Inhibition of human immunodeficiency virus type 1 infection in a T-cell line (CEM) by new dipeptidyl-peptidase IV (CD26) inhibitors.
Phenylalanyl-pyrrolidine-2 nitrile (Phe-pyrr-2-CN) and arginyl(PMC)-pyrrolidine-2-nitrile (Arg(PMC)-pyrr-2-CN) are two dipeptidyl peptidase IV/CD26 (DPP-IV/CD26) inhibitors designed and synthesized by our group. These two compounds suppress the enzymatic activity of DPP-IV/CD26 in a competitive and reversible manner. Pretreatment of CEM cells with either of the compounds yielded a marked albeit transient reduction of HIV infection, as measured by HIV1 p24 production, RT activity and syncytium formation. The ID50 value of the Phe-Pyrr-2-CN and Arg(PMC)-pyrr-2-CN in HIV1 inhibition was 5.3 microM and 2.4 microM, respectively. Administration of either of the DPP-IV/CD26 inhibitors 1 h after HIV1 infection did not suppress HIV1 production. An analog whose inhibitory activity toward DPP-IV/CD26 was abolished by blocking the N-terminal of Phe-pyrr-2-CN with the 9-fluorenymethyloxycarbonyl (Fmoc) group had no effect on HIV1 infection. An additive effect of HIV1 inhibition was observed in combinations of either of the DPP-IV/CD26 inhibitors with CD4 monoclonal antibody. These results suggest that DPP-IV/CD26 enzymatic activity may play a role in facilitating HIV1 infection of human CD4+T cells at the entry process. DPP-IV/CD26 inhibitors may therefore have potential use in combination with other drugs to prevent HIV1 transmission.
Jiang
J D
JD
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Wilk
S
S
Li
J
J
Zhang
H
H
Bekesi
J G
JG
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D002459:Cell Fusion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D016655:HIV Core Protein p24 / Q000032:analysis; D054303:HIV Reverse Transcriptase / Q000032:analysis; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D011480:Protease Inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology* / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D011480:Protease Inhibitors; D011759:Pyrrolidines; C108294:arginyl(PMC)-pyrrolidine-2-nitrile; C108293:phenylalanyl-pyrrolidine-2-nitrile; D010649:Phenylalanine; D001120:Arginine; D054303:HIV Reverse Transcriptase; D018819:Dipeptidyl Peptidase 4