Maraviroc: A CCR5-receptor antagonist for the treatment of HIV-1 infection

Lieberman-Blum, Sharon S.; Fung, Horatio B.; Bandrés, Juan C.

doi:10.1016/s0149-2918(08)80048-3

Cited by 139 publications

(100 citation statements)

References 32 publications

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“…The second, denoted fusion inhibitors (FIs), binds to the gp41 N-HR coiled coil or C-HR segments, blocking their ability to form the TOH (25)(26)(27)(28)(29)(30). The clinically approved drugs maraviroc (CoRA) and enfuvirtide (FI, also denoted T20) are currently employed as second line therapy and used when traditional highly active antiretroviral therapy (HAART) becomes ineffective (31)(32)(33)(34).…”

mentioning

confidence: 99%

Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors

Ahn

Root

2017

Journal of Biological Chemistry

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confidence: 99%

Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors

Ahn

Root

2017

Journal of Biological Chemistry

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“…Already, approval of two HIV-1 entry inhibitor drugs, enfuvirtide (Fuzeone; T-20) (4) and maraviroc (Selzentry) (5,6), has validated entry prevention as a successful strategy in antiviral drug design. Entry of the HIV-1 type is initiated by binding of the HIV-1 envelope glycoprotein gp120 to the primary cell surface receptor CD4; this induces the conformational changes to gp120 necessary for its subsequent binding to the cellular coreceptors CCR5 and CXCR4.…”

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confidence: 99%

Binding Mode Characterization of NBD Series CD4-Mimetic HIV-1 Entry Inhibitors by X-Ray Structure and Resistance Study

Curreli

Kwon

Zhang

et al. 2014

Antimicrob Agents Chemother

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We previously identified two small-molecule CD4 mimetics-NBD-556 and NBD-557-and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies. Mechanism studies indicated that they act as CD4 agonists, a potentially unfavorable therapeutic trait, in that they can bind to the gp120 envelope glycoprotein and initiate a similar physiological response as CD4. However, one of the compounds, NBD-09027, exhibited reduced agonist properties, in both functional and biophysical studies. To understand the binding mode of these inhibitors, we first generated HIV-1-resistant mutants, assessed their behavior with NBD compounds, and determined the X-ray structures of two inhibitors, NBD-09027 and NBD-10007, in complex with the HIV-1 gp120 core at ϳ2-Å resolution. Both studies confirmed that the NBD compounds bind similarly to NBD-556 and NBD-557 by inserting their hydrophobic groups into the Phe43 cavity of gp120. The basic nitrogen of the piperidine ring is located in close proximity to D368 of gp120 but it does not form any H-bond or salt bridge, a likely explanation for their nonoptimal antagonist properties. The results reveal the structural and biological character of the NBD series of CD4 mimetics and identify ways to reduce their agonist properties and convert them to antagonists.

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“…VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and it was shown that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Maraviroc (UK-427,857) is a selective CCR5 cellular receptor antagonist with potent anti-HIV-1 activity (Dorr et al, 2005, Lieberman-Blum et al, 2008. It serves to intercept viral-host protein-protein interactions mediating entry (Friedrich et al, 2011).…”

Section: Inhibitors Of Viral Attachment/entrymentioning

confidence: 99%