ArticleJournal of pharmaceutical sciences2011
Mechanisms of m-cresol-induced protein aggregation studied using a model protein cytochrome c.
Article in Journal of pharmaceutical sciences, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 38 citations in OpenAlex.
- Chlorogenic Acid Enhances the Chaperone Potential of BSA at Physiological Concentrations on Model Protein Cytochrome c.Cell biochemistry and biophysics · 2025Article
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- Development of the Extended Infusion Set and Its Mechanism of Action.Journal of diabetes science and technology · 2024Article
- Methylparaben as a preservative in the development of a multi-dose HPV-2 vaccine.Human vaccines & immunotherapeutics · 2022Article
- Antimicrobial adhesive films by plasma-enabled polymerisation of m-cresol.Scientific reports · 2022Article
- Factors affecting the physical stability (aggregation) of peptide therapeutics.Interface focus · 2017Review
- Effect of Polysorbate 20 and Polysorbate 80 on the Higher-Order Structure of a Monoclonal Antibody and Its Fab and Fc Fragments Probed Using 2D Nuclear Magnetic Resonance Spectroscopy.Journal of pharmaceutical sciences · 2017Article
- Role of benzyl alcohol in the unfolding and aggregation of interferon α-2a.Journal of pharmaceutical sciences · 2015Article
- Antimicrobial preservatives induce aggregation of interferon alpha-2a: the order in which preservatives induce protein aggregation is independent of the protein.International journal of pharmaceutics · 2014Article
- Structural transformations of cytochrome c upon interaction with cardiolipin.Chemistry and physics of lipids · 2014Review
- Chemical denaturation as a tool in the formulation optimization of biologics.Drug discovery today · 2013Review
- Effect of antimicrobial preservatives on partial protein unfolding and aggregation.Journal of pharmaceutical sciences · 2013Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Multidose protein formulations require an effective antimicrobial preservative (AP) to inhibit microbial growth during long-term storage of unused formulations. m-cresol (CR) is one such AP, but it has been shown to cause protein aggregation. However, the fundamental physical mechanisms underlying such AP-induced protein aggregation are not understood. In this study, we used a model protein cytochrome c to identify the protein unfolding that triggers protein aggregation. CR induced cytochrome c aggregation at preservative concentrations that are commonly used to inhibit microbial growth. Addition of CR decreased the temperature at which the protein aggregated and increased the aggregation rate. However, CR did not perturb the tertiary or secondary structure of cytochrome c. Instead, it populated an "invisible" partially unfolded intermediate where a local protein region around the methionine residue at position 80 was unfolded. Stabilizing the Met80 region drastically decreased the protein aggregation, which conclusively shows that this local protein region acts as an aggregation "hotspot." On the basis of these results, we propose that APs induce protein aggregation by partial rather than global unfolding. Because of the availability of site-specific probes to monitor different levels of protein unfolding, cytochrome c provided a unique advantage in characterizing the partial protein unfolding that triggers protein aggregation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.