MAIN CHAIN AND SIDE-CHAIN CHIRAL METHYLATED SOMATOSTATIN ANALOGS - SYNTHESES AND CONFORMATIONAL-ANALYSES

被引:133
作者
HUANG, ZW
HE, YB
RAYNOR, K
TALLENT, M
REISINE, T
GOODMAN, M
机构
[1] UNIV CALIF SAN DIEGO,DEPT CHEM,LA JOLLA,CA 92093
[2] UNIV PENN,DEPT PHARMACOL,PHILADELPHIA,PA 19104
关键词
D O I
10.1021/ja00050a019
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
We have developed an integrated approach for investigating the ''bioactive conformations'' of the main chain and side chains for the somatostatin analog c[Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11]. A series of analogs have been synthesized incorporating alpha-methylated and beta-methylated residues at positions 7, 8, and 11. These analogs display dramatic differences in in vitro binding affinities for somatostatin receptors. Using 500-MHz H-1 NMR and computer simulations, we have the effect of main chain and side chain chiral methylations on the overall structure. The analyses of the changes of side chain topologies and subsequent binding affinities in the beta-methylated analogs have provided definitive evidence about the ''bioactive conformation'' of the side chains of Phe7, Trp8, and Phe11. The analyses of the alpha-methylated analogs have defined a ''folded'' feature for the peptide backbone. From this study, we have proposed a binding ''pocket'' for somatostatin analogs which consists of the side chains of Trp8 and Lys9, the peptide backbone, and the side chain of Phe11 in a ''folded'' topochemical array. In this ''folded'' conformation, the Trp8 side chain assumes the trans rotamer, while the Lys9 side chain assumes the gauche-rotamer, thus allowing a close proximity between these two side chains. The Phe11 side chain assumes the trans rotamer. The peptide backbone adopts a beta II' turn about Trp8-Lys9 and a beta VI turn about Phe11-Pro6. The overall structure is folded about Phe7 and Thr10 residues assuming a C-7 conformation for their phi and psi torsions. This model should have important implications on the future design of peptide or nonpeptide ligands with somatostatin-like activities.
引用
收藏
页码:9390 / 9401
页数:12
相关论文
共 54 条
  • [1] INFERENCES ABOUT THE CONFORMATION OF SOMATOSTATIN AT A BIOLOGIC RECEPTOR BASED ON NMR-STUDIES
    ARISON, BH
    HIRSCHMANN, R
    VEBER, DF
    [J]. BIOORGANIC CHEMISTRY, 1978, 7 (04) : 447 - 451
  • [2] MLEV-17-BASED TWO-DIMENSIONAL HOMONUCLEAR MAGNETIZATION TRANSFER SPECTROSCOPY
    BAX, A
    DAVIS, DG
    [J]. JOURNAL OF MAGNETIC RESONANCE, 1985, 65 (02) : 355 - 360
  • [3] BAX A, 1985, J AM CHEM SOC, V107, P2820
  • [4] BHAT TN, 1979, INT J PEPT PROT RES, V13, P170
  • [5] MULTIPLE QUANTUM SPIN-ECHO SPECTROSCOPY
    BODENHAUSEN, G
    VOLD, RL
    VOLD, RR
    [J]. JOURNAL OF MAGNETIC RESONANCE, 1980, 37 (01) : 93 - 106
  • [6] COMATOSE, A METHOD FOR CONSTRAINED REFINEMENT OF MACROMOLECULAR STRUCTURE BASED ON TWO-DIMENSIONAL NUCLEAR OVERHAUSER EFFECT SPECTRA
    BORGIAS, BA
    JAMES, TL
    [J]. JOURNAL OF MAGNETIC RESONANCE, 1988, 79 (03): : 493 - 512
  • [7] STRUCTURE DETERMINATION OF A TETRASACCHARIDE - TRANSIENT NUCLEAR OVERHAUSER EFFECTS IN THE ROTATING FRAME
    BOTHNERBY, AA
    STEPHENS, RL
    LEE, JM
    WARREN, CD
    JEANLOZ, RW
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1984, 106 (03) : 811 - 813
  • [8] HYPOTHALAMIC POLYPEPTIDE THAT INHIBITS SECRETION OF IMMUNOREACTIVE PITUITARY GROWTH-HORMONE
    BRAZEAU, P
    VALE, W
    BURGUS, R
    LING, N
    BUTCHER, M
    RIVIER, J
    GUILLEMIN, R
    [J]. SCIENCE, 1973, 179 (4068) : 77 - 79
  • [9] CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS
    BROOKS, BR
    BRUCCOLERI, RE
    OLAFSON, BD
    STATES, DJ
    SWAMINATHAN, S
    KARPLUS, M
    [J]. JOURNAL OF COMPUTATIONAL CHEMISTRY, 1983, 4 (02) : 187 - 217
  • [10] REFINEMENT OF ANGULAR DEPENDENCE OF PEPTIDE VICINAL NH-C ALPHA H COUPLING-CONSTANT
    BYSTROV, VF
    IVANOV, VT
    PORTNOVA, SL
    BALASHOVA, TA
    OVCHINNIKOV, YA
    [J]. TETRAHEDRON, 1973, 29 (06) : 873 - 877