Abstract
Free radical pathways play a major role in the degradation of protein pharmaceuticals. Inspired by biochemical reactions carried out by thiyl radicals in various enzymatic processes, this review focuses on the role of thiyl radicals in pharmaceutical protein degradation through hydrogen atom transfer, electron transfer, and addition reactions. These processes can lead to the epimerization of amino acids, as well as the formation of various cleavage products and cross-links. Examples are presented for human insulin, human and mouse growth hormone, and monoclonal antibodies.
Highlights
The physical and chemical stability of proteins are critical for the efficacy and safety of protein therapeutics [1,2]
Thiyl radicals and amino acids is of significance for glycyl glycerolenzymes dehydrogenase, synthase,reductase and 4-hydroxyphenylacetate decarboxylase radical (GRE), benzylsuccinate such as ribonucleotide (RNR), pyruvate formate lyase (PFL), glycerol dehydrogenase, benzylsuccinate synthase, and 4-hydroxyphenylacetate decarboxylase [40]
What is of interest here is that these i.e., an SH 2 mechanism that involves the reaction of a thiyl radical with a disulfide bond [100], or via fragmentation products again give testimony to the ability of Cys thiyl radicals (CysS)
Summary
The physical and chemical stability of proteins are critical for the efficacy and safety of protein therapeutics [1,2]. Thiyltransformations radicals can indirectly affect protein structure and function, e.g., via reactions the nonchemical of monoand polyunsaturated fatty acids These transformation reactions can involve oxidation [21,22] and cis/trans-isomerization [22,23,24]. Thiyl chemical radicals can and indirectly affectand protein structure e.g.,radicals, via thewhich nonwhich can partition into the lipid environment, induce the cis/trans-isomerization of unsaturated reactions can involve oxidation [22,23,24]. Thiyl radicals, can partition into thetransformations lipid environment, induce the polyunsaturated cis/trans-isomerization of unsaturated fatty acids enzymatic chemical ofand monoand fatty acids. These transformation fatty acids in biological membranes, e.g., the HS radical [25]
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