Synthesis of constrained helical peptides from HIV gp41 by thioether ligation

ORGN 385

Florence M. Brunel, brunel@scripps.edu1, Sarah Church2, Michael B. Zwick, zwick@scripps.edu2, Dennis R. Burton, burton@scripps.edu2, and Philip E. Dawson1. (1) Department of Cell Biology and Chemistry, The Scripps Research Institute, 10550 N.Torrey Pines Rd, CVN 6, La Jolla, CA 92037, (2) Department of Immunology, The Scripps Research Institute, 10550 N.Torrey Pines Rd, IMM2, La Jolla, CA 92037
The α-helix is the most commonly observed secondary structure in proteins. Different methods exist to enhance the helical character of a peptide. One technique is to synthesize (i, i+3) and (i, i+4) lactam bridges. However, the resulting cyclic peptides are usually obtained in modest yield and purity. We have developed a simple method to constrain a peptide via the formation of a cyclothioether. A high yielding, chemoselective ring closure was achieved in aqueous solution following cleavage and side-chain deprotection. Circular dichroism showed an increase in helicity compared to the linear analog and, in some instances, an increase in helicity compared to the corresponding lactam derivative. The straight forward synthesis and high yield makes it an attractive method for enhancing helicity in peptides. This method has been applied to the synthesis of a variety of peptides designed to mimic the epitope of 4E10, an HIV neutralizing antibody.
 

Proteins, Peptides, Amino Acids, and Enzymes
8:00 AM-11:40 AM, Tuesday, 15 March 2005 Convention Center -- Room 9, Oral

Division of Organic Chemistry

The 229th ACS National Meeting, in San Diego, CA, March 13-17, 2005