Background

Pursuing drugs that combine high efficacy with low toxicity remains a relentless endeavor in pharmaceutical research. Presently, the market predominantly features three types of drugs: small molecule drugs, biological agents, and peptide drugs. Compared with traditional small molecule drugs and biological agents, peptide drugs have moderate molecular weight and low immunogenicity. Moreover, some peptide drugs are the smallest active segment of natural proteins, so they have better efficiency; At the same time, the human body naturally contains enzymes that can break down proteins, making peptide drugs a safer choice than the others. Based on the above advantages, peptide drugs are becoming more and more favored. Although peptide drugs are currently less used, we can still find that from 1960 to the present, the overall trend of approved peptide drugs has increased [1].

Figure 1. The data of the peptide drugs market [1][3].

But at the same time, peptide drugs still have some disadvantages. Peptide drugs are difficult to cross the cell membrane, function in the cell, and are easily degraded by proteases in the body, and the half-life is too short. This makes it difficult for peptide drugs to replace traditional drugs in stage completely [2].

Drug Delivery System

To make peptide drugs work better, there are two traditional treatments: amino acid modification of peptide drugs and the addition of drug delivery systems. The former is to increase the half-life by replacing unnatural amino acids and reducing the recognition site of enzymes, while the latter protects peptides by reducing direct contact between enzymes and drugs. At present, common drug delivery system models include liposomes, nanoparticles, particles, and capsules, but they all have some problems. Some of them cost too high, and some of their drug applicability can not be widespread, and some, the delivery may lead to drug leakage and low efficiency. For example, the active drug-loading technology of liposomes is only suitable for weakly alkaline or acidic drugs and can only penetrate if the drug does not have an electric charge [4].

Advantages and Future Problems

Figure 2. The structure and mechanism of T6SS [5].

Therefore, we propose a drug delivery system based on the type six secretory system of gram-negative bacteria in our project, which can overcome the above shortcomings of peptide drugs to a certain extent, making drugs work better, and facilitating the design and development of future drugs. On the other hand, it also provides a new idea and discussion for protein delivery methods, contributing to future scientific research.

Improve Peptide Drug Design and Development

In terms of improving peptide drug delivery, extending the half-life of peptide drugs, and enhancing their efficiency, our T6SS-based drug delivery system can directly secrete protein drugs into target tissue cells, improving the problem of low membrane penetration of peptide drugs. At the same time, because protein drugs directly enter tissue cells to function, the efficiency of drug action can be improved. We believe that this drug delivery method can be used in the future to treat many important diseases, such as the delivery of drugs to kill cancer cells at the right point, to achieve cancer treatment.

In future research, we can study the mechanism of regulating the number of flora, regulate the conditions of protein secretion to achieve the regulation of drug dose and strengthen the specificity of the drug delivery system, to achieve more accurate drug delivery. At the same time, there have been articles demonstrating that the heterologous assembly of T6SS in harmless strains such as E. coli can work. In the future, we can also explore how to implement this drug delivery system in the normal flora of the human body, further enhancing its safety [6].

Develop New Protein Delivery Methods

Traditional protein delivery methods, such as chemistry, are likely to irreversibly impair protein activity. The liposome carrier method has high delivery efficiency, but high toxicity and low stability at the same time, which will lead to drug leakage and off-target effects. In contrast, our T6SS-based protein delivery mechanism is highly specific and preserves the original activity of the protein, which can inspire new protein delivery methods.

In addition to drug delivery, these protein delivery systems can also be used as scientific tools to contribute to future research. For example, tissue cells specifically induce Cre recombinase to enhance the accuracy and efficiency of the Cre-loxp system. We expect this type of protein delivery system to play a greater role in the future [7].

References