Studies on the structure-activity relationship of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists. Part 2: Discovery of highly potent anti-HIV agents.

Modification of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists revealed that introducing a fluoro group at the 3-position of the 3-phenyl group to reduce metabolism did not adversely affect the high potency against HIV infection, and that replacing the piperidine ring with a tropane ring could deliver the most potent anti-HIV agents. Stereochemistry of the substituted tropane ring is essential for maintaining the potent anti-HIV activity because only exo-isomers displayed subnanomolar whole cell activity.

Studies on the structure-activity relationship of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists. Part 1: Tuning the N-substituents.

A novel series of CCR5 antagonists has been identified, utilizing the lead, nifeviroc, which were further modified based on bioisosteric principles. Lead optimization was pursued by balancing potential toxicity and potency. Potent analogues with low toxic properties were successfully developed by formation of urea and amide bonds at the nitrogen at position 4- of the pyrrolidine ring.

Preferential infection of dendritic cells during human immunodeficiency virus type 1 infection of blood leukocytes.

Human immunodeficiency virus type 1 (HIV-1) transmission by the parenteral route is similar to mucosal transmission in the predominance of virus using the CCR5 coreceptor (R5 virus), but it is unclear whether blood dendritic cells (DCs), monocytes, or T cells are the cells initially infected. We used ex vivo HIV-1 infection of sorted blood mononuclear cells to model the in vivo infection of blood leukocytes. Using quantitative real-time PCR to detect full-length HIV-1 DNA, both sorted CD11c(+) myeloid and CD11c(-) plasmacytoid DCs were more frequently infected than other blood mononuclear cells, including CD16(+) or CD14(+) monocytes or resting CD4(+) T cells.

Heterogeneity of freshly isolated human tonsil dendritic cells demonstrated by intracellular markers, phagocytosis, and membrane dye transfer.

Background: Heterogeneity within human dendritic cells (DCs) has been described but its functional relationships to cells of macrophage lineage and its role in human immunodeficiency virus (HIV) infection in vivo remain unclear.

Methods: Tonsil macrophages and DCs were isolated from low-density cells by negative selection and DCs were sorted into myeloid and plasmacytoid populations using antibodies to CD11c or CD123. Phagocytosis of latex beads and uptake of dye-labeled target cells were compared by flow cytometry and CD68 and S-100 by immunofluorescence on cytospins of sorted cells.