Stabilization of peptides against proteolysis through disulfide-bridged conjugation with synthetic aromatics.
Peptides have been promising molecular scaffolds for the development of potential therapeutics with high affinity and specificity to biomacromolecules. However, their inherent proteolytic instability significantly hampers their biological applications. Strategies that can stabilize peptides against proteolytic digestion on the basis of noncovalent interactions-without extensive manipulation of the sequence or use of unnatural residues-are greatly desired. In this work, we developed a general, convenient, and efficient strategy for the stabilization of peptides against proteolysis, which involves noncovalent π-π interactions between aromatic amino acid residues in peptides and synthetic electron-deficient aromatics (NDI), together with the implication of steric hindrance (from the bulky NDI moiety), and the enhancement of peptide α-helicity. This strategy is complementary in concept to the conventional well-established covalent approaches for peptide stabilization, and is thus promising for being utilized, in combination with the latter ones, to circumvent the problem of proteolytic instability of peptides. We envisioned that this study should provide invaluable guidelines to the design and synthesis of organic molecule-peptide hybrids with significantly improved proteolytic resistance, and benefit the development of peptide therapeutics and probes.
The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, P. R. China. chlwu@xmu.edu.cn.
Yaqi
Y
Chen
The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, P. R. China. chlwu@xmu.edu.cn.
Tao
T
Li
Singapore Eye Research Institute, 20 College Road, 169856, Singapore and Bioinformatics Institute (A*STAR), 30 Biopolis Street, Matrix, 138671, Singapore.
Jianguo
J
Li
The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, P. R. China. chlwu@xmu.edu.cn.
Shiyan
S
Cheng
The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, P. R. China. chlwu@xmu.edu.cn.
Jinghui
J
Wang
Bioinformatics Institute (A*STAR), 30 Biopolis Street, Matrix, 138671, Singapore and National University of Singapore, Department of Biological Sciences, Singapore and Nanyang Technological University, School of Biological Sciences, Singapore.
Chandra
C
Verma
The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, P. R. China. chlwu@xmu.edu.cn.
Yibing
Y
Zhao
The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, P. R. China. chlwu@xmu.edu.cn.
Chuanliu
http://orcid.org/0000-0003-2946-7299
C
Wu
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects*; D013329:Structure-Activity Relationship
D004220:Disulfides; D007094:Imides; D009281:Naphthalenes; D010455:Peptides; C542131:naphthalenediimide