Capper MJ, Wright GS, Barbieri L, Luchinat E, Mercatelli E, McAlary L, Yerbury JJ, O'Neill PM, Antonyuk SV, Banci L, Hasnain SS. The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation. Nat Commun. 2018 Apr 27;9(1):1693. PubMed.
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The Scripps Research Institute
This is a really interesting paper reporting a dual-function SOD1 folding and assembly facilitator, ebselen. Ebselen directly reacts with either Cys 57 or Cys 146 within SOD1, forming a transient selenyl-sulfide conjugate, which spontaneously rearranges by selenyl-thiol exchange to afford the native intrasubunit disulfide bond within SOD1 that completes proper tertiary structure acquisition, releasing ebselen selenol. This properly folded monomer can then dimerize with high affinity and undergo macromolecular chaperone-mediated metallization, critical for achieving the high kinetic stability of SOD1, which prevents its aggregation that drives ALS. Two ebselens also covalently react with Cys 111 and Cys111' by transient selenyl-sulfide bond formation, further stabilizing the dimer interface via π-π interactions between two proximal ebselen-derived substructures covalently linked to Cys 111 and Cys 111'. These are transient because glutathione can attack the selenium reforming Cys 111 and 111'. One wonders whether ebselen selenol or ebselen could also non-covalently stabilize the dimer interface of SOD1, since reversible binding likely facilitates the reversible reaction with Cys 111 and Cys 111'. This paper also suggests that a two-drug strategy might be superior for treating mutant SOD-based ALS, whereby ebselen is used to facilitate intrasubunit SOD1 disulfide formation, in combination with a non-reversible electrophile that reacts selectively with Cys 111 and Cys 111' and is capable of making stabilizing π-π interactions. Alternatively, if the glutathione ebselen selenol selenyl-sulfide conjugate could re-react with Cys 111 again and again, then the stoichiometry of ebselen to SOD1 might be more manageable. To my knowledge this is a novel folding and assembly corrector, which could become a drug candidate.
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