Felix A M, Heimer E P, Wang C T, Lambros T J, Fournier A, Mowles T F, Maines S, Campbell R M, Wegrzynski B B, Toome V
Physical Chemistry and Animal Science Research Dept., Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey.
Int J Pept Protein Res. 1988 Dec;32(6):441-54. doi: 10.1111/j.1399-3011.1988.tb01375.x.
A novel cyclic GRF analog, cyclo(Asp8-Lys12)-[Asp8,Ala15]-GRF(1-29)-NH2, i.e. cyclo8,12[Asp8,Ala15]-GRF(1-29)-NH2, was synthesized by the solid phase procedure and found to retain significant biological activity. Solid phase cyclization of Asp8 to Lys12 proceeded rapidly (approximately 2 h) using the BOP reagent. Substitution of Ala2 with D-Ala2 and/or NH2-terminal replacement (desNH2-Tyr1 or N-MeTyr1) in the cyclo8,12[Asp8,Ala15]-GRF(1-29)-NH2 system resulted in highly potent analogs that were also active in vivo. Conformational analysis (circular dichroism and molecular dynamics calculations based on NOE-derived distance constraints) demonstrated that cyclo8,12[Asp8,Ala15]-GRF(1-29)-NH2 contains a long alpha-helical segment even in aqueous solution. A series of cyclo8,12 stereoisomers containing D-Asp8 and/or D-Lys12 were prepared and also found to be highly potent and to retain significant alpha-helical conformation. The high biological activity of cyclo8,12[N-MeTyr1,D-Ala2,Asp8,Ala15]-GRF(1-29)- NH2 may be explained on the basis of retention of a preferred bioactive conformation.
一种新型的环化生长激素释放因子类似物，即环（天冬氨酸8-赖氨酸12）-[天冬氨酸8，丙氨酸15]-生长激素释放因子（1-29）-NH₂，也就是环8,12[天冬氨酸8，丙氨酸15]-生长激素释放因子（1-29）-NH₂，通过固相法合成，并发现其保留了显著的生物活性。使用BOP试剂，天冬氨酸8与赖氨酸12的固相环化反应进行得很快（约2小时）。在环8,12[天冬氨酸8，丙氨酸15]-生长激素释放因子（1-29）-NH₂体系中，用D-丙氨酸2取代丙氨酸2和/或进行氨基末端替换（去氨基酪氨酸1或N-甲基酪氨酸1），得到了高效类似物，它们在体内也具有活性。构象分析（圆二色性以及基于NOE衍生距离限制的分子动力学计算）表明，即使在水溶液中，环8,12[天冬氨酸8，丙氨酸15]-生长激素释放因子（1-29）-NH₂也含有一个长的α-螺旋片段。制备了一系列含有D-天冬氨酸8和/或D-赖氨酸12的环8,12立体异构体，发现它们也具有高效性并保留了显著的α-螺旋构象。环8,12[N-甲基酪氨酸1，D-丙氨酸2，天冬氨酸8，丙氨酸15]-生长激素释放因子（1-29）-NH₂的高生物活性可以基于保留了优选的生物活性构象来解释。
