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Figure 1 | Microbial Cell Factories

Figure 1

From: Post-production protein stability: trouble beyond the cell factory

Figure 1

Tool boxes through which protein solubility can be enhanced at different stages of protein production and postproduction pipelines. Targets for improvement during in vivo administration are summarized in the red framed box, some of them being modulated by protein aggregation. Appropriate codon selection [82, 83], using weak promoters or low copy number plasmids and protein engineering [84] are the most common upstream strategies (yellow box). Growth at sub-optimal temperatures [85, 86], mild induction of gene expression, co-production of chaperones [8789] or protein production in protease-deficient strains [90, 91] or in mutants with altered redox properties [92] favor correct protein folding (orange box). Buffers and purification conditions should be optimized as per protein basis to prevent aggregation [9397]. Alternatively, soluble protein species can be obtained by refolding inclusion body proteins [3032] or by extracting functional proteins from inclusion bodies by mild procedures [29] (green box). Once purified, aggregation during storage or administration of protein drugs can be inhibited by appropriate excipient formulations or by chemical modification [50, 60, 62, 98] (blue box). Also, the use of delivery systems, either through protein adsorption onto nanoparticles, nano and micro encapsulation or embedding in biocompatible materials stabilize proteins, expand their half-life in the body and permit a sustained release, resulting in enhanced bioavailability and reduced toxicity [63, 64, 99]. Upstream protein engineering strategies that enhance solubility during production can also affect aggregation and performance of protein drugs upon administration. Also, by this approach, novel functions that improve pharmacological performance of proteins can be gained without necessarily enhancing solubility (bottom, green framed box).

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