18
1 Introduction
types to expand the chemical space. How to achieve the chemical diversity of helical
peptides, obtain more peptides with variable linker structures based on a given
sequence, and expand the capacity of the screening library are very important to
optimize the binding affinity and finally result in the most promising peptide leads.
To tackle the challenge in stapled peptides, this thesis aims to establish several peptide
stapling methodology based on theoretical research.
In the second chapter, I introduce the development of a methodology of ‘chiralityinduced helicity’ from the point of view of tether chirality. This system is the first
report to introduce a chiral center on the crosslinker of a stabilized peptide. Since
this system can obtain peptide isomers with the same chemical composition but
completely different structures, it is an ideal platform for studying the relationship between the secondary structure of peptides and their physiochemical properties. In this chapter, I elaborated on the establishment process of this methodology.
Then, based on this platform, the relationship between the secondary structure of the
peptides and the cell permeability of peptide isomers, the peptides’ binding affinity
to target proteins, and the biological stability of the peptides were systematically
compared.
In the third chapter, we utilized the ‘CIH’ strategy in developing peptide modulators for P53/MDM2 interactions. The membrane penetration of peptides is one of the
key factors that affect the biological activity of peptides in the case of targeting intracellular targets. It is necessary to study the factors affecting the membrane penetration
of peptides, especially the influence of the helical structure of peptides on membrane
penetration. Because of the remarkable different cell penetration of CIH isomers,
it provides a good platform to unambiguously investigate the relationship between
bioavailability and secondary structures. The PPI of p53 and MDM2/MDMX, which
is an important cancer treatment target, was selected as a model to test the biological
activity of the CIH peptide. Both in vitro and in vivo experiments revealed that the
P53 mimetic peptide inhibitors stabilized by the CIH method have promising biological activities and safety. Through this study, I demonstrated that the CIH platform
is potential for constructing peptide inhibitors for a variety of PPI targets.
References
1. Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci
U S A 93:13–20
2. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at proteinprotein interfaces. Nat 450:1001–1009
3. Higueruelo AP, Jubb H, Blundell TL (2013) Protein-protein interactions as druggable targets:
recent technological advances. Curr Opin Pharmacol 13:791–796
4. Bogan AA, Thorn KS (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280:1–9
5. Wójcik P, Berlicki Ł (2016) Peptide-based inhibitors of protein–protein interactions. Bioorg
Med Chem Lett 26:707–713
6. Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions:
progressing toward the reality. Chem Biol 21:1102–1114
1 Introduction
types to expand the chemical space. How to achieve the chemical diversity of helical
peptides, obtain more peptides with variable linker structures based on a given
sequence, and expand the capacity of the screening library are very important to
optimize the binding affinity and finally result in the most promising peptide leads.
To tackle the challenge in stapled peptides, this thesis aims to establish several peptide
stapling methodology based on theoretical research.
In the second chapter, I introduce the development of a methodology of ‘chiralityinduced helicity’ from the point of view of tether chirality. This system is the first
report to introduce a chiral center on the crosslinker of a stabilized peptide. Since
this system can obtain peptide isomers with the same chemical composition but
completely different structures, it is an ideal platform for studying the relationship between the secondary structure of peptides and their physiochemical properties. In this chapter, I elaborated on the establishment process of this methodology.
Then, based on this platform, the relationship between the secondary structure of the
peptides and the cell permeability of peptide isomers, the peptides’ binding affinity
to target proteins, and the biological stability of the peptides were systematically
compared.
In the third chapter, we utilized the ‘CIH’ strategy in developing peptide modulators for P53/MDM2 interactions. The membrane penetration of peptides is one of the
key factors that affect the biological activity of peptides in the case of targeting intracellular targets. It is necessary to study the factors affecting the membrane penetration
of peptides, especially the influence of the helical structure of peptides on membrane
penetration. Because of the remarkable different cell penetration of CIH isomers,
it provides a good platform to unambiguously investigate the relationship between
bioavailability and secondary structures. The PPI of p53 and MDM2/MDMX, which
is an important cancer treatment target, was selected as a model to test the biological
activity of the CIH peptide. Both in vitro and in vivo experiments revealed that the
P53 mimetic peptide inhibitors stabilized by the CIH method have promising biological activities and safety. Through this study, I demonstrated that the CIH platform
is potential for constructing peptide inhibitors for a variety of PPI targets.
References
1. Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci
U S A 93:13–20
2. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at proteinprotein interfaces. Nat 450:1001–1009
3. Higueruelo AP, Jubb H, Blundell TL (2013) Protein-protein interactions as druggable targets:
recent technological advances. Curr Opin Pharmacol 13:791–796
4. Bogan AA, Thorn KS (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280:1–9
5. Wójcik P, Berlicki Ł (2016) Peptide-based inhibitors of protein–protein interactions. Bioorg
Med Chem Lett 26:707–713
6. Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions:
progressing toward the reality. Chem Biol 21:1102–1114