重组蛋白药物研发50年回顾与展望(1976～2026)OA

This review looks back on the fifty-year research and development history of recombinant protein drugs since the advent of recombinant DNA technology in the 1970s.The article outlines the research and development evolution trajectory of milestone drugs such as recombinant human insulin,recombinant erythropoietin,and monoclonal antibodies based on the central dogma;it also summarizes common technologies including major expression systems,high-density fermentation,and purification processes.Given that correct folding(renaturation)is one of the greatest challenges in the research and development of recombinant protein drugs,this paper traces the developmental history of the protein folding field and focuses on summarizing the theory of folding intermediates,particularly the dual role of disulfide bonds in folding kinetics:they can not only lock the native state of proteins but also induce folding intermediates to fall into kinetic traps,which provides a theoretical basis for the industrial renaturation of recombinant protein drugs(such as recombinant human endostatin).The author utilizes protein folding theory to further interpret the relationship between the structure of human serum albumin(17 pairs of disulfide bonds,one catalytically active free sulfhydryl group,and its amino acid residue composition)and its function,and inductively proposes the"Albumin 688 Principle":albumin accounts for approximately 60％of the total protein in human plasma,provides about 80％of the free sulfhydryl groups,and maintains roughly 80％of the colloid osmotic pressure.This reveals the quantitative benchmark of albumin concentration and quality as a core homeostatic regulator in the human life system;furthermore,it discusses how young,undamaged,and ultra-pure recombinant albumin may combat organismal aging,providing an important entry point for intervening in systemic diseases and degenerative pathologies.Accordingly,the author suggests further enriching the quality regulation strategies for recombinant protein drugs from the dimensions of protein folding and complex systems science,pointing out that while utilizing silicon-based intelligence to accelerate the successful research and development of recombinant protein drugs,the underlying laws of carbon-based life must still be strictly respected.