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目的:设计一种高活性、低副作用的降钙素类似物。方法:根据生物活性肽药物设计原理,结合前人的工作经验,提出提高降钙素分子等电点(pI)、增加N-末端疏水性和C-末端亲水性可以提高新型降钙素活性的假设。以人和鲑鱼降钙素为先导物,设计了大量的降钙素类似物,然后利用蛋白质分析计算软件,逐一分析,综合考虑到副作用与活性的矛盾,确定符合要求的新型降钙素类似物。结果:最终确定的符合要求的降钙素类似物为人和鲑鱼嵌合降钙素(hsCT)。结构预测结果显示新型降钙素类似物符合鲑鱼降钙素的空间构象,其pI值介于人源与鲑鱼源降钙素之间;N-末端疏水性比人降钙素有所增加,与鲑鱼降钙素相当;C-末端疏水情况与鲑鱼降钙素相同。C-末端亲水性与人降钙素比较有很大程度的增加。结论:新型嵌合降钙素活性高于人降钙素,而副作用较鲑鱼降钙素降低。
Objective: To design a high activity, low side effects of calcitonin analogues. Methods: According to the design principles of bioactive peptide drugs, combined with previous work experience, it is proposed that increasing calcitonin molecular isoelectric point (pI), increasing N-terminal hydrophobicity and C-terminal hydrophilicity may improve the activity of new calcitonin Assumptions. With human and salmon calcitonin as the lead, designed a large number of calcitonin analogues, and then the use of protein analysis software, one by one analysis, taking into account the contradiction between side effects and activity to determine the meet the requirements of new calcitonin analogues . Results: The final, satisfactory calcitonin analogues were human and salmon chimeric calcitonin (hsCT). Structural predictions showed that the novel calcitonin analogs conformed to the spatial conformation of salmon calcitonin, with a pI value intermediate between human and salmon-derived calcitonin, an increase in hydrophobicity at the N-terminus compared to human calcitonin, and Salmon calcitonin is comparable; C-terminal hydrophobicity is the same as salmon calcitonin. C-terminal hydrophilicity compared with human calcitonin increased to a large extent. CONCLUSION: The new chimeric calcitonin is more active than human calcitonin and the side effects are lower than salmon calcitonin.