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  Rational design of cyclic peptide inhibitors of U2AF homology motif (UHM) domains to modulate pre-mRNA splicing.

Jagtap, P. K. A., Garg, D., Kapp, T. G., Will, C. L., Demme, O., Lührmann, R., et al. (2016). Rational design of cyclic peptide inhibitors of U2AF homology motif (UHM) domains to modulate pre-mRNA splicing. Journal of Medicinal Chemistry, 59(22), 10190-10197. doi:10.1021/acs.jmedchem.6b01118.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-AC71-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-6596-C
Genre: Journal Article

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Jagtap, P. K. A., Author
Garg, D., Author
Kapp, T. G., Author
Will, C. L.1, Author              
Demme, O., Author
Lührmann, R.1, Author              
Kessler, H., Author
Sattler, M., Author
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1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              

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 Abstract: U2AF homology motifs (UHMs) are atypical RNA recognition motif domains that mediate critical protein–protein interactions during the regulation of alternative pre-mRNA splicing and other processes. The recognition of UHM domains by UHM ligand motif (ULM) peptide sequences plays important roles during early steps of spliceosome assembly. Splicing factor 45 kDa (SPF45) is an alternative splicing factor implicated in breast and lung cancers, and splicing regulation of apoptosis-linked pre-mRNAs by SPF45 was shown to depend on interactions between its UHM domain and ULM motifs in constitutive splicing factors. We have developed cyclic peptide inhibitors that target UHM domains. By screening a focused library of linear and cyclic peptides and performing structure–activity relationship analysis, we designed cyclic peptides with 4-fold improved binding affinity for the SPF45 UHM domain compared to native ULM ligands and 270-fold selectivity to discriminate UHM domains from alternative and constitutive splicing factors. These inhibitors are useful tools to modulate and dissect mechanisms of alternative splicing regulation.

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Language(s): eng - English
 Dates: 2016-10-182016
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acs.jmedchem.6b01118
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Title: Journal of Medicinal Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 59 (22) Sequence Number: - Start / End Page: 10190 - 10197 Identifier: -