Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

A screening assessment of the impact of sedimentological heterogeneity on CO2 migration and stratigraphic-baffling potential: Sherwood and Bunter Sandstones, UK

We use a combination of experimental design, sketch-based reservoir modelling, and flow diagnostics to rapidly screen the impact of sedimentological heterogeneities that constitute baffles and barriers on CO2 migration in depleted hydrocarbon reservoirs and saline aquifers of the Sherwood Sandstone Group and Bunter Sandstone Formation, UK. These storage units consist of fluvial sandstones with subordinate aeolian sandstones, floodplain and sabkha heteroliths, and lacustrine mudstones. The predominant control on effective horizontal permeability is the lateral continuity of aeolian-sandstone intervals. Effective vertical permeability is controlled by the lateral extent, thickness and abundance of lacustrine-mudstone layers and aeolian-sandstone layers, and the mean lateral extent and mean vertical spacing of carbonate-cemented basal channel lags in fluvial facies-association layers. The baffling effect on CO2 migration and retention is approximated by the pore volume injected at breakthrough time, which is controlled largely by three heterogeneities, in order of decreasing impact: (1) the lateral continuity of aeolian-sandstone intervals; (2) the lateral extent of lacustrine-mudstone layers, and (3) the thickness and abundance of fluvial-sandstone, aeolian-sandstone, floodplain-and-sabkha-heterolith and lacustrine-mudstone layers. Future effort should be focussed on characterising these three heterogeneities as a precursor for later capillary, dissolution and mineral trapping

A General Strategy to Endow Natural Fusion-protein-Derived Peptides with Potent Antiviral Activity

Fusion between the viral and target cell membranes is an obligatory step for the infectivity of all enveloped virus, and blocking this process is a clinically validated therapeutic strategy