krh-1636 and HIV-Infections

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.

Topics: Anti-HIV Agents; Arginine; Benzylamines; CD4-Positive T-Lymphocytes; Chemokine CXCL12; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; HIV Infections; HIV-1; Humans; Imidazoles; Inhibitory Concentration 50; Jurkat Cells; Pyridines; Receptors, CXCR4

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.

Topics: Animals; Arginine; Disease Models, Animal; HIV Infections; HIV-1; Humans; Interleukin-4; Mice; Mice, SCID; Mice, Transgenic; Pyridines; Receptors, CXCR4