title: Conjugation of adenosine and hexa-(D-arginine) leads to a nanomolar bisubstrate-analog inhibitor of basophilic protein kinases.
abstract: Conjugates of oligoarginine peptides with adenine, adenosine, adenosine-5'-carboxylic acid, and 5-isoquinolinesulfonic acid were synthesized and characterized as bisubstrate-analog inhibitors of cAMP-dependent protein kinase. Adenosine and adenine derivatives were connected to the N- or C-terminus of peptides containing four to six L- or D-arginine residues via a linker with a length that had been optimized in structure-activity studies. The orientation of the peptide chain strongly affected the activity of compounds incorporating D-arginines. The biligand inhibitor containing Hidaka's H9 isoquinolinesulfonamide connected to the L-peptide had 65 times higher potency than the corresponding adenosine-containing conjugate, while both types of the conjugate comprising D-peptides had similar low nanomolar activity. Two of the most active adenosine- and H9-peptide conjugates were tested in the panel of 52 different kinases. At 1 microM concentration, both compounds showed strong (more than 95%) inhibition of several basophilic AGC kinases, including pharmaceutically important kinases ROCK II and PKB/Akt.
authors.affiliation: Institute of Organic and Bioorganic Chemistry, 2 Jakobi Street, 51014 Tartu, Estonia.
authors.forename: Erki
authors.initials: E
authors.lastname: Enkvist
authors.forename: Darja
authors.initials: D
authors.lastname: Lavogina
authors.forename: Gerda
authors.initials: G
authors.lastname: Raidaru
authors.forename: Angela
authors.initials: A
authors.lastname: Vaasa
authors.forename: Indrek
authors.initials: I
authors.lastname: Viil
authors.forename: Marje
authors.initials: M
authors.lastname: Lust
authors.forename: Kaido
authors.initials: K
authors.lastname: Viht
authors.forename: Asko
authors.initials: A
authors.lastname: Uri
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D009842:Oligopeptides; D013449:Sulfonamides; D001120:Arginine; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine