Polymer Coiled-Coil Conjugates: Potential for Development as a New Class of Therapeutic “Molecular Switch”
Polymer therapeutics, including polymeric drugs and polymer-protein conjugates, are clinically established as first-generation nanomedicines. Knowing that the coiled-coil peptide motif is fundamentally important in the regulation of many cellular and pathological processes, the aim of these studies was to examine the feasibility of designing polymer conjugates containing the coiled-coil motif as a putative therapeutic "molecular switch". To establish proof of concept, we prepared a mPEG-FosW(C) conjugate by reacting mPEG-maleimide (M-w 5522 g mol(-1) M-w/M-n 1.1) with a FosW peptide synthesized to contain a terminal cysteine residue (FosW(C)). Its ability to form a stable coil-coil heterodimer with the target c-Jun sequence of the oncogenic AP-1 transcription factor was investigated using 2D N-15-HSQC NMR together with a recombinantly prepared N-15-labeled c-Jun peptide ([N-15]r-c-Jun). Observation that heterodimerization was achieved and that the polymer did not sterically disadvantage hybridization suggests an important future for this new family of polymer therapeutics.