Improved correction of F508del-CFTR biogenesis with a folding facilitator and an inhibitor of protein ubiquitination

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:48

Article

Goeckeler-Fried, Jennifer L.¹  Denny, Rajiah Aldrin^2,6  Joshi, Disha³  Hill, Clare⁴  Larsen, Mads B.^5,7  Chiang, Annette N.¹  Frizzell, Raymond A.⁵  Wipf, Peter⁴  Sorscher, Eric J.³  Brodsky, Jeffrey L.¹ 

[1] Univ Pittsburgh, Dept Biol Sci, A320 Langley Hall, Pittsburgh, PA 15260 USA

[2] Pfizer Inc, Dept Inflammat & Immunol, Cambridge, MA 02139 USA

[3] Emory Univ, Dept Pediat, Sch Med, Atlanta, GA 30322 USA

[4] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA

[5] UPMC Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15224 USA

[6] HotSpot Therapeut, Boston, MA 02109 USA

[7] Univ Pittsburgh, Aging Inst, Dept Med, Sch Med, Pittsburgh, PA 15219 USA

关键词: Cystic fibrosis;    CFTR;    ERAD;    Ubiquitin;    Protein folding;    Protein degradation;    E1 ubiquitin activating enzyme;    Trikafta;    Proteasome;    Structure-activity relationship;   

DOI  :  10.1016/j.bmcl.2021.128243

来源: Elsevier

【 摘 要 】

A growing number of diseases are linked to the misfolding of integral membrane proteins, and many of these proteins are targeted for ubiquitin-proteasome-dependent degradation. One such substrate is a mutant form of the Cystic Fibrosis Transmembrane Conductance Regulator (F508del-CFTR). Protein folding correctors that repair the F508del-CFTR folding defect have entered the clinic, but they are unlikely to protect the entire protein from degradation. To increase the pool of F508del-CFTR protein that is available for correction by existing treatments, we determined a structure-activity relationship to improve the efficacy and reduce the toxicity of an inhibitor of the E1 ubiquitin activating enzyme that facilitates F508del-CFTR maturation. A resulting lead compound lacked measurable toxicity and improved the ability of an FDA-approved corrector to augment F508del-CFTR folding, transport the protein to the plasma membrane, and maintain its activity. These data support a proof-of-concept that modest inhibition of substrate ubiquitination improves the activity of small molecule correctors to treat CF and potentially other protein conformational disorders.

【 授权许可】

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