Bcl-XL-templated assembly of its own protein-protein interaction modulator from fragments decorated with thio acids and sulfonyl azides

Xiangdong Hu, Jiazhi Sun, Hong Gang Wang, Roman Manetsch

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Protein-protein interactions have key importance in various biological processes and modulation of particular protein-protein interactions has been shown to have therapeutic effects. However, disrupting or modulating protein-protein interactions with low-molecular-weight compounds is extremely difficult due to the lack of deep binding pockets on protein surfaces. Herein we describe the development of an unprecedented lead synthesis and discovery method that generates only biologically active compounds from a library of reactive fragments. Using the protein Bcl-XL, a central regulator of programmed cell death, we demonstrated that an amidation reaction between thio acids and sulfonyl azides is applicable for Bcl-XL-templated assembly of inhibitory compounds. We have demonstrated for the first time that kinetic target-guided synthesis can be applied not only on enzymatic targets but also for the discovery of small molecules modulating protein-protein interactions.

Original languageEnglish (US)
Pages (from-to)13820-13821
Number of pages2
JournalJournal of the American Chemical Society
Volume130
Issue number42
DOIs
StatePublished - Oct 22 2008

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Azides
Modulators
Proteins
Acids
bcl-X Protein
Biological Phenomena
Therapeutic Uses
Cell death
Libraries
Membrane Proteins
Cell Death
Molecular Weight
Molecular weight
Modulation
Lead
Molecules
Kinetics

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

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abstract = "Protein-protein interactions have key importance in various biological processes and modulation of particular protein-protein interactions has been shown to have therapeutic effects. However, disrupting or modulating protein-protein interactions with low-molecular-weight compounds is extremely difficult due to the lack of deep binding pockets on protein surfaces. Herein we describe the development of an unprecedented lead synthesis and discovery method that generates only biologically active compounds from a library of reactive fragments. Using the protein Bcl-XL, a central regulator of programmed cell death, we demonstrated that an amidation reaction between thio acids and sulfonyl azides is applicable for Bcl-XL-templated assembly of inhibitory compounds. We have demonstrated for the first time that kinetic target-guided synthesis can be applied not only on enzymatic targets but also for the discovery of small molecules modulating protein-protein interactions.",
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Bcl-XL-templated assembly of its own protein-protein interaction modulator from fragments decorated with thio acids and sulfonyl azides. / Hu, Xiangdong; Sun, Jiazhi; Wang, Hong Gang; Manetsch, Roman.

In: Journal of the American Chemical Society, Vol. 130, No. 42, 22.10.2008, p. 13820-13821.

Research output: Contribution to journalArticle

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