Water soluable terphenyl derivatives as mimics of Bak peptide that targets Bcl-xL protein

ORGN 586

Hang Yin, Department of Chemistry, Yale University, P.O. BOX 208107, New Haven, CT 06511 and Andrew D. Hamilton, Yale Univeristy.
Alpha-helices play a ubiquitous role in mediating protein-protein interactions. Our group has reported functionalized terphenyls to mimic the discontinuous helical surface of the Bak peptide's BH3 domain(Kutzki, Park et al. 2002). However, relatively poor solubility in polar solvents limited further improvement of this approach. We herein report a family of proteomimetics, based on a both-side-functionalized terphenyl scaffold, that are synthesized in a modular fashion and project hydrophobic side chains with similar distance and angular relationships to those found in alpha-helices. Computational simulation suggested a thermodynonically favored binding to the surface area of Bcl-xL protein, affectively mimicing the Bcl-xL/Bak interaction. By adding a third carboxylic acid functional group on the backside of the terphenyl, significant improvement of solubility in PBS buffer solution was observed. There is ongoing pharmaceutical research based on this development.

 

Bioorganic, Molecular Recognition, Asymmetric Reactions and Syntheses
11:00 AM-1:00 PM, Wednesday, September 10, 2003 Javits Convention Center -- Hall 1B/1C, Poster

Division of Organic Chemistry
The 226th ACS National Meeting, New York, NY, September 7-11, 2003