Zheng G Q, Hu X, Cassady J M, Paige L A, Geahlen R L
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210.
J Pharm Sci. 1994 Feb;83(2):233-8. doi: 10.1002/jps.2600830224.
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.
为开发肉豆蔻酰辅酶A：蛋白质N-肉豆蔻酰转移酶（NMT）的抑制剂，合成了一系列肉豆蔻酰辅酶A类似物和肉豆蔻酰肽，包括S-(2-氧代十五烷基)-辅酶A（1）、S-(2-羟基十五烷基)-辅酶A（2）、S-(2-氧代十五烷基)-泛酰巯基乙胺（3）、肉豆蔻酰-N-甘氨酰-(L)-苯丙氨酸（4）、肉豆蔻酰-N-甘氨酰-(L)-酪氨酸（5）和肉豆蔻酰-N-甘氨酰-(L)-天冬酰胺-丙氨酸-丙氨酸-丝氨酸-丙氨酸-精氨酸-(NH2)（6）。在体外NMT酶分析中对这些化合物进行的生物学评估表明，不可水解的酰基辅酶A类似物1是最有效的抑制剂[抑制剂解离常数（Ki）=24 nM]。初步的构效关系研究表明，这种不可水解类似物中的腺苷部分和2-酮基对于抑制活性是必需的。提出了1抑制NMT的一种可能机制，其中1可能在酰基辅酶A-NMT-肽复合物阶段阻断反应。产物类似物如肉豆蔻酰化肽4-6是NMT的弱抑制剂。
