N(epsilon)-Modified lysine containing inhibitors for SIRT1 and SIRT2.
Sirtuins catalyze the NAD(+) dependent deacetylation of N(epsilon)-acetyl lysine residues to nicotinamide, O'-acetyl-ADP-ribose (OAADPR) and N(epsilon)-deacetylated lysine. Here, an easy-to-synthesize Ac-Ala-Lys-Ala sequence has been used as a probe for the screening of novel N(epsilon)-modified lysine containing inhibitors against SIRT1 and SIRT2. N(epsilon)-Selenoacetyl and N(epsilon)-isothiovaleryl were the most potent moieties found in this study, comparable to the widely studied N(epsilon)-thioacetyl group. The N(epsilon)-3,3-dimethylacryl and N(epsilon)-isovaleryl moieties gave significant inhibition in comparison to the N(epsilon)-acetyl group present in the substrates. In addition, the studied N(epsilon)-alkanoyl, N(epsilon)-alpha,beta-unsaturated carbonyl and N(epsilon)-aroyl moieties showed that the acetyl binding pocket can accept rather large groups, but is sensitive to even small changes in electronic and steric properties of the N(epsilon)-modification. These results are applicable for further screening of N(epsilon)-acetyl analogues.
Huhtiniemi
Tero
T
School of Pharmacy, University of Eastern Finland, Kuopio Campus, PO Box 1627, 70211 Kuopio, Finland. Tero.Huhtiniemi@uef.fi
Suuronen
Tiina
T
Lahtela-Kakkonen
Maija
M
Bruijn
Tanja
T
Jääskeläinen
Sanna
S
Poso
Antti
A
Salminen
Antero
A
Leppänen
Jukka
J
Jarho
Elina
E
D000595:Amino Acid Sequence; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D056572:Histone Deacetylase Inhibitors; D010455:Peptides; D056564:Sirtuin 1; D056565:Sirtuin 2; D008239:Lysine