Cyclopeptides in plant polypeptide family and their pharmaceutical research

Many therapeutic targets in human diseases are mainly protein protein interaction (PPI), because most PPI It is difficult to block this type of interaction because small molecules can not be discharged from the body, and frequent accumulation of toxic metabolites in organs can lead to adverse reactions On the contrary, protein drugs are composed of natural ingredients with low toxicity, and have fewer adverse reactions because they have more and stronger interaction with the target and have precise specificity for the molecular target, thus having higher effect However, due to their unstable metabolism, lack of oral bioavailability and poor membrane permeability, they can only target extracellular molecules, and are expensive to manufacture, which leads people to seek alternative protein scaffolds as a source of new therapeutic agents Peptide compound is a kind of compound with amide bond, which can be divided into straight chain peptide compound and cyclic peptide compound In the 1940s, the first antimicrobial peptide, ramicidin s, was discovered In the past few decades, a large number of cyclic peptides with special structures have been isolated from plants, bacteria, fungi and marine organisms Because of its high stability, special structure, rich activity and wide distribution, cyclopeptide has become a hot topic in drug development and research in recent years Cyclopeptides are hyperstable peptides from plants The three disulfide bonds that form cystine bonds and cyclization skeleton from head to tail are very stable Compared with other peptides of similar size, the unique topological structure of cyclopeptides makes them extremely stable to chemical, thermal and biological degradation, and their excellent stability and tolerance to sequence substitution can make them used as a framework for drug design The natural function of cyclopeptides is considered as plant defense molecules, because they are widely expressed in plant tissues and have anti insect, nematode and mollusc activities The abnormal stability of cyclopeptides lays a foundation for its application in protein engineering and drug design The application of cyclopeptides in pharmaceutical research can be divided into three categories according to whether the cyclopeptides have been replaced in structure and the degree of replacement: natural cyclopeptides, point mutation cyclopeptides, "grafting" cyclopeptides Naturally occurring cyclopeptides have many potential biological activities, including uterine contraction, hemolysis, antibacterial, anti HIV, anti-tumor activities and so on Although natural cyclopeptides have the above extensive biological functions, some cyclopeptides have limited development potential in medical treatment due to their hemolytic effect However, the minimal single point mutation of cyclopeptides does not affect their structural stability and biological activity, but also reduces their unwelcome hemolytic activity in pharmaceutical applications Therefore, we explore a single amino acid The influence on the structural integrity and biological activity of cyclopeptides is very important to promote their application in protein engineering and pharmacy As a therapeutic agent, cyclopeptide has the most promising application not only in the development of natural activity of cyclopeptide, but also in the local change of its original activity On the basis of point mutation, cyclopeptide is highly resistant to sequence change, so that they can be used as a framework for molecular "grafting" with longer segments to produce new biology Active cyclic peptide Although linear bioactive peptides may have great potential, they are usually easy to be degraded by protease, so they may not be able to reach their target if they are administered throughout the body; on the contrary, incorporation of bioactive epitopes into cyclopeptide scaffolds can protect them from degradation This process is also known as "grafting", which refers to one or more natural peptide scaffolds replaced by a sequence of bioactive peptides Ring to form a ring heterozygote with "tailor-made" properties Bioactive epitopes come from a wide range of sources, such as peptides (including natural or synthetic peptides), a peptide sequence (i.e protein fragment) from a larger protein, or a peptide sequence based on a phage library Generally, this kind of cyclopeptide scaffold should not have any unwelcome natural activity For example, in most cases, grafting can remove the hemolytic activity of natural KB1, which is an important aspect of cyclopeptide used in the pharmaceutical field Cyclopeptides are a family of plant polypeptides that have been widely studied and are being accepted as potential drug design scaffolds Although it has potential related to pharmacy, but because some cyclopeptides have different activities, such as the ideal inhibitory activity on the growth of cancer cells, often accompanied by the toxicity to normal cells, so far no cyclopeptides have entered the human clinical trial stage However, the research in this field is still in its infancy, and the experimental results of cyclopeptides in animal models mean that this situation is likely to be realized in the near future At present, the biggest challenge in this field is how to improve the oral bioavailability of cyclopeptides Although some cyclopeptides have been proved to have oral activity, there are few literatures about the actual oral bioavailability, so more quantitative research reports on these parameters are expected in the next few years