Conformationally rigid histone deacetylase inhibitors correct DF508-CFTR protein function

Chris J. Vickers, Christian Adam Olsen, Darren M. Hutt, Ana Montero, Luke J. Leman, Bruce E. Maryanoff, William E. Balch, M. Reza Ghadiri

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Abstract

Histone deacetylase (HDAC) inhibitors have shown partial efficacy toward correcting cystic fibrosis transmembrane conductance regulator (CFTR) protein function in ΔF508- CFTR models. While current treatment options for CF generally concentrate on disease symptoms such as management of inflammation and bacterial infection, therapy using HDAC inhibitors has the potential to treat and correct the underlying etiology associated with the disorder. Subsequently, we have synthesized conformationally well-defined cyclic tetrapeptide derivatives based on the natural product HDAC inhibitor Apicidin, in order to formulate a pharmacophore model to describe and enhance the bioactivity of these molecules. Through this study we have developed HDAC inhibitors which improve CFTR trafficking from the endoplasmic reticulum (ER) while ultimately increasing ion conductance across the plasma membrane of a lung epithelial cell line expressing ΔF508-CFTR.
Original languageEnglish
JournalABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Volume242
Pages (from-to)MEDI 293
ISSN0065-7727
Publication statusPublished - 2011
Event242nd National Meeting of the American-Chemical-Society (ACS) - Denver, CO, United States
Duration: 28 Aug 20111 Sep 2011
Conference number: 242
http://cen.acs.org/articles/89/i26/242nd-ACS-National-Meeting.html

Conference

Conference242nd National Meeting of the American-Chemical-Society (ACS)
Number242
CountryUnited States
CityDenver, CO
Period28/08/201101/09/2011
Internet address

Cite this

Vickers, C. J., Olsen, C. A., Hutt, D. M., Montero, A., Leman, L. J., Maryanoff, B. E., Balch, W. E., & Ghadiri, M. R. (2011). Conformationally rigid histone deacetylase inhibitors correct DF508-CFTR protein function. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 242, MEDI 293.