The DOI matches its Crossref record; 259 of the 266 references it cites were found in a registry or an index.
Unconventional microbial systems for the cost-efficient production of high-quality protein therapeutics
Abstract
Both conventional and innovative biomedical approaches require cost-effective protein drugs with high therapeutic potency, improved bioavailability, biocompatibility, stability and pharmacokinetics. The growing longevity of the human population, the increasing incidence and prevalence of age-related diseases and the better comprehension of genetic-linked disorders prompt to develop natural and engineered drugs addressed to fulfill emerging therapeutic demands. Conventional microbial systems have been for long time exploited to produce biotherapeutics, competing with animal cells due to easier operation and lower process costs. However, both biological platforms exhibit important drawbacks (mainly associated to intracellular retention of the product, lack of post-translational modifications and conformational stresses), that cannot be overcome through further strain optimization merely due to physiological constraints. The metabolic diversity among microorganisms offers a spectrum of unconventional hosts, that, being able to bypass some of these weaknesses, are under progressive incorporation into production pipelines. In this review we describe the main biological traits and potentials of emerging bacterial, yeast, fungal and microalgae systems, by comparing selected leading species with well established conventional organisms with a long run in protein drug production.
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“Moreover, there is evidence that the interplay of protein mutational robustness, protein folding and environmental stress is an additional key factor that determines the evolution of new traits [145,146].”
From Adaptive laboratory evolution—Principles and applications for biotechnology (2013) · cites this paper as [145]
Citations
Cites
Commercial Applications of Microalgae
Spolaore, P., Joannis-Cassan, C., Duran, E., & Isambert, A. (2006) · Journal of Bioscience and Bioengineering · doi:10.1263/jbb.101.87 · Cited by 4,285
Aggresomes: A Cellular Response to Misfolded Proteins
Johnston, J. A., Ward, C. L., & Kopito, R. R. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.7.1883 · Cited by 2,148
Production of recombinant protein therapeutics in cultivated mammalian cells
Wurm, F. M. (2004) · Nature Biotechnology · doi:10.1038/nbt1026 · Cited by 2,032
Aggresomes, inclusion bodies and protein aggregation
Kopito, R. R. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01852-3 · Cited by 1,942
Recombinant protein folding and misfolding in Escherichia coli
Baneyx, F., & Mujacic, M. (2004) · Nature Biotechnology · doi:10.1038/nbt1029 · Cited by 1,497
Microbial Ecology: Fundamentals and Applications
Atlas, R. M., & Bartha, R. (1978) · Cited by 1,261
Protein drug stability: a formulation challenge
Frøkjær, S., & Otzen, D. E. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1695 · Cited by 1,116
Microbial Ecology: Fundamentals and Applications.
Swift, M. J., Atlas, R. M., & Bartha, R. (1982) · Journal of Ecology · doi:10.2307/2259932 · Cited by 1,113
Production of recombinant proteins by microbes and higher organisms
Demain, A. L., & Vaishnav, P. (2009) · Biotechnology Advances · doi:10.1016/j.biotechadv.2009.01.008 · Cited by 1,043
Durocher, Y. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.2.e9 · Cited by 1,037
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Research works printed but not linked: 2
- Evans, 2009, Method of controlling O-linked glycosylation of antibodies, Novozymes Biopharm
- Meyer, 2008, An emerging star for therapeutic and catalytic protein production, BioProcess Int, 6, 10
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Metadata
- Authors
- Corchero, J. L., Gasser, B., Resina, D., Smith, W., Parrilli, E., Vázquez, F., Abasolo, I., Giuliani, M., Jäntti, J., Ferrer, P., Saloheimo, M., Mattanovich, D., Schwartz, S., Tutino, M. L., & Villaverde, A.
- Affiliations
- Austrian Centre of Industrial Biotechnology (Austria) (AT)
- Parc Científic de Barcelona (ES)
- VTT Technical Research Centre of Finland (FI)
- University of Naples Federico II (IT)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Villaverde, Antonio
- ORCID
- Venue
- Biotechnology Advances
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 31
- Issue
- 2
- Pages
- 140-153
- ISSN
- 0734-9750 (ISSN-L)
- OpenAlex
- W2069940872
- Cited by
- 133
- References
- 266
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 10 · 2021: 7 · 2020: 6 · 2019: 8 · 2018: 3 · 2017: 11 · 2016: 20 · 2015: 14 · 2014: 17 · 2013: 11
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biotechnology Advances (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institució Catalana de Recerca i Estudis Avançats
- Steirische Wirtschaftsförderungsgesellschaft
- Instituto de Salud Carlos III
- European Regional Development Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- therapeutic proteins, recombinant protein expression, microbial cell factories, post-translational modification, intracellular retention, recombinant yeast, recombinant bacteria
- MeSH terms
- Animals, Cost-Benefit Analysis, Escherichia coli, Industrial Microbiology, Mammals, Pichia, Protein Processing, Post-Translational, Recombinant Proteins, Saccharomyces cerevisiae, Trichoderma, Protein Engineering, Chlamydomonas reinhardtii, Protein Folding, Pseudoalteromonas
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