Impact of Dehydroamino Acids on the Structure and Stability of Incipient 310-Helical Peptides

• Published in: Journal of organic chemistry Vol. 85; no. 3; pp. 1601 - 1613
• Main Authors: Joaquin, Daniel, Lee, Michael A, Kastner, David W, Singh, Jatinder, Morrill, Shardon T, Damstedt, Gracie, Castle, Steven L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.02.2020; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; DESIGN; CONFORMATIONAL PROPERTIES; CRYSTAL-STRUCTURE; AMINO-ACIDS; NMR STRUCTURE CALCULATION; GAMMA-AAPEPTIDES; ALPHA,BETA-DEHYDRO RESIDUES; ENZYME STABILITY; LINEAR PEPTIDES; STEREOSPECIFIC DEHYDRATION
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.9b02747

A comparative study of the impact of small, medium-sized, and bulky α,β-dehydroamino acids (ΔAAs) on the structure and stability of Balaram’s incipient 310-helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a–c that maintained the 310-helical shape of 1. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a–c that preferred a β-sheet-like conformation. The impact of the ΔAA on peptide structure was independent of size, with small (ΔAla), medium-sized (Z-ΔAbu), and bulky (ΔVal) ΔAAs exerting similar effects. The proteolytic stabilities of 1 and its analogs were determined by incubation with Pronase. Z-ΔAbu and ΔVal increased the resistance of peptides to proteolysis when incorporated at the 3-position and had negligible impact on stability when placed at the 1-position, whereas ΔAla-containing peptides degraded rapidly regardless of position. Exposure of peptides 2a–c and 3a–c to the reactive thiol cysteamine revealed that ΔAla-containing peptides underwent conjugate addition at room temperature, while Z-ΔAbu- and ΔVal-containing peptides were inert even at elevated temperatures. These results suggest that both bulky and more accessible medium-sized ΔAAs should be valuable tools for bestowing rigidity and proteolytic stability on bioactive peptides.