Synthesis of single- and double-chain fluorocarbon and hydrocarbon galactosyl amphiphiles and their anti-HIV-1 activity

Faroux-Corlay, Barbara; Clary, Laurence; Gadras, Catherine; Hammache, Djilali; Greiner, Jacques; Santaella, Catherine; Aubertin, Anne-Marie; Vierling, Pierre; Fantini, Jacques

doi:10.1016/s0008-6215(00)00055-0

Cited by 25 publications

(52 citation statements)

References 65 publications

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“…Pioneer studies have shown that synthetic analogs of GSL could recognize HIV-1 gp120 and inhibit HIV-1 fusion (18,19). These studies and others (20)(21)(22) have shown that the structure of the aglycone of natural and synthetic glycoconjugates can alter the affinity of the GSLligand interaction.…”

mentioning

confidence: 94%

A novel soluble analog of the HIV-1 fusion cofactor, globotriaosylceramide (Gb3), eliminates the cholesterol requirement for high affinity gp120/Gb3 interaction

Mahfoud

Mylvaganam

Lingwood

et al. 2002

Journal of Lipid Research

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We have analyzed the interaction of adamantyl Gb 3 (adaGb 3 ), a semi-synthetic soluble analog of Gb 3 , with HIV-1 surface envelope glycoprotein gp120. In this analog, which was orginally designed to inhibit verotoxin binding to its glycolipid receptor, Gb 3 , the fatty acid chain is replaced with a rigid globular hydrocarbon frame (adamantane). Despite its solubility, adaGb 3 forms monolayers at an air-water interface. Compression isotherms of such monolayers demonstrated that the adamantane substitution resulted in a larger minimum molecular area and a more rigid, less compressible film than Gb 3 . Insertion of gp120 into adaGb 3 monolayers was exponential whereas the gp120/Gb 3 interaction curve was sigmoidal with a lag phase of 40 min. Adding cholesterol into authentic Gb 3 monolayers abrogated the lag phase and increased the initial rate of interaction with gp120. This effect of cholesterol was not observed with phosphatidylcholine or sphingomyelin. In addition, verotoxin-bound adaGb 3 or Gb 3 plus cholesterol was recovered in fractions of comparable low density after ultracentrifugation through sucrose-density gradients in the presence of Triton X-100. The unique biological and physico-chemical properties of adaGb 3 suggest that this analog may be a potent soluble mimic of Gb 3 , providing a novel concept for developing GSL-derived viral fusion inhibitors. -Mahfoud, R., M. Mylvaganam, C.A. Lingwood, and J. Fantini. A novel soluble analog of the HIV-1 fusion cofactor, globotriaosylceramide (Gb 3 ), eliminates the cholesterol requirement for high affinity gp120/Gb 3 interaction.

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confidence: 94%

A novel soluble analog of the HIV-1 fusion cofactor, globotriaosylceramide (Gb3), eliminates the cholesterol requirement for high affinity gp120/Gb3 interaction

Mahfoud

Mylvaganam

Lingwood

et al. 2002

Journal of Lipid Research

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“…Some members of a series of galactose-based fluorinated amphiphiles showed very interesting anti-HIV activity coupled to a very low toxicity, making them candidates for applications in AIDS therapy. [3] Moreover, thanks to their lyophobic character, fluorinated surfactants can be used for the in vitro synthesis of membrane proteins [4] because they can minimize the denaturing propensity of surfactants towards membrane proteins. [5] In recent years, the synthetic challenge to find cationic structures good enough for applications in gene therapy light on the aggregation process.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Highly Fluorinated Gemini Pyridinium Surfactants

Quagliotto¹,

Barolo²,

Barbero³

et al. 2009

Eur J Org Chem

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A series of fluorinated gemini pyridinium amphiphiles have been prepared, purified and fully characterized. The synthesis was performed using alkyl trifluoromethanesulfonates as the quaternizing agents, provided very good yields and overcame problems arising with other less powerful alkylating agents. The use of different characterization techniques, such as conductivity and surface tension measurements, shed

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“…In another study analogs of GalCer were synthesized which consist of single and double hydrocarbon and/or fluorocarbon chain beta-linked to galactose and galactosamine. In vitro these compounds have low anti-HIV activity (IC 50 in the 20-220 µM range) [79]. This approach was furthered to create new galactosyl amphiphiles which contain one or two galactose residues.…”

Section: Antiviral Implicationsmentioning

confidence: 99%

Dissecting HIV Fusion: Identifying Novel Targets for Entry Inhibitors

Finnegan¹,

Blumenthal²

2006

IDDT

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Significant momentum has been recently generated in understanding the HIV fusion process. This has led to the development of a host of HIV entry inhibitors which are currently in preclinical and/or clinical development or have been approved for clinical use. In this review we update our understanding of HIV fusion, specifically highlighting novel mechanisms and agents that inhibit this process. Major focus will be placed on three key areas. Initially viral attachment will be reviewed as recent developments in this field emphasize the importance of understanding cell type specific interactions with HIV. This has aided in identifying promising targets for the development of attachment inhibitors. Secondly, we will review the role of cellular lipids in HIV entry. Glycosphingolipids have been shown to interact with different components of the HIV fusion machinery and agents that perturb glycosphingolipid biosynthesis have inhibitory effects on HIV fusion. Likewise, manipulating ceramide biosynthesis also inhibits HIV fusion. Here, we describe how manipulating cellular lipids inhibits HIV fusion and how lipid biosynthesis can be modulated to potentially prevent HIV infection. We end this review by discussing the notion of targeting select host cell proteins for HIV therapy. We will review the role of the cellular proteins PDI, defensins and cytoskeletal proteins in facilitating the fusion reaction. As our understanding of the HIV fusion process increases, the identification of targets for developing entry inhibitors becomes more diverse. Given the rapid resistance of HIV to any selective pressure this is an important avenue in the advancement of drug therapy.

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Synthesis of single- and double-chain fluorocarbon and hydrocarbon galactosyl amphiphiles and their anti-HIV-1 activity

Cited by 25 publications

References 65 publications

A novel soluble analog of the HIV-1 fusion cofactor, globotriaosylceramide (Gb3), eliminates the cholesterol requirement for high affinity gp120/Gb3 interaction

A novel soluble analog of the HIV-1 fusion cofactor, globotriaosylceramide (Gb3), eliminates the cholesterol requirement for high affinity gp120/Gb3 interaction

Synthesis and Characterization of Highly Fluorinated Gemini Pyridinium Surfactants

Dissecting HIV Fusion: Identifying Novel Targets for Entry Inhibitors

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