Access denied? The status of co-receptor inhibition to counter HIV entry

  title={Access denied? The status of co-receptor inhibition to counter HIV entry},
  author={Priscilla Biswas and G. Tambussi and Adriano Lazzarin},
  journal={Expert Opinion on Pharmacotherapy},
  pages={923 - 933}
As resistance and long-term metabolic abnormalities hamper the efficacy of previous drugs against HIV-1, targeting of HIV co-receptors represents an exciting new frontier for antiretroviral therapeutics. CCR5 inhibitors are most likely to be the new available drugs within the class of entry inhibitors. This paper reviews the most recent clinical data available on the small-molecule compounds vicriviroc and maraviroc and on the antibodies PRO 140 and CCR5mAb004, as well as some novel genetic… 

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

A survey of the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection finds the dual C CR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies.

Inhibitors of HIV-1 entry.

Although already in clinical use, this approach to HIV therapy is still being investigated to produce new promising antiviral compounds and the latest advances in this area are reviewed.

Novel Targets for Antiretroviral Therapy

Two new classes of antiretroviral medications for HIV treatment, the CCR5 and integrase inhibitors, have recently been approved for use in patients in whom previous HIV treatment regimens have failed.

Maraviroc, risks and benefits: a review of the clinical literature

Its proven efficacy in cases of virological failure and three-class ARV-drug resistance is a major benefit of maraviroc compared to the so far commercially available drugs from existing (non-) nucleoside reverse transcriptase inhibitors ([N]NRTI) and protease inhibitors drug-classes, particularly in times of increasing ARV drug resistance.

Progress in HIV-1 Prevention, Control and Treatment: Genetic Manipulation or Pharmacological Blockade of Chemokine Receptor 5?

The current trend in HIV-1 control, prevention and treatment is highlighted, and the two promising approaches are compared: Genetic manipulation of CCR5 gene and the pharmacological blockade of C CR5 using chemokine receptor antagonists.

Targeting protein-protein interactions for HIV therapeutics

This review article discusses the general method used to identify anti-HIV drugs that function through targeting protein–protein interactions, and discusses the currently known cellular cofactors that may serve as targets in future drugs screens.

Closing two doors of viral entry: Intramolecular combination of a coreceptor- and fusion inhibitor of HIV-1

A novel strategy in which two inhibitors of HIV viral entry were incorporated into a single molecule which may offer potential for improved pharmacokinetic parameters for a fusion inhibitor in humans and the combination of two active antiviral agents in one molecule may provide better durability in controlling the emergence of resistant viruses.

Recent progress in antiretrovirals--lessons from resistance.




Oral CCR5 inhibitors: will they make it through?

The therapeutic armamentarium against HIV has recently gained a drug belonging to a novel class of antiretrovirals, the entry inhibitors, and promising small-molecule, orally bioavailable CCR5 antagonists are under development for the treatment of HIV-1 infection.

HIV's response to a CCR5 inhibitor: I'd rather tighten than switch!

  • J. FarberE. Berger
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
The mechanism by which HIV-1 escapes in vitro from a low molecular weight inhibitor targeted against the CCR5 coreceptor is analyzed, which raises important questions not only about the clinical applications of this novel class of anti-HIV agents, but also about coreceptor usage in HIV- 1 disease.

Assessing chemokine co-receptor usage in HIV

The development of rapid, reliable tropism assays has been useful in advancing the development of novel antiviral agents and defining the role of these assays in routine clinical practice will be the next important step.

Monoclonal antibodies and small-molecules as distinct subclasses of CCR5-targeted therapies for HIV-1

The findings suggest that mAb and small-molecule CCR5 drugs may provide complementary HIV-1 treatment subclasses.

Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes

This work describes the discovery and development of enfuvirtide (Fuzeon), the first drug to inhibit the entry of HIV-1 into host cells, and the growing problem of the emergence of HIV strains that are resistant not only to individual drugs, but to whole drug classes.

Enfuvirtide: the first HIV fusion inhibitor

  • A. Lazzarin
  • Biology
    Expert opinion on pharmacotherapy
  • 2005
Targeting viral fusion or entry will hopefully provide respite for patients who have limited treatment options following the emergence of multi-drug resistance.

Potent Antiviral Synergy between Monoclonal Antibody and Small-Molecule CCR5 Inhibitors of Human Immunodeficiency Virus Type 1

High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels, suggesting that synergy occurs at the level of receptor binding.

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.

Sequencing antiretroviral drugs for long-lasting suppression of HIV replication.

Although the question is still controversial, NNRTIs may best be used as second-line options in both simplification and salvage regimens, because the optimal timing for starting entry inhibitors during the course of HIV disease has not yet been fully elucidated.