Structural Bioinformatics Study On The Design Of Peptibody Drugs

Peptides play an important role in the metabolism of human body, including cell proliferation, cell differentiation, digestion and metabolism, immune defense, tumor lesions, etc.. In 1953, the first time the American biochemist synthesized oxytocin, a peptide that could be used by people. After a long period of development, there are now more than 80 kinds of polypeptide drugs listed in the world, and there are many polypeptide drugs in the research stage. Compared with other drugs, peptide drugs have some unique advantages: good efficiency, high specificity, usually not accumulate in the human body, and very few interactions with other drugs.Compared to other drugs, peptides also have some disadvantages: polypeptide often digested into amino acids with its instability, resulting a very short half-life,so inconveniently patients need reduplicated treatment. In order to solve this problem, a lot of new methods have been tried,and Fusion Protein Technology is one of the effective methods to prolong the half-life of protein and peptide drugs. Fc-Fusion is the most studied and the most developed Protein Fusion Technology, which usually conbines the Fc domain of IgG with the selected peptide. Such Peptide-Antibody fusion proteins are known as Peptibody.Scientists have found that, in the romiplostim, the activity of a complex (Fc segments combines with peptides) was significantly different in different linking ways.The activity of Fc C terminal linking with polypeptide is 10 times higher than that of the Fc N terminal linking with polypeptide. However, it is still unclear whether there is such a general mechanism in all the peptide drugs or not, and so far the researches have more focus on the experimental data rather than theoretical studies.In this thesis, from the perspective of structural bioinformatics, we constructed a model to predict the better linking peptides by the molecular dynamics stimulation.Through analysis of different ways linking peptides with recepters using free energy and energy decomposition methods. Finally we want to uncover a mechanism in which peptide drugs with different connection ways will have different medical activity. It could also provide a theoretical prediction for the future design of peptide drugs.