Structure-activity relationship of marinostatin, a serine protease inhibitor isolated from a marine organism.
A 12-residue MST isolated from a marine organism is a potent serine protease inhibitor that has a double cyclic structure composed of two ester linkages formed between the beta-hydroxyl and beta-carboxyl groups, Thr(3)-Asp(9) and Ser(8)-Asp(11). MST was synthesized by a regioselective esterification procedure employing two sets of orthogonally removable side-chain protecting groups for the Asp and Ser/Thr residues. In the MST molecule, there were no significant changes observed in yield by changing the order of esterification. SAR study of MST revealed that the minimum required structure for expressing the inhibitory activity is the sequence (1-9) in a monocyclic structure where Pro(7) located in the ring plays a crucial role in keeping the structural rigidity. By applying the structural motif of MST, we rationally designed protease inhibitory specificities that differ from those of the natural product.
Taichi
Misako
M
SAITO Research Center, Peptide Institute, Inc., Ibaraki, Osaka 567-0085, Japan.
Yamazaki
Tohimasa
T
Kawahara
Kazuki
K
Motooka
Daisuke
D
Nakamura
Shota
S
Harada
Shusaku
S
Teshima
Tadashi
T
Ohkubo
Tadayasu
T
Kobayashi
Yuji
Y
Nishiuchi
Yuji
Y
D000818:Animals; D015195:Drug Design; D008386:Marine Biology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D010456:Peptides, Cyclic; D015842:Serine Proteinase Inhibitors; C073224:marinostatin D