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Statements

Subject Item
n2:RIV%2F60077344%3A_____%2F08%3A00318080%21RIV09-GA0-60077344
rdf:type
skos:Concept n8:Vysledek
dcterms:description
Aza-peptidy tzv. Michael acceptors s obecnou chemickou strukturou Cbz-Ala-Ala-AAsn-trans-CH CHCOR jsou novou třídou inhibitorů specifických pro asparaginylové peptidázy (AE, legumainy). Screening vztahů mezi jejich struktorou a aktivitou (SARs) zahrnoval 31 aza-peptidů Michael acceptors a AE ze tří parazitů Trichomonas vaginalis, Ixodes ricinus, and Schistosoma mansoni. I když se jedná o evolučně vzdálené druhy, všechny tři enzymy sdílely nápadně podobné SAR s nejnižšími IC50 hodnotami zasahujícími do pikomolarních koncentrací. Výsledky ukazují na evoluční rezervovanost v topografii %22prime side%22 aktivního centra AE. SAR také odhalily že estery v P1 pozici jsou více účinné než disubstituované amidy a že monosubstituované amidy a alkylové deriváty v této pozici vedou k malé nebo žádné inhibici. Preferovanými P1 zbytky jsou aromatické substituenty. Michael acceptors reagují s thioly, což naznačuje mechanismus inhibice aktivního cysteinu AE. Aza-peptide Michael acceptors with the general structure of Cbz-Ala-Ala-AAsn-trans-CH CHCOR are a new class of inhibitors specific for the asparaginyl endopeptidases (AE) (legumains). Structure–activity relationships (SARs) were characterized for a set of 31 aza-peptide Michael acceptors with AEs derived from three parasites: Trichomonas vaginalis, Ixodes ricinus, and Schistosoma mansoni. Despite arising from phylogenetically disparate organisms, all three AEs shared a remarkably similar SAR with lowest IC50 values extending into the picomolar range. The results suggest an evolutionary constraint on the topography of the prime side of the active site. SAR also revealed that esters in the P1 position are more potent than disubstituted amides and that monosubstituted amides and alkyl derivatives show little or no inhibition. The preferred P1 residues have aromatic substituents. Michael acceptors react with thiols what provides an insight into the mechanism of their inhibition. Aza-peptide Michael acceptors with the general structure of Cbz-Ala-Ala-AAsn-trans-CH CHCOR are a new class of inhibitors specific for the asparaginyl endopeptidases (AE) (legumains). Structure–activity relationships (SARs) were characterized for a set of 31 aza-peptide Michael acceptors with AEs derived from three parasites: Trichomonas vaginalis, Ixodes ricinus, and Schistosoma mansoni. Despite arising from phylogenetically disparate organisms, all three AEs shared a remarkably similar SAR with lowest IC50 values extending into the picomolar range. The results suggest an evolutionary constraint on the topography of the prime side of the active site. SAR also revealed that esters in the P1 position are more potent than disubstituted amides and that monosubstituted amides and alkyl derivatives show little or no inhibition. The preferred P1 residues have aromatic substituents. Michael acceptors react with thiols what provides an insight into the mechanism of their inhibition.
dcterms:title
Aza-peptidy Michael Acceptors. Nová třída účinných a selektivních inhibitorů asparaginylových peptidáz (legumainů) z evolučně vzdálených patogenů Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens
skos:prefLabel
Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens Aza-peptidy Michael Acceptors. Nová třída účinných a selektivních inhibitorů asparaginylových peptidáz (legumainů) z evolučně vzdálených patogenů
skos:notation
RIV/60077344:_____/08:00318080!RIV09-GA0-60077344
n3:aktivita
n10:Z n10:P
n3:aktivity
P(GA206/06/0865), P(LC06009), Z(AV0Z60220518)
n3:cisloPeriodika
9
n3:dodaniDat
n9:2009
n3:domaciTvurceVysledku
n4:2092484 n4:2928868
n3:druhVysledku
n15:J
n3:duvernostUdaju
n7:S
n3:entitaPredkladatele
n16:predkladatel
n3:idSjednocenehoVysledku
357514
n3:idVysledku
RIV/60077344:_____/08:00318080
n3:jazykVysledku
n14:eng
n3:klicovaSlova
legumain; IrAE; aza-peptide Michael acceptors
n3:klicoveSlovo
n6:aza-peptide%20Michael%20acceptors n6:legumain n6:IrAE
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[BABA99E7DF77]
n3:nazevZdroje
Journal of Medicinal Chemistry
n3:obor
n13:ED
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
10
n3:projekt
n12:GA206%2F06%2F0865 n12:LC06009
n3:rokUplatneniVysledku
n9:2008
n3:svazekPeriodika
51
n3:tvurceVysledku
Götz, M. G. Hansell, E. James, K. E. Kopáček, Petr McKerrow, J. H. Sojka, Daniel Dvořák, J. Seshaadri, A. Caffrey, C. R. Powers, J. C.
n3:wos
000255500000027
n3:zamer
n18:AV0Z60220518
s:issn
0022-2623
s:numberOfPages
17