Magdeburg, Germany
Magdeburg, Germany

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Biton A.,Hebrew University of Jerusalem | Ansorge S.,IMTM GmbH | Bank U.,IMTM GmbH | Tager M.,IMTM GmbH | And 3 more authors.
Immunobiology | Year: 2011

Dipeptidyl peptidase IV (DP IV)/CD26 and aminopeptidase N (APN)/CD13 family enzymes control T cell functions. We have previously defined these peptidases as targets to treat autoimmune disease, but the underlying mechanism is unclear. Here, we determined the effect of enzymatic inhibitors on chemotaxis by CD4 + effector T (Teff) cells. Exposure of Teff cells to the inhibitor of DP IV activity, Lys[Z(NO2)]-pyrrolidide (LZNP) and the inhibitor of APN activity, actinonin has no effect on chemotaxis or unstimulated cell migration, even at high inhibitor concentrations. LZNP and actinonin also fail to suppress migration of unfractionated lymph node cells, excluding paracrine action through other leukocyte subsets. In contrast, inhibition of DP IV and APN activities selectively suppresses lymphocyte functions including proliferation and production of the T helper type (Th)1 cytokine IFN-γ, the Th17 cytokine IL-17, as well as TNF-α, and ameliorates autoimmunity in vivo. The present results combined with previous studies suggest that LZNP and actinonin do not prevent migration of pathogenic Teff cells into target tissues, but rather suppress disease through inhibitor induced release of TGF-β by T cells at the site of inflammation. © 2011 Elsevier GmbH.


Bank U.,IMTM GmbH | Heimburg A.,IMTM GmbH | Wohlfarth A.,IMTM GmbH | Koch G.,IMTM GmbH | And 7 more authors.
Biological Chemistry | Year: 2011

The discovery of the DP4-related enzymes DP8 and DP9 raised controversial discussion regarding the physiological and pathophysiological function of distinct members of the DP4 family. Particularly with regard to their potential relevance in regulating immune functions, it is of interest to know which role the subcellular distribution of the enzymes play. Synthetic substrates as well as low molecular weight inhibitors are widely used as tools, but little is yet known regarding their features in cell experiments, such as their plasma membrane penetration capacity. The fluorogenic substrates Gly-Pro-AMC or (Ala-Pro)2-R110 predominantly detect plasma membrane-bound activities of viable cells (less than 0.1% of fluorochromes R110 or AMC inside viable cells after 1 h incubation). Additionally, the selective and nonselective DP8/9 inhibitors allo-Ile-isoindoline and Lys wZ(NO2)x-pyrrolidide were found to be incapable of passing the plasma membrane easily. This suggests that previously reported cellular effects are not due to inhibition of the cytosolic enzymes DP8 or DP9. Moreover, our enzymatic studies with viable cells provided evidence that DP8 and/or DP9 are also present on the surface of immune cells under certain circumstances and could gain relevance particularly in the absence of DP4 expression. In summary, in cells which do express DP4 on the surface, this archetypical member of the DP4 family is the most relevant peptidase in the regulation of cellular functions. Copyright © by Walter de Gruyter.


Ansorge S.,IMTM GmbH | Nordhoff K.,IMTM GmbH | Bank U.,IMTM GmbH | Heimburg A.,IMTM GmbH | And 5 more authors.
Biological Chemistry | Year: 2011

The cellular dipeptidyl peptidase IV (DPIV, E.C.3.4.14.5, CD26) is a type II membrane peptidase with various physiological functions. Our main knowledge on DPIV comes from studies of soluble DPIV which plays a role in regulation of glucose homeostasis by inactivation of the incretins glucagon- like peptide-1 and glucose-dependent insulinotropic polypeptide. It has been reported that membrane-bound DPIV plays a crucial role in the immune system and in other tissues and cells, but the knowledge on the action of cellular DPIV and its regulation is limited. In this study, we show particularly for immune cells that DPIV and not DP8 or DP9 is the most potent member of the DPIV family in regulating cellular immune functions. Moreover, we provide evidence that soluble and cellular DPIV differ in functions and handling of substrates and inhibitors owing to the different accessibility of peptide substrates to the two access paths of DPIV. The different functions are based on the favored access path of the central pore of cellular DPIV and a special central pore binding site which assists substrate access to the active site of the enzyme. The newly discovered central pore binding\ site mediates an autosterical regulation of cellular DPIV and is its most crucial target site to regulate cellular functions such as growth and cytokine production. Neuropeptide Y (NPY) processing by cellular DPIV was found to be inhibited by ligands which interact with the central pore binding site. This finding suggests a crucial role of the immunosuppressive cytokine NPY in the function of DPIV in growth regulation. Copyright © by Walter de Gruyter.


