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Obligatory involvem...
Obligatory involvement of CD26/dipeptidyl peptidase IV in the activation of the antiretroviral tripeptide glycylprolylglycinamide (GPG-NH(2)).
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Balzarini, Jan (författare)
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- Andersson, Elin, 1975 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för laboratoriemedicin, Avdelningen för klinisk virologi,Institute of Laboratory Medicine, Dept of Clinical Virology
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Schols, Dominique (författare)
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Proost, Paul (författare)
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Van Damme, Jo (författare)
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- Svennerholm, Bo, 1949 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för laboratoriemedicin, Avdelningen för klinisk virologi,Institute of Laboratory Medicine, Dept of Clinical Virology
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- Horal, Peter, 1955 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för laboratoriemedicin, Avdelningen för klinisk virologi,Institute of Laboratory Medicine, Dept of Clinical Virology
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- Vahlne, Anders (författare)
- Karolinska Institutet
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(creator_code:org_t)
- Elsevier BV, 2004
- 2004
- Engelska.
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Ingår i: The international journal of biochemistry & cell biology. - : Elsevier BV. - 1357-2725. ; 36:9, s. 1848-59
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Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- Adenosine Deaminase
- antagonists & inhibitors
- metabolism
- Animals
- Anti-Retroviral Agents
- metabolism
- pharmacology
- Antigens
- CD26
- metabolism
- Cattle
- Cells
- Cultured
- Enzyme Inhibitors
- pharmacology
- Fetal Blood
- enzymology
- Glycoproteins
- antagonists & inhibitors
- metabolism
- HIV-1
- drug effects
- HIV-2
- drug effects
- Humans
- Isoleucine
- analogs & derivatives
- pharmacology
- Oligopeptides
- metabolism
- pharmacology
- Proline
- metabolism
- Serum
- enzymology
- T-Lymphocytes
- enzymology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Balzarini, Jan
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Andersson, Elin, ...
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Schols, Dominiqu ...
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Proost, Paul
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Van Damme, Jo
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Svennerholm, Bo, ...
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visa fler...
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Horal, Peter, 19 ...
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Vahlne, Anders
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- Artiklar i publikationen
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The internationa ...
- Av lärosätet
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Göteborgs universitet
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Karolinska Institutet