Sequence-specific polypeptoids: A diverse family of heteropolymers with stable secondary structure

Sequence-specific polypeptoids: A diverse family of heteropolymers with stable secondary structure

Departments of ^†Pharmaceutical Chemistry, ^‖Biomedical Sciences, ^‡‡Cellular and Molecular Pharmacology, and ^††Medicine, University of California, San Francisco, CA 94143; and ^§Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608

Edited by Peter G. Schultz, University of California, Berkeley, CA, and approved January 27, 1998 (received for review September 17, 1997)

Abstract

We have synthesized and characterized a family of structured oligo-N-substituted-glycines (peptoids) up to 36 residues in length by using an efficient solid-phase protocol to incorporate chemically diverse side chains in a sequence-specific fashion. We investigated polypeptoids containing side chains with a chiral center adjacent to the main chain nitrogen. Some of these sequences have stable secondary structure, despite the achirality of the polymer backbone and its lack of hydrogen bond donors. In both aqueous and organic solvents, peptoid oligomers as short as five residues give rise to CD spectra that strongly resemble those of peptide α-helices. Differential scanning calorimetry and CD measurements show that polypeptoid secondary structure is highly stable and that unfolding is reversible and cooperative. Thermodynamic parameters obtained for unfolding are similar to those obtained for the α-helix to coil transitions of peptides. This class of biomimetic polymers may enable the design of self-assembling macromolecules with novel structures and functions.

Footnotes

↵ ‡ Present address: Department of Chemical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208.
↵ ¶ Present address: Axys Pharmaceuticals, 180 Kimball Way, South San Francisco, CA 94080.
↵ ** Present address: CombiChem Inc., 1804 Embarcadero Rd., Suite 201, Palo Alto, CA 94303.
↵ §§ To whom reprint requests should be addressed. e-mail: Ron_Zuckermann{at}cc.chiron.com.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: DSC, differential scanning calorimetry; TFA, trifluoroacetic acid.