(489aj) Employing Thiol-Ene Radical and Azide-Acetylene Click Chemistries for the Preparation of New Polycephalic Peptide Amphiphiles: From Synthesis to Applications

Peptide-amphiphiles (PAs) are gaining interest as a class of self-assembling soft materials for its bio-relevance and biomimetic properties. FMOC solid supported peptide synthesis (FMOC SSPS) is the standard method employed for its preparation. The technique involves the synthesis of a peptide; then selectively acylating an amine on the peptide with a fatty acid. PAs have been exhaustively investigated as self-adjuventing vaccines. In micellar form, PAs have been investigated for applications such as in vivo cell targeting, supported cell growth, inorganic material templating, and catalysis.

The most commonly explored PA architecture consists of a single peptide conjugated to a fatty acid. With this architecture, the aggregation morphology is highly dependent on the peptide sequence and in most cases form elongated micelles. Some strategies have been investigated to control the aggregation morphology. For example, methylating the backbone amides near the peptide-fatty acid interface results in spherical micelles [1]. However it remains a challenge to predict the aggregation morphology a priori based on peptide sequence alone [2]. Some lesser explored architectures include branched and dendron-like PAs [3.4].

Our efforts have been directed toward the synthesis and applications of a PA architecture described as polycephalic. In this architecture peptides diverge from a single point from the fatty acid tail, whether it would be two or three peptides etc. FMOC SSPS compatible click chemistries, specifically thiol-ene and azide-acetylene cycloaddition are employed for the synthesis. There are several motivations for this effort. First it provides a platform to investigate the critical packing parameters of PAs, possibly providing a reliable handle to control aggregate morphology. Second, the multi-headed architecture presents multivalency, otherwise is present only in micellar forms in classical PAs, and could enhance in vivo efficacy. Finally this architecture provides a platform to investigate the cooperativity between peptides on a single PA (e.g. enzymatic activity). Here we present our recent activities involving polycephalic PAs.

[1] Paramonov, S.E.; Jun, H.-W.; Hartgerink, J.D. J. Am. Chem. Soc 2006, 128, 7291-7298.

[2] Makovitzki, A.; Baram, J.; Shai, Y. Biochemistry 2008, 47, 10630-10636.

[3] Guler, M.O., Hsu, L.; Soukasene, S.; Harrington, D. A.; Hulvat, J. F.; Stupp, S. I. Biomacromolecules 2006, 7, 1855-1863.

[4] Toth, I.; Simerska, P.; Yoshio F. Murata, Y. Int. J. Pept. Res. Ther. 2008, 14, 333-330.