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Mutant protein chemical rescue: From mechanisms to therapeutics.

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Title: Mutant protein chemical rescue: From mechanisms to therapeutics.
Authors: O'Meara TR; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Palanski BA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Chen M; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Qiao Y; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Cole PA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: pacole@bwh.harvard.edu.
Source: The Journal of biological chemistry [J Biol Chem] 2025 Apr; Vol. 301 (4), pp. 108417. Date of Electronic Publication: 2025 Mar 18.
Publication Type: Journal Article; Review; Research Support, N.I.H., Extramural
Language: English
Journal Info: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Imprint Name(s): Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
MeSH Terms: Mutant Proteins*/genetics , Mutant Proteins*/chemistry , Mutant Proteins*/metabolism , Protein Engineering*/methods , Mutation*, Humans ; Protein Folding ; Animals ; Mutagenesis, Site-Directed
Abstract: Chemical rescue is a technique for restoring the activity and/or structure of an engineered or naturally occurring (e.g., disease-associated) mutant protein by the introduction of a "molecular crutch" that abrogates the mutation's effect. This method was developed about 4 decades ago to facilitate mechanistic analysis of enzymes. Since then, a variety of purified proteins inactivated by site-directed mutagenesis have been successfully rescued by substrate moieties or exogenous small molecules, an approach that has continued to serve as an important tool for mechanistic enzymologists. More recently, chemical rescue has been applied to activate engineered proteins in intact biological systems for phenotypic and pathway-level analyses. There is growing interest in therapeutic applications of chemical rescue to correct protein mutations that give rise to human diseases. In this review, we first contextualize chemical rescue and discuss its utility in protein mechanistic analysis. Second, we review the advantages and caveats associated with using this approach to study protein function within biological settings. Third, we provide an overview of efforts to develop folding correctors that restore the proper function of disease-associated protein mutants. To conclude, future directions and challenges for the chemical rescue field are discussed.
(Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Conflicts of interest The authors declare that they do not have conflicts of interest with the contents of this article.
Grant Information: R01 CA074305 United States CA NCI NIH HHS; F32 CA259214 United States CA NCI NIH HHS
Contributed Indexing: Keywords: cells; enzyme; mutation; small molecule; therapeutics
Substance Nomenclature: 0 (Mutant Proteins)
Entry Date(s): Date Created: 20250320 Date Completed: 20250515 Latest Revision: 20260307
Update Code: 20260307
PubMed Central ID: PMC12018205
DOI: 10.1016/j.jbc.2025.108417
PMID: 40113044
Database: MEDLINE
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  Data: Mutant protein chemical rescue: From mechanisms to therapeutics.
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  Data: <searchLink fieldCode="AU" term="%22O'Meara+TR%22">O'Meara TR</searchLink>; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Palanski+BA%22">Palanski BA</searchLink>; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Chen+M%22">Chen M</searchLink>; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Qiao+Y%22">Qiao Y</searchLink>; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.<br /><searchLink fieldCode="AU" term="%22Cole+PA%22">Cole PA</searchLink>; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: pacole@bwh.harvard.edu.
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  Data: <searchLink fieldCode="JN" term="%222985121R%22">The Journal of biological chemistry</searchLink> [J Biol Chem] 2025 Apr; Vol. 301 (4), pp. 108417. <i>Date of Electronic Publication: </i>2025 Mar 18.
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  Data: Journal Article; Review; Research Support, N.I.H., Extramural
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  Data: Chemical rescue is a technique for restoring the activity and/or structure of an engineered or naturally occurring (e.g., disease-associated) mutant protein by the introduction of a "molecular crutch" that abrogates the mutation's effect. This method was developed about 4 decades ago to facilitate mechanistic analysis of enzymes. Since then, a variety of purified proteins inactivated by site-directed mutagenesis have been successfully rescued by substrate moieties or exogenous small molecules, an approach that has continued to serve as an important tool for mechanistic enzymologists. More recently, chemical rescue has been applied to activate engineered proteins in intact biological systems for phenotypic and pathway-level analyses. There is growing interest in therapeutic applications of chemical rescue to correct protein mutations that give rise to human diseases. In this review, we first contextualize chemical rescue and discuss its utility in protein mechanistic analysis. Second, we review the advantages and caveats associated with using this approach to study protein function within biological settings. Third, we provide an overview of efforts to develop folding correctors that restore the proper function of disease-associated protein mutants. To conclude, future directions and challenges for the chemical rescue field are discussed.<br /> (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)
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  Data: Conflicts of interest The authors declare that they do not have conflicts of interest with the contents of this article.
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  Data: R01 CA074305 United States CA NCI NIH HHS; F32 CA259214 United States CA NCI NIH HHS
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  Data: <i>Keywords: </i>cells; enzyme; mutation; small molecule; therapeutics
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  Data: 0 (Mutant Proteins)
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