Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs

Curr Pharm Des. 2004;10(17):2041-62. doi: 10.2174/1381612043384312.


Combination therapy with reverse transcriptase and protease inhibitors greatly reduces morbidity and mortality in HIV-1-infected individuals. However, current anti-retroviral treatment cannot eradicate the virus from infected individuals and is often limited by the emergence of drug-resistant HIV-1 strains and long-term toxicity. These problems emphasize the need to develop new anti-HIV-1 drugs targeting different steps in the viral replication cycle. HIV-1 entry into host cells represents a complex sequence of events involving several viral and cellular proteins that are potential drug targets. In particular, HIV-1 entry requires a sequential interaction of the viral envelope glycoprotein gp120 with CD4 and a co-receptor on the host cell plasma membrane. The CC-chemokine receptor 5 (CCR5) and the CXC-chemokine receptor 4 (CXCR4) are the primary HIV-1 co-receptors in vivo, and are attractive targets for the development of new anti-HIV-1 drugs. CCR5 and CXCR4 belong to the protein superfamily of G protein-coupled receptors (GPCRs). Many orally bioavailable small-molecules interact with specific GPCRs and many existing drugs are orally bioavailable small-molecule agonists or antagonists of GPCRs. Several small-molecule antagonists of CCR5 and CXCR4 that block chemokine binding and HIV-1 entry have been identified in recent years and are now in pre-clinical or clinical development as drug candidates. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Binding Sites
  • CCR5 Receptor Antagonists*
  • Clinical Trials, Phase I as Topic
  • HIV-1 / drug effects
  • Humans
  • Receptors, CCR5 / chemistry
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / chemistry
  • Receptors, CXCR4 / metabolism
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Receptors, CCR5
  • Receptors, CXCR4