Peptide Knowledge Center

Overcoming the 4 problems of new peptide drug study

Peptide drugs have many advantages and have become one of the hot spots of innovative drug research and development worldwide.However, its metabolic stability, short half-life, and difficulty in passing through the tissue barrier hinder the clinical application of new peptide drugs.For this reason, scientists have studied a series of new peptide drug development strategies


What is peptide ?

Peptides are organic molecular compounds formed by condensation between amino acid molecules. Generally, the number of amino acids less than 50 is called a peptide, and those with more than 50 are called proteins. From a chemical point of view, there is no essential difference between peptides and proteins.


Tens of thousands of peptides have been discovered so far. Peptides are involved in hormones, nerves, cell growth and reproduction and other fields, and extensively regulate the functional activities of systems, organs and cells in the system. Therefore, many active peptides have been developed into drugs, which are widely used in the diagnosis and treatment of endocrine, immune, neurological, tumor and infection diseases.


6 advantages of peptide drugs

1. Peptide drugs have a wide range of indications and significant effects.

2. It has low side effects and almost no metabolic toxicity. Will not accumulate in the body and cause poisoning.

3. Peptide has good stability, high purity and almost no immunogenicity.

4. The molecule is small, and easier to study its structure-activity relationship which means peptide can be easily modified.

5. Peptide drugs are highly targeted, have clear goals and short development cycle, has a high development success rate.

6. Easy to synthesize and obtain raw materials , suitable for industrial development.


2 disadvantages

1. Poor metabolic stability and short half-life

2. Difficult to pass through the human tissue barrier, low bioavailability.


In this article, 5 directions for solving new peptide drug development problems are discussed.


1. Synthesis of unnatural amino acids

Amino acids are the most basic unit of peptides. There are only 20 naturally occurring amino acids, but these 20 amino acids can form a variety of peptide molecules and proteins through different combinations. The introduction of non-natural amino acids can give new peptide drugs new activities, such as improved stability, enhanced penetration, and increased therapeutic effects.


The use of asymmetric synthesis technology can realize the efficient, convenient, economical and environmentally friendly synthesis of unnatural amino acids.With rosin amine-chiral thiourea bifunctional catalyst as the main system, the efficient synthesis of а,ß,ƴ unnatural amino acids is realized.Using binuclear zinc as a catalyst, the asymmetric formation of phosphorous acid on unsaturated carbonyl compounds and imines is realized.A series of organic catalytic reaction systems were constructed to obtain various indole functional groups and unnatural tryptophan modules.


2. Antimicrobial peptide research (AMP)

What is antimicrobial peptide?

Antimicrobial peptide (AMP) is a part of the molecular defense mechanism that has been preserved during biological evolution. It is generally an amphipathic cationic peptide composed of less than 50 amino acids. Since the discovery of cecropins in the 1980s, it has been more than 1,700 antimicrobial peptides have been found in insects, amphibians, mammals, plants and even bacteria.


Antimicrobial peptides have small molecular weight, good thermal stability and water solubility, broad antibacterial spectrum, and also have antiviral, antifungal, antitumor effect. Compared with general antibiotics and anti-tumor drugs, there is no immunogenicity and drug resistance.


Study on anti-tumor activity of antibacterial peptides:

Tumor cell membranes and bacterial cell membranes have common characteristics. The content of phosphatidylserine in tumor cell membranes is 3-7 times that of normal cells, so the surface of tumor cells is also negatively charged. Amphiphilic cationic antimicrobial peptides can selectively bind to and destroy tumor cell membranes through electrostatic attraction, causing tumor cell content to flow out and die.


Polybia-MPI is an antimicrobial peptide containing 14 amino acids extracted from bee venom. The research team conducted research on its anti-tumor activity. The experimental results showed that Polybia-MPI has a strong inhibitory effect on tumor cells. However, its less toxic to normal cells, showing very significant selectivity. Compared with traditional anti-tumor drugs, the unique membrane rupture mechanism of antimicrobial peptides makes it less susceptible to resistance mechanisms.


3.Design and activity study of analgesic peptides

In April 1997, Zadina’s research team discovered two endogenous opioid peptides from bovine brains. Because their properties are similar to morphine, they were named endomorphin-1 (EM-l) and endomorphin-2 (EM-2), these two opioid peptides were also subsequently isolated from the human cerebral cortex.


Endogenous morphine can produce an analgesic effect equivalent to morphine at a lower concentration without morphine-like side effects, so it has the potential to develop into a powerful and low-toxic analgesic drug. However, the development of endomorphin into an analgesic drug for clinical application still faces many difficulties: (1) Receptor selectivity and affinity need to be improved; (2) Enzymatic hydrolysis is poor; (3) Blood-brain barrier (BBB) poor permeability; (4) Problem about tolerance and addiction.


The introduction of some unnatural amino acids can improve the affinity and analgesic activity of endomorphin analogs.Linking the cell-penetrating peptide to the N-terminus of the endomorphin can improve the ability of the endomorphin to penetrate the blood-brain barrier, thereby allowing the peripheral injection of drugs to enter the central nervous system to produce analgesic effects.

Modifying some key restriction sites in the peptide chain can also effectively avoid the recognition of proteolytic enzymes and improve its molecular stability.


4.Design of targeted anti-tumor peptides

Due to the lack of selectivity of traditional anti-tumor drugs, they not only kill tumor cells but also cause serious damage to normal tissue cells, resulting in strong toxic side effects.Connecting traditional anti-tumor drugs with targeted molecules can significantly improve the anti-tumor activity and selectivity of drugs, while reducing toxic and side effects, so targeted drugs have become a hot spot in the development of anti-tumor drugs.


Cell penetrating peptides (CPPs) are a class of short cationic peptides containing 10-30 amino acids. They have been widely used to mediate the entry of large molecules such as proteins, nucleic acids, liposomes, and nanoparticles into cells. When the penetrating peptide is connected with traditional anti-tumor drugs (such as paclitaxel, doxorubicin, etc.), it can significantly enhance the drug's sensitivity to drug-resistant cells.In addition, penetrating peptides also help to improve the water solubility, tissue permeability and distribution of traditional antitumor drugs in tumor tissues.


In recent years, anti-tumor drugs targeting the acidic microenvironment of tumor tissues have developed rapidly. Due to the rapid metabolism of tumor tissue cells and insufficient oxygen supply, cells provide energy through glycolysis to produce large amounts of lactic acid, but tumor blood vessels are abnormal. It cannot be cleared in time, and eventually the pH of the tumor tissue microenvironment is between 5.7 and 7.2, which is significantly lower than the pH 7.4 of normal tissue. This acidic microenvironment is a very effective target for improving the selectivity of penetrating peptides.


Peptide drugs still face many problems in the research and development process, but their potential advantages as clinical drugs promote the rapid development of the peptide industry. This article focuses on solving the problems of poor enzymolysis stability, toxic side effects, and difficulty in penetrating the blood-brain barrier of peptide drugs. By using the advantages of multi-disciplinarity, taking the construction of unnatural amino acids as the forerunner, based on structure-activity research and chemical modification, develop new transformation strategies for the development of innovative peptide drug candidates. Through the application of these strategies, some promising peptide compounds have been obtained.


Through in-depth research on the mechanism and structure-activity relationship of peptide drugs, as well as the development and application of various strategies, the pace of clinical application of peptide drugs has been accelerated.