title: Obligatory involvement of CD26/dipeptidyl peptidase IV in the activation of the antiretroviral tripeptide glycylprolylglycinamide (GPG-NH(2)).
abstract: GPG-NH2 and G-NH2 are highly selective antiretroviral agents in cell culture, and both compounds inhibit HIV replication in CEM cell cultures to an equal extent (50% effective concentration: approximately 30 microM). The lymphocyte surface glycoprotein marker CD26, which is identical to dipeptidyl peptidase IV, efficiently converted GPG-NH2 to G-NH2 releasing the dipeptide GP-OH. The closely related QPG-NH2 derivative was also inhibitory to HIV, presumably by the dipeptidyl peptidase IV (DPP IV)-catalyzed release of G-NH2. In contrast, the cyclic pQPG-NH2 derivative in which the glutamine at the amino terminal position of QPG-NH2 was replaced by pyroglutamine and which is resistant to cleavage by purified CD26, was devoid of antiviral activity. CD26 is abundantly expressed on a variety of HIV target cells and is also present in serum of bovine, murine and human origin. The CD26/DPP IV enzymatic activity in serum and in cell suspensions could be efficiently inhibited by the CD26/DPP IV inhibitor L-isoleucinepyrrolidine (IlePyr) with 50% inhibitory concentrations ranging between 20 and 100 microM. When combined in HIV-1-infected cell cultures, IlePyr and Diprotin A (DP-A), another CD26/DPP IV inhibitor, abrogated the antiviral activity of GPG-NH2 but not of G-NH2. Therefore, it was concluded that the anti-HIV drug GPG-NH2 is not active as such, but rather behaves as a prodrug that must be obligatorily cleaved by CD26/DPP IV to G-NH2 to exert its antiretroviral activity. This is the first demonstration of a lymphocyte activation/differentiation marker (i.e. CD26) that plays a direct regulatory and indispensable role in the eventual antiretroviral activity of small synthetic molecules such as the antiretroviral (pro)drug GPG-NH2.
authors.affiliation: Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Elin
authors.initials: E
authors.lastname: Andersson
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
authors.forename: Bo
authors.initials: B
authors.lastname: Svennerholm
authors.forename: Peter
authors.initials: P
authors.lastname: Horal
authors.forename: Anders
authors.initials: A
authors.lastname: Vahlne
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D044966:Anti-Retroviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005312:Fetal Blood / Q000201:enzymology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology*; D011392:Proline / Q000378:metabolism; D044967:Serum / Q000201:enzymology; D013601:T-Lymphocytes / Q000201:enzymology
chemical_list: D058892:Adenosine Deaminase Inhibitors; D044966:Anti-Retroviral Agents; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D009842:Oligopeptides; D007532:Isoleucine; C425285:glycylprolylglycine amide; C041445:diprotin A; D011392:Proline; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase