Inhibition of human immunodeficiency virus type 1 infection in a T-cell line (CEM) by new dipeptidyl-peptidase IV (CD26) inhibitors

Abstract

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.