A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion-Reference-Cited by-同舟云学术

A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion

Published:2021-07-16 Issue:1 Volume:12 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

Sharma Jyoti,Du Ming,Wong Eric,Mutyam Venkateshwar,Li Yao,Chen Jianguo,Wangen Jamie^ORCID,Thrasher Kari,Fu Lianwu,Peng Ning,Tang Liping,Liu Kaimao,Mathew Bini,Bostwick Robert J.,Augelli-Szafran Corinne E.,Bihler Hermann^ORCID,Liang Feng,Mahiou Jerome,Saltz Josef,Rab Andras,Hong Jeong,Sorscher Eric J.,Mendenhall Eric M.^ORCID,Coppola Candice J.,Keeling Kim M.^ORCID,Green Rachel^ORCID,Mense Martin^ORCID,Suto Mark J.,Rowe Steven M.^ORCID,Bedwell David M.^ORCID

Abstract

AbstractPremature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

Link

http://www.nature.com/articles/s41467-021-24575-x.pdf

Reference70 articles.

1. Cutting, G. R. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat. Rev. Genet. 16, 45–56 (2015).

2. Rowe, S. M., Miller, S. & Sorscher, E. J. Cystic fibrosis. N. Engl. J. Med. 352, 1992–2001 (2005).

3. Quon, B. S. & Rowe, S. M. New and emerging targeted therapies for cystic fibrosis. BMJ 352, i859 (2016).

4. Corvol, H., Thompson, K. E., Tabary, O., le Rouzic, P. & Guillot, L. Translating the genetics of cystic fibrosis to personalized medicine. Transl. Res. 168, 40–49 (2016).

5. Welsh, M. J. & Smith, A. E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73, 1251–1254 (1993).

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