The invention relates to compounds of the general formula (1) or the acid addition salts thereof with organic and/or inorganic acids; as well as to the use of the compounds of the general formula (1) in medicine.


The invention relates to compounds of the general formula (I)


The invention relates to a method for characterization and validation of inhibitors or ligands of DPIV, DP8 or DP9 by their interaction with specific binding sites in silico and in vitro. It describes the use of special binding properties at the binding site of the DPIV in the central pore of DPIV, which is distant from the catalytic domain by at least 10 Angstrm (1 nm) which is essential for the steric inhibition of this peptidase and related enzymes like DP8 and DP9 by DPIV ligands or steric inhibitors for the use of these compounds to suppress DNA synthesis of lymphocytes, dermal cells and other cells. This finding is also important in that this technique can be used to predict unwanted side effects of DPIV related drugs and exclude effects of DPIV inhibitors developed for the treatment of Diabetes mellitus type II on immune functions and vice versa.


The invention relates to compounds of the general formula (1)


Patent
Imtm Gmbh | Date: 2011-07-19

The invention relates to compounds of general formula (I) as set forth in the claims as well as to the use of the compounds of the general formula (1) in the medical field, specifically for use in the suppression of DNA synthesis and inflammatory cytokine production as well as in the stimulation of anti-inflammatory cytokine production in vitro and in vivo. This abstract is neither intended to define the invention disclosed in this specification nor intended to limit the scope of the invention in any way.


PubMed | IMTM GmbH
Type: Journal Article | Journal: Biological chemistry | Year: 2011

The cellular dipeptidyl peptidase IV (DPIV, E.C.3.4.14.5, CD26) is a type II membrane peptidase with various physio-logical functions. Our main knowledge on DPIV comes from studies of soluble DPIV which plays a role in regulation of glucose homeostasis by inactivation of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic poly-peptide. It has been reported that membrane-bound DPIV plays a crucial role in the immune system and in other tissues and cells, but the knowledge on the action of cellular DPIV and its regulation is limited. In this study, we show particularly for immune cells that DPIV and not DP8 or DP9 is the most potent member of the DPIV family in regulating cellular immune functions. Moreover, we provide evidence that soluble and cellular DPIV differ in functions and hand-ling of substrates and inhibitors owing to the different accessibility of peptide substrates to the two access paths of DPIV. The different functions are based on the favored access path of the central pore of cellular DPIV and a special central pore binding site which assists substrate access to the active site of the enzyme. The newly discovered central pore binding site mediates an autosterical regulation of cellular DPIV and is its most crucial target site to regulate cellular functions such as growth and cytokine production. Neuropeptide Y (NPY) processing by cellular DPIV was found to be inhibited by ligands which interact with the central pore binding site. This finding suggests a crucial role of the immunosuppressive cytokine NPY in the function of DPIV in growth regulation.


PubMed | IMTM GmbH
Type: Journal Article | Journal: Biological chemistry | Year: 2011

The discovery of the DP4-related enzymes DP8 and DP9 raised controversial discussion regarding the physiological and pathophysiological function of distinct members of the DP4 family. Particularly with regard to their potential relevance in regulating immune functions, it is of interest to know which role the subcellular distribution of the enzymes play. Synthetic substrates as well as low molecular weight inhibitors are widely used as tools, but little is yet known regarding their features in cell experiments, such as their plasma membrane penetration capacity. The fluorogenic substrates Gly-Pro-AMC or (Ala-Pro)-R110 predominantly detect plasma membrane-bound activities of viable cells (less than 0.1% of fluorochromes R110 or AMC inside viable cells after 1 h incubation). Additionally, the selective and non-selective DP8/9 inhibitors allo-Ile-isoindoline and Lys[Z(NO)]-pyrrolidide were found to be incapable of passing the plasma membrane easily. This suggests that previously reported cellular effects are not due to inhibition of the cytosolic enzymes DP8 or DP9. Moreover, our enzymatic studies with viable cells provided evidence that DP8 and/or DP9 are also present on the surface of immune cells under certain circumstances and could gain relevance particularly in the absence of DP4 expression. In summary, in cells which do express DP4 on the surface, this archetypical member of the DP4 family is the most relevant peptidase in the regulation of cellular functions.

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