ﻣﺮوري ﺑﺮ روشﻫﺎي اﻓﺰاﯾﺶ ﭘﺎﯾﺪاري ﭘﺮوﺗﺌﯿﻦﻫﺎي ﻧﻮﺗﺮﮐﯿﺐ داروﯾﯽ در ﻃﻮل ﻓﺮاﯾﻨﺪ ﺗﻮﻟﯿﺪ و ﻧﮕﻬﺪاري

A review of methods to increase the stability of recombinant pharmaceutical proteins during the production and storage process

ﺗﻮﻟﯿﺪ ﭘﺮوﺗﺌﯿﻦﻫﺎي داروﯾﯽ زﯾﺴﺖ ﻓﻨﺎور ﻧﻘﺶ ﻣﻬﻤﯽ در ﻣﺒﺎرزه ﺑﺮ ﻋﻠﯿﻪ ﺑﯿﻤﺎريﻫﺎ اﯾﻔﺎ ﻣﯽﮐﻨﺪ. ﻓﺮاﯾﻨﺪ ﺗﻮﻟﯿﺪ ﭘﺮوﺗﺌﯿﻨﯽﻫﺎي ﻧﻮﺗﺮﮐﯿﺐ داروﯾﯽ ﻣﺴﯿﺮي ﻣﺴﺘﻘﯿﻢ ﻧﯿﺴﺖ، زﯾﺮا ﻧﯿﺎز ﺑﻪ ﮐﺎر ﻓﺮاوان دارد و از ﺳﻮي دﯾﮕﺮ ﯾﮑﯽ از ﺟﻨﺒﻪﻫﺎي ﻣﻬﻢ و ﻗﺎﺑﻞ ﺗﻮﺟﻪ در ﺗﻮﻟﯿﺪ ﭘﺮوﺗﺌﯿﻦﻫﺎ ﺑﺤﺚ ﭘﺎﯾﺪاري و ﺣﻼﻟﯿﺖ آﻧﻬﺎ در ﻃﻮل ﻓﺮاﯾﻨﺪ ﺑﯿﺎن و ﺧﺎﻟﺺ ﺳﺎزي اﺳﺖ. ﭘﺮوﺗﺌﯿﻦﻫﺎ ﺗﻨﻬﺎ در ﺑﺎزه ﻣﺤﺪودي از ﺷﺮاﯾﻂ دﻣﺎﯾﯽ و اﺳﯿﺪﯾﺘﻪ ﭘﺎﯾﺪار ﻫﺴﺘﻨﺪ و ﺑﺴﯿﺎر ﻣﺴﺘﻌﺪ ﺗﺨﺮﯾﺐ ﻓﯿﺰﯾﮑﯽ و ﺷﯿﻤﯿﺎﯾﯽ ﻫﺴﺘﻨﺪ. اﻣﺮوزه راﻫﮑﺎرﻫﺎي ﻣﺨﺘﻠﻔﯽ ﺑﻪ ﻣﻨﻈﻮر اﻓﺰاﯾﺶ ﻣﯿﺰان ﺣﻼﻟﯿﺖ و ﭘﺎﯾﺪاري ﭘﺮوﺗﺌﯿﻦﻫﺎ اراﯾﻪ ﺷﺪه اﺳﺖ ﮐﻪ ﺷﺎﻣﻞ ﺗﻐﯿﯿﺮات ﻫﺪاﯾﺖ ﺷﺪه در ﻣﻠﮑﻮل ﭘﺮوﺗﺌﯿﻦ و ﺑﻬﯿﻨﻪ ﺳﺎزي در دﺳﺘﻮراﻟﻌﻤﻞﻫﺎي ﺑﯿﺎن، ﺧﺎﻟﺺ ﺳﺎزي و ﻓﺮآﯾﻨﺪ ﺣﻼﻟﯿﺖ ﭘﺮوﺗﺌﯿﻦﻫﺎ اﺳﺖ ﮐﻪ در اﻏﻠﺐ اوﻗﺎت روﯾﮑﺮد اول ﻣﻤﮑﻦ و دﺳﺖ ﯾﺎﻓﺘﻨﯽ ﻧﯿﺴﺖ. اﯾﻦ ﻣﻄﺎﻟﻌﻪ ﻣﺮوري ﺑﻪ اراﺋﻪ راﻫﮑﺎرﻫﺎي ﺟﻬﺖ اﻓﺰاﯾﺶ ﭘﺎﯾﺪاري ﭘﺮوﺗﺌﯿﻦﻫﺎ در ﺳﻄﻮح ﻣﺨﺘﻠﻒ ﻣﯽﭘﺮدازد، از ﺟﻤﻠﻪ ﺑﺮرﺳﯽ ﺗﺎﺛﯿﺮ ﻃﺮاﺣﯽ ﺳﺎزه ﺑﯿﺎﻧﯽ، ﺗﻮاﻟﯽ و دﻧﺒﺎﻟﻪ ﻫﺎي ﭘﺮوﺗﺌﯿﻨﯽ ﺑﺮ روي ﭘﺎﯾﺪاري، اﻧﺘﺨﺎب ﺑﻬﯿﻨﻪ ﺳﻠﻮل ﻣﯿﺰﺑﺎن و ﺑﻬﺒﻮد ﺷﺮاﯾﻂ ﺑﯿﺎن ﻧﯿﺰ ﻣﻮرد ﺑﺤﺚ ﻗﺮار ﻣﯽﮔﯿﺮد، ﻫﻤﭽﻨﯿﻦ ﺗﺎﺛﯿﺮ ﺑﻬﯿﻨﻪ ﺳﺎزي ﺑﺎﻓﺮﻫﺎي ﺑﻪ ﮐﺎر رﻓﺘﻪ در ﻓﺮﻣﻮﻻﺳﯿﻮن داروﯾﯽ ﻣﺎﻧﻨﺪ اﻧﺘﺨﺎب آﻣﯿﻨﻮ اﺳﯿﺪ ﻫﺎ و اﺳﻤﻮﻻﯾﺖ ﻫﺎي ﻣﻨﺎﺳﺐ ﺑﻪ ﻣﻨﻈﻮر اﻓﺰاﯾﺶ ﭘﺎﯾﺪاري ﭘﺮوﺗﺌﯿﻦ و ﭼﮕﻮﻧﮕﯽ ﺗﺎﺛﯿﺮ ﻗﻨﺪ ﻫﺎ و ﭘﻠﯽ اُلﻫﺎ ﺑﺮ روي ﭘﺎﯾﺪاري ﭘﺮوﺗﺌﯿﻦﻫﺎ ﻧﻮﺗﺮﮐﯿﺐ داروﯾﯽ ﻧﯿﺰ ﻣﻮرد ﺑﺮرﺳﯽ ﻗﺮار ﻣﯽﮔﯿﺮد.

The production of biotechnological drug proteins plays an important role against disease. The process of producing drug recombinant proteins is not a direct path, because it requires a lot of work and on the other hand, one of the important and significant aspects in the production of proteins is the discussion of their stability and solubility during the expression and purification process. Proteins are stable only in a limited range of temperature and acidity conditions and are highly susceptible to physical and chemical degradation. Today, various solutions have been proposed to increase the solubility and stability of proteins, including guided changes in the protein molecule, and optimization of the instructions for expression, purification and solubility of proteins, which is often the first approach that is not possible. This review article provides solutions to increase the stability of proteins at different levels, including the study of the effect of expression construct design, protein tags and sequences on stability, optimal host cell selection and improved expression conditions. The effect of optimizing buffers used in pharmaceutical formulations such as selecting appropriate amino acids and osmolytes to increase protein stability and how sugars and polyols affect the stability of recombinant pharmaceutical proteins is also investigated.