New Selective Aminopeptidase N Inhibitors as Potential Therapeutics

Fournié‐Zaluski, Marie‐Claude; Roques, Bernárd P.

doi:10.1007/978-1-4615-0619-5_3

Cited by 5 publications

(3 citation statements)

References 124 publications

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“…This section will focus on more recently reported compounds. Reviews of APN inhibitors are available (Shimazawa et al 1999;Abe and Aoyagi 2002;Fourni e-Zaluski and Roques 2002;Xu and Li 2005;Bauvois and Dauzonne 2006;Luan and Xu 2007;Zhang and Xu 2008;Mucha et al 2010;Su et al 2011;Wickstr€ om et al 2011;Zhang et al 2011b;Luan et al 2012b;Hitzerd et al 2014;Drinkwater et al 2017;Amin et al 2018). A compilation of APN inhibitors is available on the MEROPS website (https:// www.ebi.ac.uk/merops/cgi-bin/pepsum?id=M01.001; accessed 31 October 2019).…”

Section: Substrates Apn Catalyzes the Hydrolysis Of N-ter-mentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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Section: Substrates Apn Catalyzes the Hydrolysis Of N-ter-mentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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“…Inhibitors of DP IV-like activity have potent immunosuppressive and anti-inflammatory effects in various disease models such as murine experimental autoimmune encephalomyelitis (EAE) (11), collagen-and alkyldiamone-induced arthritis (12) and rat cardiac transplantation (13); and DP IV has become a novel target for the treatment of type 2 diabetes (14). APN inhibitors have shown therapeutic efficacy in analgesia models and tumor neo-angiogenesis (15); bestatin is clinically used as an immunomodulator in cancer patients and has antiangiogenic properties (16,17).…”

Section: Introductionmentioning

confidence: 99%

The ectopeptidases dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) and their related enzymes as possible targets in the treatment of skin diseases

Thielitz

Ansorge²,

Bank³

et al. 2008

Front Biosci

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Skin cells express dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) and their related molecules of the DP IV-like family DP2, DP6, DP8, DP9 and fibroblast activation protein (FAP), as well as the cytoplasmic alanyl aminopeptidase (cAAP). The inhibitors of DP IV-like activity, Lys(Z(NO2))-thiazolidide (LZNT) and Lys(Z(NO2))-pyrrolidide (LZNP), and the APN inhibitors actinonin and bestatin affect proliferation, differentiation and cytokine production in sebocytes and keratinocytes, which are involved in the initiation of acne. Furthermore, they suppress proliferation of Propionibacterium acnes-stimulated T cells ex vivo and induce an anti-inflammatory cytokine profile. In the mouse tail model of psoriasis they have a pro-differentiative effect. In addition, these inhibitors suppress skin fibroblast proliferation, whereas only inhibition of DP IV-like activity decreases TGF-beta1 expression and abrogates the TGF-beta1 mediated stimulatory effects on TGF-beta1 and fibronectin production, collagen synthesis and matrix deposition in these cells. Targeting enzyme activity of DP IV and APN and their related molecules might be a novel approach for the treatment of acne, psoriasis or keloids.

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“…APN inhibitors have shown therapeutic efficacy in analgesia models and tumor neoangiogenesis (Fournié-Zaluski and Roques, 2002), and bestatin (B) is clinically used as an immunomodulator in cancer patients (Fujisaki et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of Dipeptidyl Peptidase IV and Aminopeptidase N Target Major Pathogenetic Steps in Acne Initiation

Thielitz

Reinhold

Vetter

et al. 2007

Journal of Investigative Dermatology

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Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-beta1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner.

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New Selective Aminopeptidase N Inhibitors as Potential Therapeutics

Cited by 5 publications

References 124 publications

The mercapturic acid pathway

The mercapturic acid pathway

The ectopeptidases dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) and their related enzymes as possible targets in the treatment of skin diseases

Inhibitors of Dipeptidyl Peptidase IV and Aminopeptidase N Target Major Pathogenetic Steps in Acne Initiation

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