The selectivity of statine-based inhibitors against various human aspartic proteinases.
The interactions of five human enzymes (renin, pepsin, gastricsin, cathepsin D and cathepsin E) and the aspartic proteinase from Endothia parasitica with several series of synthetic inhibitors were examined. All of the inhibitors contained the dipeptide analogue statine or its phenylalanine or cyclohexylalanine homologues in the P1-P1' positions. The residues occupying the peripheral sub-sites (P4 to P3') were varied systematically and inhibitory constants were determined for the interactions with each of the proteinases. Inhibitors were elucidated that specifically inhibited human renin and did not affect any of the other human enzymes or the fungal proteinase. With suitable selection of residues to occupy individual sub-sites, effective inhibitors of specific human aspartic proteinases may now be designed.
Department of Biochemistry, University of Wales College of Cardiff, U.K.
R A
RA
Jupp
B M
BM
Dunn
J W
JW
Jacobs
G
G
Vlasuk
K E
KE
Arcuri
D F
DF
Veber
D S
DS
Perlow
L S
LS
Payne
J
J
Boger
S
S
de Laszlo
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases; D055598:Chemical Phenomena; D002621:Chemistry; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology*; D013379:Substrate Specificity
D000596:Amino Acids; D011480:Protease Inhibitors; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C013165:statine