Novel Isoindoline Compounds for Potent and Selective Inhibition of Prolyl Dipeptidase DPP8.

Jiaang, Weir‐Torn; Chen, Yuan‐Shou; Hsu, Tsu; Wu, Ssu-Hui; Chien, Chia‐Hui; Chang, Chung-Nien; Chang, Sheng-Ping; Lee, Shiow‐Ju; Chen, Xin

doi:10.1002/chin.200525117

Cited by 8 publications

(14 citation statements)

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“…For DPP-IV-related dipeptidyl peptidases (Table 3), inhibition was only observed for DPP-IV and the related dipeptidyl peptidases, QPP, DPP8, and DPP9. Inhibition of DPP8 and QPP by isoleucyl thiazolidine has been previously reported (27). Comparable QPP inhibition activity was observed for both isomers; however, the potency for inhibition of DPP8 and DPP9 differed by ϳ10-fold, with the allo isomer being more potent in each case.…”

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confidence: 55%

Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

et al. 2005

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Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents. Diabetes

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confidence: 55%

Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

et al. 2005

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“…Subsequently, selective inhibitors were developed, and investigation of the above cytotoxic effects revealed the inhibition of DPP8 and DPP9 to be responsible for the side effects [52]. Therefore, the second generation of anti-diabetic DPP4 inhibitors focused on the selectivity of the various DPP4-like enzymes [52,[119][120][121][122]. Conversely, the requirement of selectivity is currently debated controversially, as some of the selective inhibitors against DPP8/9 were unable to enter the cell, suggesting that the cytotoxic effects observed were not due to inhibition of these cytosolic enzymes [53][54][55][56].…”

Section: History and Development Of Dpp Inhibitors As Well As Modulatmentioning

confidence: 99%

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

Wagner¹,

Klemann²,

Stephan

et al. 2016

Clinical and Experimental Immunology

100

107

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SummaryDipeptidyl peptidase (DPP) 4 (CD26, DPP4) is a multi-functional protein involved in T cell activation by co-stimulation via its association with adenosine deaminase (ADA), caveolin-1, CARMA-1, CD45, mannose-6-phosphate/insulin growth factor-II receptor (M6P/IGFII-R) and C-X-C motif receptor 4 (CXC-R4). The proline-specific dipeptidyl peptidase also modulates the bioactivity of several chemokines. However, a number of enzymes displaying either DPP4-like activities or representing structural homologues have been discovered in the past two decades and are referred to as DPP4 activity and/or structure homologue (DASH) proteins. Apart from DPP4, DASH proteins include fibroblast activation protein alpha (FAP), DPP8, DPP9, DPP4-like protein 1 (DPL1, DPP6, DPPX L, DPPX S), DPP4-like protein 2 (DPL2, DPP10) from the DPP4-gene family S9b and structurally unrelated enzyme DPP2, displaying DPP4-like activity. In contrast, DPP6 and DPP10 lack enzymatic DPP4-like activity. These DASH proteins play important roles in the immune system involving quiescence (DPP2), proliferation (DPP8/DPP9), antigen-presenting (DPP9), costimulation (DPP4), T cell activation (DPP4), signal transduction (DPP4, DPP8 and DPP9), differentiation (DPP4, DPP8) and tissue remodelling (DPP4, FAP). Thus, they are involved in many pathophysiological processes and have therefore been proposed for potential biomarkers or even drug targets in various cancers (DPP4 and FAP) and inflammatory diseases (DPP4, DPP8/DPP9). However, they also pose the challenge of drug selectivity concerning other DASH members for better efficacy and/or avoidance of unwanted side effects. Therefore, this review unravels the complex roles of DASH proteins in immunology.Keywords: antigen presentation/processing, CD26, co-stimulation, DPP4 activity and/or structure homologue proteins (DASH), signal transductionThe dipeptidyl peptidase (DPP)4 family of DPP4 activity and/or structure homologue (DASH) proteins Within the last two decades a number of enzymes have been discovered to also display DPP4-like activity or are structural homologues to DPP4. These enzymes/proteins are referred to as DPP4 activity and/or structure homologue (DASH) proteins, and can be grouped into the DPP4 gene family and non-related DPP4-like enzymes. Except for DPL1 and DPL2, all members display DPP4-like activity with neutral to basic pH optima and similar inhibition profiles [6,7]. DPP4 (CD26). DPP4 (CD26) is the best-known DASH protein and has been described in detail elsewhere [7][8][9].

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“…All inhibitors described so far are competitive and target both DPP8 and DPP9 (32)(33)(34)(35)(36). The best selectivity was described recently by Van Goethem et al (36), who systematically dissected and modified the DPP8/9 inhibitor 1G244 to increase the selectivity of the inhibitor toward DPP8.…”

Section: Discussionmentioning

confidence: 99%

The SUMO1-E67 Interacting Loop Peptide Is an Allosteric Inhibitor of the Dipeptidyl Peptidases 8 and 9

Pilla

Kilisch

Lenz

et al. 2013

Journal of Biological Chemistry

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Background: SUMO1 binds to an arm motif in the prolyl-peptidase DPP9, leading to allosteric activation of the peptidase. Results: A SUMO1 peptide covering the DPP9 interaction surface inhibits DPP9 activity. Inhibition is dependent on residues in the DPP9 arm motif. Conclusion: The SUMO1 peptide and its variants are allosteric DPP9 inhibitors. Significance: This work highlights the potential use of peptides mimicking interaction surfaces for modulating enzyme activity.

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Novel Isoindoline Compounds for Potent and Selective Inhibition of Prolyl Dipeptidase DPP8.

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 8 publications

References 1 publication

Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

The SUMO1-E67 Interacting Loop Peptide Is an Allosteric Inhibitor of the Dipeptidyl Peptidases 8 and 9

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