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Helix mimetic
alpha-Helices are one of the major secondary structures involved in protein recognition.1 Although terphenyl based alpha-helix mimetics have been shown to inhibit certain protein-protein interactions,2 Jacoby suggested that the simpler biphenyl scaffold can function as a helix mimetic by demonstrating that a 2,6,3',5'-tetrasubstituted biphenyl is superimposable on the side chains of an alpha-helix.3 Since a 2,3’-disubstituted biphenyl therefore represents one face of an alpha-helix, we sought a novel alternative to the 2,3’-disubstituted biphenyl scaffold.
Library HM01 is based on an a-substituted phenyl cyclopropane which is known to mimic the bioactive conformation of an ortho substituted biphenyl scaffold.4 The novel scaffold and linking groups of HM01 are designed to be superimposable on a 2,3’-disubstituted biphenyl group and can be similarly overlayed on the backbone of an alpha-helix.
The library is designed to target protein-protein interactions and other helical recognition motifs such as the pore region of ion channels.
1Murray, J. K., Gellman, S. H., PeptideScience, 2007, 68(5), 657
2 Hamilton et al, J. Am. Chem. Soc., 2001, 5382
3Jacoby, E., Bioorg., Med. Chem. Lett., 2002, 891
4Qiao, J. X., et al, Bioorg. Med. Chem. Lett., 2008, 4118
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