The Design, Synthesis, and Application of a Refined Photo-Switchable Cyclic Peptide Scaffold for Beta-Turn Manipulation

Corey Johnson, Purdue University


The concept of manipulating secondary structure has been a powerful method to alter chemical processes and interactions. One of the most recent avenues used in achieving this goal is the field of photopharmacology. The use of light to activate and control chemical processes has been extensively studied for this purpose. It was proposed in Chmielewski group that a cyclic peptide containing a azobenzene-like amino acid could be used to modulate a peptide conformation, into a β-turn. This first-generation macrocycle, FLAp, consisting of four alanine residues split by the azobenzene amino acid and a test β-turn sequence (Asn-Pro-Gly-Gly) showed type II β-turn conformation in the cis form, but no turn in the trans. This result, although promising, showed only a two-fold difference in inhibition of somatostatin receptor when using the somatostatin β-turn sequence (Phe-Trp-Lys-Thr). This small difference in activity was attributed to the flexibility of the macrocycle in the two conformations. Efforts have been made to create a better, more rigid scaffold than that used with FLAp to allow for improved differences between the two conformations of the azobenzene. The FLAp cyclic peptide was altered by only having one alanine residue on either side of the azobenzene to create TAp, for increased rigidity. A second peptide, TApβ, was synthesized using β-alanine residues in place of alanine, for added flexibility within the peptide. The TAp and TApβ peptides were shown to possess type II and type II’ β-turn properties respectively, supported by 2D NOESY NMR and restrained molecular dynamics. The trans isomer of TAp, however showed a kink in the peptide backbone, while the TApβ peptide showed a linear backbone with no kink. With the scaffold of TApβ shown to be optimum for structural distinction between the cis and trans conformations. This sequence was carried forward for biological testing. As a proof of concept, the β-turn of tendamistat (Ser-Trp-Arg-Tyr) was chosen, for its hydrophilicity and its target α-amylase. The resulting peptide tendamistat β (TSβ) was synthesized and compared against its linear form (L-TSβ), as well as a literature control (Bartlett control). The cis conformation of the cyclic peptide TSβ showed lesser activity than its trans counterpart, as well as its linear cis and trans counterpart, against α-amylase. Due to unexpected results it was deemed that tendamistat was not suitable for use within the TApβ scaffold because of conformational restriction of the tendamistat sequence. This may be due to the type I β-turn of tendamistat where Tapβ induces type II’ β-turn formation.




Chmielewski, Purdue University.

Subject Area

Biochemistry|Molecular chemistry

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