6
1 Introduction
growing exponentially and is expected to reach US$25.4 billion in 2018. Notably,
there are still many challenges for endogenous peptide sequences as drugs. These
molecules are usually metabolically unstable and therefore have poor oral availability and membrane penetration. Linear peptides have a short half-life, therefore,
the effective drug concentration to reach the target tissue is insufficient. The short
half-life in plasma is mainly caused by the enzymatic degradation in the blood,
liver, and kidneys, and it is also quickly eliminated by the kidneys. Considering that
oral peptide drugs will be digested by the digestive system, many peptide drugs are
administered through intraperitoneal and intravenous injection [28, 29].
The existing deficiencies of polypeptide drugs can be modified or chemically
altered to improve drug activity and reduce possible side effects. For example, desmopressin (DDAVP) is obtained by modifying an amino acid of vasopressin. This change
can reduce the risk of high blood pressure caused by vasopressin. Another method is
to design interface peptides that specifically bind to a specific area on the surface of
a target protein [30]. The interface peptide strategy has been developed for decades.
The core idea of interface peptide is that the critical sequence in the binding interface
of a PPI can specifically inhibit the interactions between the two proteins. As shown
in Fig. 1.5, it is a general flowchart for designing interface peptide inhibitors [31].
Based on this strategy, several important protein-protein interactions were effectively
blocked by their interfaces peptides, for example, Bcl-2/Bax, P53/MDM2.
The development of peptide drugs has received unprecedented attention and
achieved extraordinary achievements in the past decade. This phenomenon is
largely due to the emergence of a new class of drug modality-stapled peptides.
Stapled peptides are structurally stabilized peptides that adapt α-helical conformation enforced by an artificial side chain crosslinker. The stapled peptides are very
important in interfering with disease-related protein-protein interactions. Compared
with other types of drug modalities, they show remarkable pharmacokinetic advantages, such as high affinity, high specificity, and resistance to protease degradation.
A series of stapled peptides have been devised, as either a single-agent treatment
method or combination therapies. Stapled peptides are considered a breakthrough
with huge potentials and may even change the blueprint of a protein drug development
[31–35].
In the past ten years, the paradigm of disease treatment has undergone fundamental changes from a methodological point of view. Specific targeted therapy has
become the main direction of disease treatment and dominates the trend of future drug
development. Understanding the intracellular processes of drug molecules and the
biological molecules that interact with them are the most critical tasks in the development of drugs for specific diseases. Targeted therapy has led to the arrival of a new
era of drug development, especially the exponential growth of new drug development
strategies for specific cancers. These recently developed drug molecules can be categorized to two types: small-molecular and large-molecular drugs. Small-molecular
drugs are a class of organic/inorganic substances that are structurally stable through
chemical synthesis. Although most small molecules can effectively penetrate cell
membranes and target specific proteins in cells, protein-protein interactions have
a large surface area and a shallow binding pocket, making small-molecular drugs
1 Introduction
growing exponentially and is expected to reach US$25.4 billion in 2018. Notably,
there are still many challenges for endogenous peptide sequences as drugs. These
molecules are usually metabolically unstable and therefore have poor oral availability and membrane penetration. Linear peptides have a short half-life, therefore,
the effective drug concentration to reach the target tissue is insufficient. The short
half-life in plasma is mainly caused by the enzymatic degradation in the blood,
liver, and kidneys, and it is also quickly eliminated by the kidneys. Considering that
oral peptide drugs will be digested by the digestive system, many peptide drugs are
administered through intraperitoneal and intravenous injection [28, 29].
The existing deficiencies of polypeptide drugs can be modified or chemically
altered to improve drug activity and reduce possible side effects. For example, desmopressin (DDAVP) is obtained by modifying an amino acid of vasopressin. This change
can reduce the risk of high blood pressure caused by vasopressin. Another method is
to design interface peptides that specifically bind to a specific area on the surface of
a target protein [30]. The interface peptide strategy has been developed for decades.
The core idea of interface peptide is that the critical sequence in the binding interface
of a PPI can specifically inhibit the interactions between the two proteins. As shown
in Fig. 1.5, it is a general flowchart for designing interface peptide inhibitors [31].
Based on this strategy, several important protein-protein interactions were effectively
blocked by their interfaces peptides, for example, Bcl-2/Bax, P53/MDM2.
The development of peptide drugs has received unprecedented attention and
achieved extraordinary achievements in the past decade. This phenomenon is
largely due to the emergence of a new class of drug modality-stapled peptides.
Stapled peptides are structurally stabilized peptides that adapt α-helical conformation enforced by an artificial side chain crosslinker. The stapled peptides are very
important in interfering with disease-related protein-protein interactions. Compared
with other types of drug modalities, they show remarkable pharmacokinetic advantages, such as high affinity, high specificity, and resistance to protease degradation.
A series of stapled peptides have been devised, as either a single-agent treatment
method or combination therapies. Stapled peptides are considered a breakthrough
with huge potentials and may even change the blueprint of a protein drug development
[31–35].
In the past ten years, the paradigm of disease treatment has undergone fundamental changes from a methodological point of view. Specific targeted therapy has
become the main direction of disease treatment and dominates the trend of future drug
development. Understanding the intracellular processes of drug molecules and the
biological molecules that interact with them are the most critical tasks in the development of drugs for specific diseases. Targeted therapy has led to the arrival of a new
era of drug development, especially the exponential growth of new drug development
strategies for specific cancers. These recently developed drug molecules can be categorized to two types: small-molecular and large-molecular drugs. Small-molecular
drugs are a class of organic/inorganic substances that are structurally stable through
chemical synthesis. Although most small molecules can effectively penetrate cell
membranes and target specific proteins in cells, protein-protein interactions have
a large surface area and a shallow binding pocket, making small-molecular drugs