Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor

Wu, Jiajing; Tang, Hung-Kuan; Yeh, Teng‐Kuang; Chen, Chi-Min; Shy, Hrong-Shing; Chu, Yue-Ru; Chien, Chia‐Hui; Tsai, Tsung‐Yen; Huang, Yu‐Chen; Huang, Yuping; Huang, Chiung‐Shiann; Tseng, Huan-Yi; Jiaang, Weir‐Torn; Chao, Yu‐Sheng; Chen, Xin

doi:10.1016/j.bcp.2009.03.032

Cited by 82 publications

(72 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibitors the DPP8/9-specific inhibitor 1G244 was purchased from aK Scientific (Union City, Ca, USa), first described in [36].…”

Section: Methodsmentioning

confidence: 99%

“…to test whether GP-aMC hydrolysis in the nuclear fractions can indeed be attributed to DPP9, we performed cleavage-activity assays in the presence of the DPP8/9-specific inhibitor 1G244 and compared the activity to mock-treated samples (Fig. 6c) [36]. a DPP8/9 inhibitor was used in this assay since there are no available inhibitors that differentiate between DPP8 and DPP9 due to their high homology.…”

Section: Dpp9-l Is An Active Peptidasementioning

confidence: 99%

“…So far, no nuclear candidate substrates for these peptidases are known. the only endogenous DPP9 substrate known so far is the RU1 [34][35][36][37][38][39][40][41] antigen, which is stabilized in the cytosol upon DPP9 silencing, linking DPP9 to the MhC class I pathway [28]. Recently, a large degradome screen from cells overexpressing DPP9 or DPP8 was performed, leading to the identification of several cytosolic candidate substrates [27].…”

Section: Dpp9-l Is An Active Peptidasementioning

confidence: 99%

“…Silencing experiments show that DPP9 and not DPP8 is rate-limiting for the hydrolysis of prolinecontaining peptides in the cytosol suggesting that DPP9 may have a house-keeping role for amino acid homeostasis [28]. the first identified endogenous substrate of DPP9 was the tumor-related epitope RU1 [34][35][36][37][38][39][40][41][42] . Its hydrolysis by DPP9 results in its limited presentation on MhC class I molecules to the immune system linking DPP9 to the MhC class I antigen presentation pathway [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

Justa-Schuch

Möller

Geiss‐Friedlander

2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Inhibitors the DPP8/9-specific inhibitor 1G244 was purchased from aK Scientific (Union City, Ca, USa), first described in [36].…”

Section: Methodsmentioning

confidence: 99%

Section: Dpp9-l Is An Active Peptidasementioning

confidence: 99%

Section: Dpp9-l Is An Active Peptidasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

Justa-Schuch

Möller

Geiss‐Friedlander

2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Furthermore, DPP8/DPP9 appears to be involved in T cell proliferation, thereby releasing IL-2 as well as macrophage activation causing activation of caspase 1 and induction of IL-1b [45,[47][48][49][50][51]. However, the suggested cytotoxicity of DPP8/DPP9 inhibition is currently discussed controversially [52][53][54][55][56]. An increase of DPP8/DPP9 activity has been associated with asthma [44].…”

Section: Dpp4 Gene Familymentioning

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

107

View full text Add to dashboard Cite

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].

show abstract

Chemoproteomik‐basierte Identifikation von 4‐Oxo‐β‐lactamen als Inhibitoren der Dipeptidylpeptidasen 8 und 9

et al. 2022

View full text Add to dashboard Cite

Die Dipeptidylpeptidasen 8 und 9 (DPP8/9) sind aufgrund ihrer wichtigen Rolle in biologischen Prozessen wie der Immunität und Tumorgenese in den letzten Jahren in den Fokus der Wirkstoffforschung gerückt. Der individuelle Beitrag der jeweiligen Protease innerhalb dieser Prozesse ist bisher jedoch meistens noch unbekannt. Die Untersuchung ihrer individuellen Funktion kann dabei von der Verfügbarkeit Protease‐selektiver und chemisch‐diverser Hemmstoffe profitieren. In dieser Arbeit stellen wir die durch Anwendung von Aktivitäts‐basiertem Protein‐Profiling (ABPP) entdeckten 4‐Oxo‐β‐lactame als potente, nicht‐Substrat‐abgeleitete, nanomolare DPP8/9‐Inhibitoren vor. Röntgenkristallographische Untersuchungen von Liganden‐DPP‐Komplexen offenbarten dabei unterschiedliche Ligandenbindungsmodi für DPP8 und DPP9, einschließlich einer neuartigen Adressierung einer erweiterten S2′ (eS2′)‐Bindetasche in DPP8. Zusätzliche Assays bestätigten ihre Hemmwirkung sowohl auf biochemischer als auch auf zellulärer Ebene. Zusammenfassend führte unser kombinierter Ansatz aus chemischer Proteomik und strukturbasiertem Design somit zu der Entwicklung neuartiger DPP8/9‐Inhibitoren mit einem alternativem molekularen Hemmmechanismus und einem bisher nicht erreichten Selektivitätsindex.

show abstract

Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor

Cited by 82 publications

References 32 publications

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

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

Chemoproteomik‐basierte Identifikation von 4‐Oxo‐β‐lactamen als Inhibitoren der Dipeptidylpeptidasen 8 und 9

Contact Info

Product

Resources

About