A GENERAL-METHOD FOR CONSTRAINING SHORT PEPTIDES TO AN ALPHA-HELICAL CONFORMATION

A method for constraining short peptides (<20 residues) of arbitrary s equence to an alpha-helical conformation (similar to 100% helical in H 2O at 25 degrees C) is presented. Glutamine residues at positions i an d i + 7 of the peptides were tethered with an alkanediyl chain between the side chain nitrogen atoms. Peptides containing this tether were r eadily synthesized on the solid phase by amide formation between an al pha,omega-diaminoallcane and the side chain carboxylates of glutamate residues. The resulting cyclic peptides were studied by NMR and CD and were found to adopt an alpha-helical conformation in aqueous solution . The alpha-helix was thermally stable to greater than or equal to 40 degrees C. Corresponding untethered control peptides with N-methylglut amine at the i and i + 7 positions lacked helicity under the same cond itions. Analogous peptides were also prepared for comparison using the thiolysine cross-linking method described previously [Jackson, D. Y.; King, D. S.; Chmielewski, J.; Singh, S.; Schultz, P. G. J. Am Chem. S oc. 1991, 113, 9391-9392].