Conformational consequences of cooperative binding of a coiled-coil peptide motif to poly(N-(2-hydroxypropyl) methacrylamide) HPMA copolymers.

Small-angle neutron scattering and pulsed-gradient spin-echo NMR have been used to examine the solution conformation of a series of water soluble poly(N-(2-hydroxypropyl) methacrylamide) P(HPMA) co-polymer drug delivery vehicles incorporating a coiled-coil peptide motif as a novel pH sensitive non-covalent linker. The conformation of the HPMA homopolymer is well-described by a Gaussian coil model and changing pH from pH 7 to pH 5 has little effect on the solution conformation, as quantified via the radius of gyration. Copolymerisation with 5-10mol% of the K3 peptide bearing methacrylate monomer (K3-MA), gave a series of copolymers that exhibited an increase in radius of gyration at both pH's, despite being typically 30% lower in molecular weight, indicating that the K3-MA causes a perturbation (expansion) of the copolymer conformation.

Cell uptake and trafficking behavior of non-covalent, coiled-coil based polymer-drug conjugates.

This paper reports on the cell uptake and trafficking properties of a series of non-covalent polymer-drug conjugates. These nanomedicines are composed of a poly(N-(2-hydroxypropyl)methacrylamide) backbone functionalized with multiple copies of a drug. The drug moieties are attached to the polymer via a non-covalent, so called coiled coil motif, which is formed by heterodimerization of two complementary peptide strands, one of which is attached to the polymer carrier and the other to the drug.

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.

Coiled coils: attractive protein folding motifs for the fabrication of self-assembled, responsive and bioactive materials.

The coiled coil is a superhelical protein structural motif that consists of two or more alpha-helical peptides that are wrapped around each other in superhelical fashion. Coiled coils are amongst the most ubiquitous folding motifs found in proteins and have not only been identified in structural proteins but also play an important role in various intracellular regulation processes as well as membrane fusion. The aim of this critical review is to highlight the potential of coiled coil peptide sequences for the development of self-assembled, responsive and/or bioactive materials.

Hybrid polymer therapeutics incorporating bioresponsive, coiled coil peptide linkers.

This article reports the design, synthesis and results of first in vitro model studies of a conceptually novel class of polymer therapeutics in which the cargo is attached to a polymer backbone via a noncovalent, biologically inspired coiled coil linker, which is formed by heterodimerization of two complementary peptide sequences that are linked to the polymer carrier and the cargo, respectively. In contrast with the polymer-drug conjugates prepared so far, in which the drug is typically attached via an enzymatically or hydrolytically cleavable linker, the noncovalent polymer therapeutics proposed in this article offer several potential advantages, including facile access to combination therapeutics and rapid production of compound libraries to screen for structure-activity relationships. Furthermore, the coiled coil based peptide linkers may not only be useful to bind and release guests but may also play an active role in enhancing and directing intracellular transport and trafficking, which may make these constructs of particular interest for the cytosolic delivery of biomolecular therapeutics.

pH-sensitivity of the E3/K3 heterodimeric coiled coil.

This manuscript reports on the self-assembly properties of two complementary peptide sequences, E3 and K3, which are derived from the known IAAL E3/K3 heterodimeric coiled coil motif. Circular dichroism spectroscopy, analytical ultracentrifugation, and fluorescence resonance energy transfer experiments indicated that a stoichiometric mixture of these two peptides forms a stable heterodimeric coiled coil at pH 7. At pH 5, in contrast, the E3/K3 heterodimeric coiled coil is unstable and unfolds to generate E3 homotrimers that coexist with K3 unimers and a small fraction of K3 homodimers.