The orally bioavailable allosteric CXCR4 HIV-1 entry inhibitor AMD11070

In order to enter and infect human cells HIV must bind to the CD4 receptor in addition to either CXCR4 or CCR5. {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 was the first orally available small molecule inhibitor of CXCR4 to enter the clinic. Here, we report in detail the molecular pharmacology of {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 which is a potent inhibitor of X4 HIV-1 replication in various CD4+ T cell lines, CXCR4-transfected cell lines and in PBMC (IC50 values of 14 ± 3 nM). In addition, {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 potently inhibited cell fusion between a CHO-K1 cell line expressing viral gp120 and the P4-R5 MAGI cells which express CD4 and CXCR4 with an IC50 of 1.5 ± 0.3 nM. No antiviral activity was observed with {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 against CCR5-using (R5) HIV-1 replication. Using CD4+ T cell lines that endogenously express CXCR4 we demonstrate that {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 is an antagonist of CXCL-12 (SDF-1a)-ligand binding (IC50: 12.5 ± 1.3 nM), inhibits CXCL-12-mediated signaling (IC50: 9 ± 2 nM) and that it inhibits CXCL-12-mediated chemotaxis (IC50: 19 ± 4 nM). {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 does not inhibit chemokine-induced Ca2+-signaling in cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, demonstrating the compound selectivity for the CXCR4 receptor. In addition, {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 is able to inhibit the SDF-1beta isoform interactions with CXCR4 and N-terminal truncated variants of CXCR4 with equal potency as to the wild type CXCR4 receptor. These data indicate that {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 is an allosteric antagonist of CXCR4. A proof-of-concept clinical trial has shown that {type:entrez-protein,attrs:{text:AMD11070,term_id:985559755,term_text:AMD11070}}AMD11070 can reduce the viral load of X4 HIV-1 in HIV-1-infected persons. Together these data further support to the potential beneficial role of orally bioavailable CXCR4 inhibitors as a therapeutic option for HIV/AIDS treatment.