Non-substrate peptides influencing dipeptidyl peptidase IV/CD26 activity and immune cell function.

Abstract

Investigations using inhibitors of dipeptidyl peptidase IV (DP IV) activities and DP IV-/- mice indicated an immunoregulatory role of DP IV that could not be compensated by DP IV-like enzymes. The HIV-1 Tat protein was identified as the first natural inhibitor of DP IV and as immunosuppressor. This review summarizes our investigations on the identification of the amino acid motif of Tat responsible for DP IV inhibition and of endogenous DP IV-inhibitory ligands that suppress immune cell activation. Examinations on numerous peptides carrying the N-terminal Xaa-Xaa-Pro motif of Tat revealed that tryptophan at position two strongly enhanced DP IV inhibition and immunosuppression. Here, we present evidence that the thromboxane A2 receptor exposing N-terminal Met-Trp-Pro at the cell surface could be a potential endogenous, inhibitory DP IV ligand. Moreover, our data suggest that the major envelope proteins p37k of the orthopoxviruses variola virus and vaccinia virus, as well as the B2L antigen of the parapoxvirus orf, that also carry N-terminal Met-Trp-Pro, could mediate immunosuppressive effects. Further examinations are in progress to identify new physiologic, inhibitory DP IV ligands and to enlighten the mechanism underlying the DP IV-mediated effects.

• Authors: Sabine Wrenger, Jurgen Faust, Carmen Mrestani-Klaus, Wolfgang Brandt, Anja Thielitz, Klaus Neubert, Dirk Reinhold
• Journal: Frontiers in bioscience : a journal and virtual library (Front Biosci) Vol. 13 Pg. 3194-201 (May 01 2008) ISSN: 1093-9946 [Print] United States
• PMID: 18508427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Peptides
• tat Gene Products, Human Immunodeficiency Virus
• Dipeptidyl Peptidase 4

Topics

• Animals
• Dipeptidyl Peptidase 4 (immunology, metabolism)
• Dipeptidyl-Peptidase IV Inhibitors
• HIV-1 (immunology, metabolism)
• Immunosuppression Therapy
• Kinetics
• Lymphocyte Activation
• Mice
• Mice, Knockout
• Peptides (metabolism, pharmacology)
• Substrate Specificity
• T-Lymphocytes (immunology)
• tat Gene Products, Human Immunodeficiency Virus (metabolism)