Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions

被引:19
作者
Perell, Gabriella T. [1 ]
Staebell, Rachel Lynn [1 ]
Hairani, Mehrdad [1 ]
Cembran, Alessandro [2 ]
Pomerantz, William C. K. [1 ]
机构
[1] Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Dept Chem & Biochem, 1039 Univ Dr, Duluth, MN 55812 USA
关键词
peptide macrocycles; peptidomimetics; protein-protein interactions; stapled peptides; sulfur oxidation; P53-DEPENDENT CANCER-THERAPY; ALPHA-HELICES; STAPLED PEPTIDES; KIX DOMAIN; DRUGGABILITY ASSESSMENT; PI-INTERACTION; CROSS-LINKING; SIDE-CHAIN; BH3; HELIX; METHIONINE;
D O I
10.1002/cbic.201700222
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Thioethers, sulfoxides, and sulfonium ions, despite diverse physicochemical properties, all engage in noncovalent interactions with proteins. Thioether-containing macrocycles are also attracting attention as protein-protein interaction (PPI) inhibitors. Here, we used a model PPI between -helical mixed lineage leukemia (MLL) protein and kinase-inducible domain interacting (KIX) domain to evaluate oxidation effects on sulfurcontaining macrocycle structure, stability, and protein affinity. Desolvation effects from various polarity states were evaluated computationally and experimentally at the side chain, amino acid, and peptide level. Sulfur-containing side chains spanned polarity ranges between all-hydrocarbon and lactam bridges for modulating solubility, cellular uptake, and affinity. Helical propensity studies showed that, although oxidized sulfur-containing side chains could be tolerated, conformational effects were sequence-dependent. In some cases, proteolytic stability, binding capacity with KIX, and increased helicity were obtained as first steps toward developing PPI inhibitors.
引用
收藏
页码:1836 / 1844
页数:9
相关论文
共 57 条
[51]   SIDE-CHAIN INTERACTIONS BETWEEN SULFUR-CONTAINING AMINO-ACIDS AND PHENYLALANINE IN ALPHA-HELICES [J].
VIGUERA, AR ;
SERRANO, L .
BIOCHEMISTRY, 1995, 34 (27) :8771-8779
[52]   Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix [J].
Walensky, LD ;
Kung, AL ;
Escher, I ;
Malia, TJ ;
Barbuto, S ;
Wright, RD ;
Wagner, G ;
Verdine, GL ;
Korsmeyer, SJ .
SCIENCE, 2004, 305 (5689) :1466-1470
[53]   Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease [J].
Wang, J ;
Iwasaki, H ;
Krivtsov, A ;
Febbo, PG ;
Thorner, AR ;
Ernst, P ;
Anastasiadou, E ;
Kutok, JL ;
Kogan, SC ;
Zinkel, SS ;
Fisher, JK ;
Hess, JL ;
Golub, TR ;
Armstrong, SA ;
Akashi, K ;
Korsmeyer, SJ .
EMBO JOURNAL, 2005, 24 (02) :368-381
[54]  
Wang Y. X., 2015, ANGEW CHEM, V127, P11081
[55]   A Thiol-Ene Coupling Approach to Native Peptide Stapling and Macrocyclization [J].
Wang, Yuanxiang ;
Chou, Danny Hung-Chieh .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2015, 54 (37) :10931-10934
[56]   Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity [J].
Zhang, Qingzhou ;
Jiang, Fan ;
Zhao, Bingchuan ;
Lin, Huacan ;
Tian, Yuan ;
Xie, Mingsheng ;
Bai, Guoyun ;
Gilbert, Adam M. ;
Goetz, Gilles H. ;
Liras, Spiros ;
Mathiowetz, Alan A. ;
Price, David A. ;
Song, Kun ;
Tu, Meihua ;
Wu, Yujie ;
Wang, Tao ;
Flanagan, Mark E. ;
Wu, Yun-Dong ;
Li, Zigang .
SCIENTIFIC REPORTS, 2016, 6
[57]   Solution structure of the KIX domain of CBP bound to the transactivation domain of c-Myb [J].
Zor, T ;
De Guzman, RN ;
Dyson, HJ ;
Wright, PE .
JOURNAL OF MOLECULAR BIOLOGY, 2004, 337 (03) :521-534