Serious Doubts on Safety and Efficacy of CCR5 Antagonists

  title={Serious Doubts on Safety and Efficacy of CCR5 Antagonists},
  author={Sophia Horster and Frank D. Goebel},
Entry inhibitors constitute a new drug class for treatment of HIV-1 infection. They are divided into subclasses, each aiming at a crucial step during the complex event of HIV entry into the target cell. Attachment inhibitors are designed to prevent the HIV envelope glycoprotein gp120 attachment to CD4 receptors, co-receptor antagonists to inhibit, e.g. CCR5 co-receptor binding after conformational changes within gp120 and fusion inhibitors to hamper fusion of viral and cellular membranes, the… 
In general, maraviroc at dosages of up to 300mg twice daily was well tolerated in treatment-experienced patients infected with R5-tropic HIV-1 and a significant difference was maintained at 48 weeks in MOTIVATE-1.
Is gene therapy a good therapeutic approach for HIV-positive patients?
Despite advances and options available in gene therapy for HIV-1 infection, its application in the clinical setting has been challenging. Although published data from HIV-1 clinical trials show
Role of 3D Structures in Understanding, Predicting, and Designing Molecular Interactions in the Chemokine Receptor Family
An overview of pre- and post-structure efforts in understanding, predicting, and designing chemokine receptor interactions with small molecules and peptides, chemokines, and HIV gp120 proteins is provided, as well as structure-guided insights regarding chemokin receptor dimerization and the impact of structures on rational molecular design initiatives.
Neue Arzneimittel 2007
Im Jahre 2007 wurden 31 Arzneimittel mit neuen Wirkstoffen in Deutschland auf den Markt gebracht. Damit liegt die Zahl der Neueinfuhrungen wieder etwas hoher als im Vorjahr (28 Wirkstoffe) und in


Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs.
This review discusses structural and functional aspects of these compounds and summarizes recent insights into how small-molecule antagonists interact with CCR5 and CXCR4, focusing on drug development programs that are well documented in the scientific literature.
Resistance to CCR5 antagonists
  • M. Westby
  • Biology, Medicine
    Current opinion in HIV and AIDS
  • 2007
New ways of interpreting phenotypic resistance data may be required for CCR5 antagonists, aided by a consideration of receptor pharmacology rather than enzyme kinetics, as growing in-vitro evidence identifies an alternative pathway to resistance.
Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity
Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel, indicating potential for an excellent clinical safety profile.
HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use
HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of C CR5 for entry and then probably by using the drug-bound form of the receptor.
Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults
873140 demonstrated potent antiretroviral activity and was well tolerated following short-term monotherapy in HIV-infected adults and support further evaluation in Phase 2b/3 studies.
Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1
Results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach for HIV-1-positive individuals prescreened for the absence of CXCR4-using virus.
Genetic and Phenotypic Analyses of Human Immunodeficiency Virus Type 1 Escape from a Small-Molecule CCR5 Inhibitor
A series of mutant viruses were made and it was found that full AD101 resistance was conferred by four amino acid changes in V3, which alter how the HIV-1 Env complex interacts with CCR5.
A genotypic analysis of HIV-1 sequences from emerging resistant virus after in vitro serial passage with the CCR5 antagonist maraviroc (UK-427857). 3rd European HIV Drug Resistance Workshop
  • March 30-April
  • 2005
Isolation of TAK-779-resistant HIV-1 from an R5 HIV-1 GP120 V3 Loop Library*
Results indicated that a certain structure of the V3 loop containing amino acid substitutions derived from 31 R5 viruses can contribute to the acquisition of resistance to entry inhibitors binding to CCR5.