Synthesis of myristoyl CoA analogues and myristoyl peptides as inhibitors of myristoyl CoA:protein N-myristoyltransferase.
To develop inhibitors of myristoyl CoA:protein N-myristoyltransferase (NMT), a series of myristoyl coenzyme A analogues and myristoyl peptides were synthesized, including S-(2-oxopentadecyl)-CoA (1), S-(2-hydroxypentadecyl)-CoA (2), S-(2-oxopentadecyl)-pantetheine (3), Myr-N-Gly-(L)-Phe (4), Myr-N-Gly-(L)-Tyr (5), and Myr-N-Gly-(L)-Asn-Ala- Ala-Ser-Ala-Arg-(NH2) (6). Biological evaluation of these compounds in an in vitro NMT enzyme assay revealed that the nonhydrolyzable acyl CoA analogue 1 was the most potent inhibitor [inhibitor dissociation constant (Ki) = 24 nM]. A preliminary structure-activity relationship study showed that the adenosine moiety and the 2-keto group in this nonhydrolyzable analogue were necessary for inhibitory activity. A possible mechanism for the inhibition of NMT by 1 was proposed, in which 1 might block the reaction at the stage of an acyl-CoA-NMT-peptide complex. Product analogues such as the myristoylated peptides 4-6 were poor inhibitors of NMT.
Zheng
G Q
GQ
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210.
Hu
X
X
Cassady
J M
JM
Paige
L A
LA
Geahlen
R L
RL
D000214:Acyl Coenzyme A / Q000138:chemical synthesis* / Q000494:pharmacology; D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000214:Acyl Coenzyme A; D009842:Oligopeptides; C040349:S-tetradecanoyl-coenzyme A; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase