Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs.
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.
Box 187, Rockefeller University, 1230 York Ave., New York, NY 10021, USA.
Christoph
C
Seibert
Thomas P
TP
Sakmar
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D017321:Clinical Trials, Phase I as Topic; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D019713:Receptors, CCR5 / Q000737:chemistry / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D019713:Receptors, CCR5; D019718:Receptors, CXCR4