Cumulative updating approved biopharmaceuticals
Recent insights about conformational stress, and in general, to cell responses to protein production in recombinant yeasts have been extensively reviewed elsewhere  and correspond to hormones (insulin, insulin analogues, non glycosylated human growth hormone somatotropin, glucagon), vaccines (hepatitis B virus surface antigen -in the formulation of 15 out of the 28 yeast derived products-) and virus-like particles (VLPs) of the major capsid protein L1 of human papillomavirus type 6, 11, 16 and 18, urate oxidase from Cultured insect cells are used as hosts for recombinant baculovirus infections.
This has generated specific strains of many microbial species adapted to protein production, and has allowed the progressive incorporation of yeasts and eukaryotic systems for this purpose.While IBs formed by enzymes can be efficient catalysers in enzymatic reactions , pharmaceutical proteins need, in contrast, to be dispersed as soluble entities to reach their targets at therapeutic doses.IBs essentially contain the recombinant protein in variable proportions (from 60 to more than 90%) and some contaminants as chaperones, DNA, RNA and lipids [ include hormones (human insulin and insulin analogues, calcitonin, parathyroid hormone, human growth hormone, glucagons, somatropin and insulin growth factor 1), interferons (alfa-1, alfa 2a, alfa-2b and gamma-1b), interleukins 11 and 2, light and heavy chains raised against vascular endothelial growth factor-A, tumor necrosis factor alpha, cholera B subunit protein, B-type natriuretic peptide, granulocyte colony stimulating factor and plasminogen activator (Additional file Production in yeast is usually approached when the target protein is not produced in a soluble form in the prokaryotic system or a specific PTM, essential for its biological activity, cannot be produced artificially on the purified product .In addition, initial methionine removal depends on the side chain of the penultimate amino acid of N-terminal in final recombinant proteins produced in strains have been developed to promote disulfide bond formation (AD494, Origami, Rosetta-gami) and/or with reduced protease activity (BL21).As an additional technical obstacle, proteins larger than 60 k Da are inefficiently obtained in soluble forms in ].The entering into the market of a progressively increasing number of protein drugs produced in non-microbial systems has not impaired the development of products obtained in microbial cells, proving the robustness of the microbial set of cellular systems (so far ) developed for protein drug production.
We summarize here the nature, properties and applications of all those pharmaceuticals and the relevant features of the current and potential producing hosts, in a comparative way.
There is only one approved biopharmaceutical product containing recombinant proteins from infected insect cell line Hi Five, Cervarix, consisting on recombinant papillomavirus C-terminal truncated major capsid protein L1 types 16 and 18.
Nonetheless, this expression system has been extensively used in structural studies since correctly folded eukaryotic proteins can be obtained in a secreted form in serum free media which enormously simplifies protein capture in purification protocols.
Interestingly, it is possible to attach or bind synthetic PTMs in the case of pegylated products  such as human growth hormone, granulocyte colony stimulating factor, interferons alfa-2a and alfa-2b, which renders versions of the protein in serum more stable than the naked product. Furthermore, through genetic engineering of the underlying DNA, the amino acid sequence of the protein can be changed to alter its ADME (absorption, distribution, metabolism, and excretion) properties, as it has been observed for insulin (Table Insulin is a polypeptide of 51 amino acid, 30 of which constitute A chain, and 21 of which comprise B chain. Mutations in amino acid sequences are noted for each of the chains.
strains BL21 codon plus and Rosetta were designed for this purpose).
Recombinant proteins obtained in ] but many others, such as disulfide bond formation, phosphorylation and proteolytic processing might be essential for biological activity.