ABSTRACT
The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
Subject(s)
Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV-1/drug effects , Receptors, CXCR4/antagonists & inhibitors , Animals , CHO Cells , Calcium Signaling/drug effects , Cell Line , Cells, Cultured , Chemokine CXCL12/pharmacology , Cricetinae , Cricetulus , Fluorescent Antibody Technique , Humans , Mice , Mice, SCID , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Receptors, CXCR4/metabolismABSTRACT
CXC chemokine receptor-4, the receptor for stromal cell-derived factor-1alpha as well as human immunodeficiency virus type 1, belongs to the chemokine receptor family and has been shown to play a critical role in directing the migration of cancer cells to sites of metastasis as well as human immunodeficiency virus type 1 infection. We had previously reported that a duodenally absorbable CXC chemokine receptor-4 antagonist, KRH-1636, showed a potent anti-human immunodeficiency virus type 1 activity both in vivo and in vitro. In this study, we initially examined the effect of the compound and its derivatives on stromal cell-derived factor-1alpha-mediated chemotaxis of cancer cells in order to evaluate if they could be applicable as a novel inhibitor of cancer metastasis. We found that both KRH-2731 and KRH-3955 were highly potent antagonists of stromal cell-derived factor-1alpha-mediated chemotaxis, i.e. the derivatives exhibited 50% effective concentrations of less than 10 nM, for more than 1000-fold efficacy improvement over the prototype KRH-1636. We further demonstrated the greater anti-human immunodeficiency virus type 1 efficacy of the derivatives compared with the original KRH-1636. Taken together, the KRH-1636 derivatives KRH-2731 and KRH-3955 may be promising as a novel inhibitory drug for cancer metastasis as well as for human immunodeficiency virus type 1 infection.
Subject(s)
Anti-HIV Agents/pharmacology , Chemokine CXCL12/pharmacology , Chemotaxis, Leukocyte/drug effects , HIV-1/drug effects , Receptors, CXCR4/antagonists & inhibitors , Arginine/analogs & derivatives , Arginine/pharmacology , Benzylamines/pharmacology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Dose-Response Relationship, Drug , HIV Infections/prevention & control , Humans , Imidazoles/pharmacology , Inhibitory Concentration 50 , Jurkat Cells , Pyridines/pharmacologyABSTRACT
CXCR4-tropic (X4) human immunodeficiency virus type 1 (HIV-1) does not efficiently infect and replicate in severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood mononuclear cells, termed "hu-PBL-SCID mice," due to, at least in part, relatively low levels of expression of the CXCR4 coreceptor. To overcome this limitation, interleukin (IL)-4-transgenic hu-PBL-SCID mice were derived that spontaneously synthesized human IL-4, which has been shown to enhance CXCR4 expression and promote X4 virus infection in vitro. Experiments reported here show that (1) synthesis of human IL-4 in vivo augmented CXCR4 expression on human CD4(+) lymphocytes and importantly led to productive infection of not only X4 HIV-1(NL4-3) but also multidrug-resistant primary clinical isolates and that (2) the in vivo infection could be significantly blocked by the administration of a CXCR4 antagonist. Altogether, IL-4-transgenic hu-PBL-SCID mice provide a useful model for X4 HIV-1 study and testing/screening of anti-X4 viral drugs.
Subject(s)
Disease Models, Animal , HIV Infections/virology , HIV-1/drug effects , Interleukin-4/genetics , Mice, SCID/genetics , Receptors, CXCR4/genetics , Animals , Arginine/analogs & derivatives , Arginine/pharmacology , HIV Infections/drug therapy , Humans , Interleukin-4/metabolism , Mice , Mice, Transgenic , Pyridines/pharmacology , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolismABSTRACT
A low molecular weight nonpeptide compound, KRH-1636, efficiently blocked replication of various T cell line-tropic (X4) HIV type 1 (HIV-1) in MT-4 cells and peripheral blood mononuclear cells through the inhibition of viral entry and membrane fusion via the CXC chemokine receptor (CXCR)4 coreceptor but not via CC chemokine receptor 5. It also inhibited binding of the CXC chemokine, stromal cell-derived factor 1alpha, to CXCR4 specifically and subsequent signal transduction. KRH-1636 prevented monoclonal antibodies from binding to CXCR4 without down-modulation of the coreceptor. The inhibitory effect against X4 viral replication by KRH-1636 was clearly reproduced in the human peripheral blood lymphocytesevere combined immunodeficiency mouse system. Furthermore, this compound was absorbed into the blood after intraduodenal administration as judged by anti-HIV-1 activity and liquid chromatography MS in the plasma. Thus, KRH-1636 seems to be a promising agent for the treatment of HIV-1 infection.
