Author:
Hossain Md Amin,Sarin Richa,Donnelly Daniel P.,Miller Brandon C.,Salisbury Joseph P.,Conway Jeremy B.,Watson Samantha,Winters Jenifer N.,Alam Novera,Sivasankar Durgalakshmi,Ponmudiyan Aparna C.,Gawde Tanvi,Kannapadi Sunanda,Auclair Jared R.,Makowski Lee,Petsko Gregory A.,Ringe Dagmar,Greenblatt David J.,Ondrechen Mary Jo,Chen Yunqiu,Manetsch Roman,Agar Jeffrey N.
Abstract
AbstractMutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS). One effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers. Considerable research efforts have been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but these have not yet resulted in an approved drug. We demonstrate that a cyclic thiosulfinate cross-linker can stabilize prevalent disease-causing SOD1 variants. The degree of stabilization afforded by cyclic thiosulfinates (up to 24 °C) is unprecedented. We show this compound works rapidly in vivo with a half-life of ~3 days. The efficacy, low toxicity, and pharmacodynamics of cross-linker mediated stabilization make it a promising therapeutic approach for SOD1-related fALS.Significance statementCyclic thiosulfinate S-XL6 enables the kinetic stabilization of ALS-associated SOD1 variants, in vivo.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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