Process signatures in glatiramer acetate synthesis: structural and functional relationships
| Autor: | Luis Vallejo-Castillo, Isabel Gracia-Mora, Néstor O. Pérez, Leslie Muñoz-García, Rodolfo Salazar-Ceballos, Luis F. Flores-Ortiz, Daniel Herrera-Fernández, Carlos E. Espinosa-de la Garza, Lenin Pavón, Sonia Mayra Pérez-Tapia, Emilio Medina-Rivero, Víctor R. Campos-García, Sandra Avila, German González |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Multidisciplinary Chemistry Manufacturing process lcsh:R lcsh:Medicine Peptide Computational biology Article Amino acid 03 medical and health sciences Hydrolysis 030104 developmental biology 0302 clinical medicine medicine lcsh:Q Glatiramer acetate lcsh:Science 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-12416-1 |
| Popis: | Glatiramer Acetate (GA) is an immunomodulatory medicine approved for the treatment of multiple sclerosis, whose mechanisms of action are yet to be fully elucidated. GA is comprised of a complex mixture of polypeptides with different amino acid sequences and structures. The lack of sensible information about physicochemical characteristics of GA has contributed to its comprehensiveness complexity. Consequently, an unambiguous determination of distinctive attributes that define GA is of highest relevance towards dissecting its identity. Herein we conducted a study of characteristic GA heterogeneities throughout its manufacturing process (process signatures), revealing a strong impact of critical process parameters (CPPs) on the reactivity of amino acid precursors; reaction initiation and polymerization velocities; and peptide solubility, susceptibility to hydrolysis, and size-exclusion properties. Further, distinctive GA heterogeneities were correlated to defined immunological and toxicological profiles, revealing that GA possesses a unique repertoire of active constituents (epitopes) responsible of its immunological responses, whose modification lead to altered profiles. This novel approach established CPPs influence on intact GA peptide mixture, whose physicochemical identity cannot longer rely on reduced properties (based on complete or partial GA degradation), providing advanced knowledge on GA structural and functional relationships to ensure a consistent manufacturing of safe and effective products. |
| Databáze: | OpenAIRE |
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