celigoy

Ramirez

Lin

et al. 2011

Journal of Biological Chemistry

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The HIV envelope glycoprotein gp120 plays a critical role in virus entry, and thus, its structure is of extreme interest for the development of novel therapeutics and vaccines. To date, high resolution structural information about gp120 in complex with gp41 has proven intractable. In this study, we characterize the structural properties of gp120 in the presence and absence of gp41 domains by NMR. Using the peptide probe 12p1 (sequence, RINNIPWSEAMM), which was identified previously as an entry inhibitor that binds to gp120, we identify atoms of 12p1 in close contact with gp120 in the monomeric and trimeric states. Interestingly, the binding mode of 12p1 with gp120 is similar for clades B and C. In addition, we show a subtle difference in the binding mode of 12p1 in the presence of gp41 domains, i.e. the trimeric state, which we interpret as small differences in the gp120 structure in the presence of gp41.

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Probing the HIV gp120 Envelope Glycoprotein Conformation by NMR

Celigoy

Ramirez

Lin

et al. 2011

Journal of Biological Chemistry

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“…Both non-covalently linked proteins undergo extensive N-linked glycosylation and trimerization of the heterodimers on their way to functional surface expression [16,17]. Although trimeric Env interacts with a broad array of cellular proteins, the essential receptors for primary HIV-1 infection in vivo are the CD4 receptor and the chemokine receptor CCR5 on hematopoietic cells, in particular on T4 helper cells.…”

Section: Cellular Cofactors For Hiv Entrymentioning

confidence: 99%

Targeting Cellular Cofactors in HIV Therapy

Dürr

Keppler

Christ

et al. 2014

Topics in Medicinal Chemistry

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Besides viral proteins cellular factors play a key role in the replication of the human immunodeficiency virus HIV-1. The outcome of virus replication is determined by the balance between the activity of a number of cellular dependency factors and restriction factors. Whereas the first are essential cofactors for diverse steps in the viral replication cycle, the latter counteract virus replication by sensing particular viral components as non-self, often as mediators of the innate immune system. Cellular cofactors include receptors for HIV-1 entry, LEDGF as cofactor for the viral integrase, the RNA helicase DDX3 involved in the nuclear export of unspliced viral RNAs, and diverse cellular kinases that promote viral replication. Cellular restriction factors are often antagonized by HIV-1 accessory proteins in order to counteract their restrictive function on viral replication. Although cellular cofactors in the HIV field are understood as factors promoting viral replication, we add a subchapter on the most important restriction factors (Trim5α, APOBEC3G, SAMHD1, and tetherin/BST-2). Today highly active antiretroviral therapy (HAART) mostly targets HIV proteins like reverse transcriptase, protease, or integrase to specifically interfere with virus replication. However, the identification of cellular cofactors and the increasing knowledge on their mode of action at R. Dürr and U. Dietrich (*) Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany e-mail: duerr@gsh.uni-frankfurt.de; ursula.dietrich@gsh.uni-frankfurt.de O. Keppler Institute of Medical Virology, Goethe University, Frankfurt, Germany e-mail: oliver.keppler@kgu.de F. Christ Laboratory for Molecular Virology and Gene Therapy, K.U. Leuven, Leuven, Belgium e-mail: frauke.christ@med.kuleuven.be E. Crespan, A. Garbelli, and G. Maga Institute of Molecular Genetics, IGM-CNR, Pavia, Italy e-mail: emmanuelecrespan@gmail.com; agarbelli@gmail.com; maga@igm.cnr.it defined steps in the HIV-1 replication cycle have opened new avenues towards the development of HIV-1 inhibitors. Here we summarize the most important cellular factors involved in HIV-1 replication along with therapeutic approaches developed to target them, preferentially without harming their normal cellular function.

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“…The literature describes three main HIV-1 RT inhibitor types, divided by the mechanism of action including: inhibitors of HIV-1 RT polymeric activity; competitive inhibitors subdivided into the class of nucleosides (NRTI) and nucleotide (NtRTI) inhibitors; and non-competitive non-nucleoside inhibitors (NNRTI) (Caffrey 2011, Hatse et al, 1999Menéndez-Arias, 2002).…”

Section: Hiv-1 Reverse Transcriptase (Hiv-1 Rt) -Still An Effective Tmentioning

confidence: 99%

HIV-1 Reverse Transcriptase: a potential target for marine products

Miceli¹,

Souza²,

Rodrigues³

et al. 2012

Rev. bras. farmacogn.

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HIV-1 reverse transcriptase (HIV-1 RT) is a therapeutic target for the treatment of HIV-positive individuals or those already showing AIDS symptoms. In this perspective, the identifi cation of new inhibitors for this enzyme is of great importance in view of the growing viral resistance to the existing treatments. This resistance has compromised the quality of life of those infected with multidrug-resistant strains, whose treatment options are already limited, putting at risk these individuals lives. The literature has recognized marine organisms and their products as natural sources for the identifi cation of new therapeutic options for different pathologies. In this brief review, we consider the structure of HIV-1 RT and its most common inhibitors, as well as some marine diterpenes originally reported as HIV-1 RT inhibitors to encourage the identifi cation and development of new marine antiviral prototypes.

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HIV envelope: challenges and opportunities for development of entry inhibitors

Cited by 74 publications

References 91 publications

Probing the HIV gp120 Envelope Glycoprotein Conformation by NMR

Probing the HIV gp120 Envelope Glycoprotein Conformation by NMR

Targeting Cellular Cofactors in HIV Therapy

HIV-1 Reverse Transcriptase: a potential target for marine products

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