The DNA binding activity of the transcriptional regulator activator protein-1 shows considerable promise as a target in cancer therapy. A number of different strategies have been employed to inhibit the function of this protein with promise having been demonstrated both in vitro and in vivo. Peptidebased therapeutics have received renewed interest in the last few years, and a number of 37-amino acid peptides capable of binding to the coiled coil dimerization domain of Jun and Fos have been derived. Here, we demonstrate how truncation and semirational library design, followed by protein-fragment complementation, can be used to produce a leucine zipper binding peptide by iterative means. To this end, we have implemented this strategy on the FosW peptide to produce 4hFosW. This peptide is truncated by four residues with comparably favorable binding properties and demonstrates the possibility to design progressively shorter peptides to serve as leucine zipper antagonists while retaining many of the key features of the parent peptide. Whether or not the necessity for low molecular weight antagonists is required from the perspective of druggability and efficacy is subject to debate. However, antagonists of reduced length are worthy of perusal from the point of view of synthetic cost as well as identifying the smallest functional unit that is required for binding.

Truncation, Randomization, and Selection GENERATIONOFAREDUCEDLENGTHc-JunANTAGONISTTHATRETAINSHIGH INTERACTIONSTABILITY *

Activator Protein-1 (AP-1) is an oncogenic transcription factor that is dysregulated in numerous human cancers, making it an attractive therapeutic target. AP-1 forms via interaction of cJun and cFos proteins, which intertwine to generate a ‘coiled coil’ (CC) structure. Thus, the cJun/cFos α-helical CC domains responsible for dimerisation are appealing targets for inhibiting AP-1 formation and activity. Helical peptide antagonists that sequester cJun can be derived from the cFos CC domain by selection of more optimal amino acids for increased binding affinity. Peptides can then be downsized and modified to improve therapeutic potential. Two approaches aimed to identify novel short peptides against cJun. The first was to covalently cyclise amino acid side chains in existing cFos-derived peptide “FosW”, with the aim of constraining FosW into a stable helix to allow downsizing without significant loss of binding structure and affinity. Using circular dichroism spectroscopy and isothermal titration calorimetry, a series of helix constrained peptides were characterised, from which a peptide was identified that retained 88 % of FosW binding affinity whilst being 22 % shorter, and which entered breast cancer cells in vitro, with preliminary data suggesting potential ability to inhibit AP-1 in cellulo. The second approach was to combine two existing high-throughput peptide selection systems, with the aim of benefitting from overlap in their strengths and weaknesses. Combination of in vitro CIS display and in cellulo Protein-fragment Complementation Assay successfully isolated a high affinity peptide from a hugely diverse library, and future refinements to further exploit this approach, particularly for short peptide selection, were formulated. Thus, molecules and techniques derived here may expedite the future development of therapies for cancers featuring AP-1 dysregulation.

Combining library screening approaches, and modifying peptides with helix constraints, to generate novel antagonists of oncogenic Activator Protein-1

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Combining library screening approaches, and modifying peptides with helix constraints, to generate novel antagonists of oncogenic Activator Protein-1