Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

Veken, Pieter Van der; Haemers, Achiel; Augustyns, Koen

doi:10.2174/156802607780091046

Cited by 50 publications

(39 citation statements)

References 75 publications

(125 reference statements)

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“…The ((5-cyanopyridin-2-yl)amino)acetamide 16 and 3-hydroxyadamantane-1-carboxamide 17 are nonbasic analogues of the N-substituted glycyl-(2-cyanopyrroldine) DPPIV inhibitors NVP-DPP 728 and vildagliptin, respectively. 24 By introducing an amide group instead of the parent structures' basic P2-amine function that is critical for DPP IV interaction, we hoped to decrease DPP IV potency, while retaining affinity for the phylogenetically very closely related FAP. Only moderate inhibition of the latter was observed however.…”

Section: * S Supporting Informationmentioning

confidence: 99%

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Jansen

Heirbaut

Cheng

et al. 2013

ACS Med. Chem. Lett.

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169

147

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Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp 2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10 3 ) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.

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Section: * S Supporting Informationmentioning

confidence: 99%

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Jansen

Heirbaut

Cheng

et al. 2013

ACS Med. Chem. Lett.

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169

147

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“…DPP IV/CD26, FAP, DPP8 i DPP9 su prolil-specifične dipeptidil--peptidaze koje sudjeluju u regulaciji različitih biokemijskih procesa putem hidrolize N-terminalnih dipeptida iz proteinskih lanaca s prolinom na pretposljednjem mjestu u aminokiselinskoj sekvenci, odnosno u primarnoj strukturi proteina 24 . Osim navedenih proteina, u obitelj DPP IV proteina ubrajamo i DLP1 i DLP2 koji nisu enzimski aktivni 25 .…”

Section: Obitelj Dpp IV Proteinaunclassified

Untitled

2017

Med. flum.

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Sažetak. Cijeljenje rane dinamičan je proces koji se odvija u više međuovisnih faza koje uključuju reguliranu interakciju među različitim vrstama stanica, izvanstaničnog matriksa, proteaza i njihovih supstrata. Rastući znanstveni dokazi naglašavaju važnost proteaza u regulaciji ključnih procesa cijeljenja rane. Dipeptidil-peptidaza IV (DPP IV/CD26, EC 3.4.14.5), glavni je član obitelji DPP IV proteina. Riječ je o ubikvitarnom multifunkcionalnom transmembranskom glikoproteinu koji je prisutan i u topljivom obliku, a djeluje kao proteolitička i kostimulacijska molekula te vezni protein. Izražena je na površini različitih vrsta stanica, uključujući epitelne, endotelne stanice i limfocite. Pokazano je da ima značajnu ulogu u različitim fiziološkim i patološkim procesima. DPP IV/CD26 je u velikoj mjeri istraživana zbog svoje sposobnosti održavanja homeostaze glukoze. Štoviše, budući na utvrđene pozitivne učinke inhibicije DPP IV/CD26 u cijeljenju kroničnih dijabetičkih ulkusa, kao i uključenosti u drugim patološkim procesima, ova je molekula od rastućeg znanstvenog interesa u cilju razjašnjavanja mehanizama njezinog djelovanja. Poznato je da DPP IV/CD26 sudjeluje u regulaciji stanične adhezije, migracije i apoptoze stanica kao i angiogenezi te razgradnji ekstracelularnog matriksa, ključnim procesima u cijeljenju rana. Prethodne studije pokazale su da DPP IV/CD26 ima posebno važnu ulogu u regeneraciji kože, gdje je utvrđeno da može posredovati upalne procese i utjecati na epitelizaciju ranjenog tkiva. Stoga je cilj ovog preglednog rada sažeti ključna otkrića u procesima cijeljenja rana te prikazati nove spoznaje o ulozi DPP IV/CD26 u procesima regeneracije tkiva.Ključne riječi: angiogeneza; CD26; cijeljenje rane; dipeptidil-peptidaza IV Abstract. Wound healing is a dynamic process occurring in multiple interdependent stages that include a regulated interaction between different cell types, extracellular matrix, proteases and their substrates. Increasing scientific evidence emphasizes the importance of proteases playing crucial roles in the regulation of processes of wound healing. Dipeptidyl peptidase IV (DPP IV/CD26, EC 3.4.14.5), the main member of the DPP IV family of proteins, is a ubiquitous multifunctional transmembrane as well as soluble glycoprotein, acting as a proteolytic and costimulation molecule, and binding protein. It is expressed on the surface different cell types, including epithelial, endothelial cells and lymphocytes. It has been shown to play a significant role in different physiological as well as pathological processes. DPP IV/ CD26 was largely investigated given its ability to maintain glucose homeostasis. Moreover, since positive effects of DPP IV/CD26 inhibition in healing of chronic diabetic foot ulcers as well as other pathologies have been shown, growing efforts are made in order to elucidate its mechanisms of action. It is known that DPP IV/CD26 is involved in the regulation of cell adhesion, migration, apoptosis, angiogenesis and extracellular matrix degradation, which are all key proces...

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“…Prolin-selektivne dipeptidil-peptidaze skupina su serinskih proteaza koje sudjeluju u regulaciji različitih biokemijskih procesa putem hidrolize N-terminalnih dipeptida s polipeptidnih i proteinskih lanaca koji sadržavaju aminokiselinu prolin na pretposljednjem mjestu (53). Porodicu DPP IV proteina čine DPP IV/CD26, FAP (protein aktivacije fi broblasta), DPP8 i DPP9 te DPL1 i DPL2, koji nemaju enzimsku ulogu (tablica 1).…”

Section: Porodica Proteina Sličnih Dipeptidil-peptidazi IVunclassified

Dipeptidyl Peptidase IV in Inflammatory Bowel Diseases (DPP IV/CD26)

Pučar

Detel

Varljen

2012

Archives of Industrial Hygiene and Toxicology

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Dipeptidil-peptidaza IV (DPP IV/CD26) i upalne bolesti crijevaUpalne bolesti crijeva (Crohnova bolest, ulcerozni kolitis, nedeterminirani kolitis) skupina su kroničnih autoimunosnih upalnih bolesti obilježenih ponavljanim upalama različitih dijelova gastrointestinalnog trakta koje su važan javnozdravstveni problem današnjice. Unatoč brojnim temeljnim i kliničkim istraživanjima etiologija ovih bolesti, kao i sama patogeneza upale ostaju nedovoljno razjašnjene. Dosadašnja su istraživanja potvrdila uzročno-posljedičnu vezu između medijatora upalnog odgovora i molekula uključenih u regulaciju njihove biološke aktivnosti, osobito proteaza. Cilj ovoga preglednog rada jest sažeti prikaz dosadašnjih saznanja o različitim aspektima upalnih bolesti crijeva, s posebnim naglaskom na potencijalnu ulogu i uključenost dipeptidil-peptidaze IV, odnosno molekule CD26 (DPP IV/CD26) u mehanizme nastanka upalnih procesa u probavnom sustavu. Dan je i pregled životinjskih modela kolitisa koji su znatno pridonijeli razumijevanju i terapiji ovih bolesti, s osobitim naglaskom na mišji model ulceroznog kolitisa (DSS-kolitis) te Crohnove bolesti (TNBS-kolitis).

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Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

Cited by 50 publications

References 75 publications

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Untitled

Dipeptidyl Peptidase IV in Inflammatory Bowel Diseases (DPP IV/CD26)

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