Panchami Prabhakaran

Sequence-Specific Unusual (1→2)-Type Helical Turns in α/β-Hybrid Peptides

This article describes novel conformationally ordered alpha/beta-hybrid peptides consisting of repeating l-proline-anthranilic acid building blocks. These oligomers adopt a compact, right-handed helical architecture determined by the intrinsic conformational preferences of the individual amino acid residues. The striking feature of these oligomers is their ability to display an unusual periodic pseudo beta-turn network of nine-membered hydrogen-bonded rings formed in the forward direction of the sequence by 1-->2 amino acid interactions both in solid-state and in solution. Conformational investigations of several of these oligomers by single-crystal X-ray diffraction, solution-state NMR, and ab initio MO theory suggest that the characteristic steric and dihedral angle restraints exerted by proline are essential for stabilizing the unusual pseudo beta-turn network found in these oligomers. Replacing proline by the conformationally flexible analogue alanine (Ala) or by the conformationally more constrained alpha-amino isobutyric acid (Aib) had an adverse effect on the stabilization of this structural architecture. These findings increase the potential to design novel secondary structure elements profiting from the steric and dihedral angle constraints of the amino acid constituents and help to augment the conformational space available for synthetic oligomer design with diverse backbone structures.

Smart Vaults: Thermally-Responsive Protein Nanocapsules

Synthetic modification of a recombinant protein cage called a vault with stimuli-responsive smart polymers provides access to a new class of biohybrid materials; the polymer nanocapsules retain the structure of the protein cage and exhibit the responsive nature of the polymer. Vaults are naturally occurring ubiquitous ribonucleoprotein particles 41 × 41 × 72.5 nm composed of a protein shell enclosing multiple copies of two proteins and multiple copies of one or more small untranslated RNAs. Recombinant vaults are structurally identical but lack the vault content. Poly(N-isopropylacrylamide) (pNIPAAm), a polymer responsive to heat, was conjugated to recombinant vaults that were composed of ~78 copies of the major vault protein (MVP) modified to contain a cysteine rich region at the N-terminus (CP-MVP). The polymer was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization to have a dansyl group at the alpha end and modified to have a thiol-reactive pyridyl disulfide at the omega end, which readily coupled to CP-MVP vaults. The resulting vault nanocapsules underwent reversible aggregation upon heating above the lower critical solution temperature (LCST) of the polymer as determined by electron microscopy (EM), dynamic light scattering experiments, and UV-vis turbidity analysis. The vault structure remained entirely intact throughout the phase transition; suggesting its use in a myriad of biomedical and biotechnology applications.

Foldamers: They’re Not Just for Biomedical Applications Anymore

Conformationally ordered synthetic oligomers, called foldamers, are a class of compounds that have ushered into prominence, and interest in these systems continues unabated, primarily as a result of the fact that they hold considerable promise for potential applications in biomedical sciences. These synthetic oligomers may provide excellent starting points for the elaboration of peptide mimics that could only be designed with difficulty on the basis of small-molecule scaffolds. By means of diverse synthetic tools, the “bottomup” foldamer approach is also highly useful in engineering new frameworks that can be successfully molded to mimic the structure and functions of biopolymers. The scope and feasibility of this concept is reflected in the exponential growth from its foundation in the early 21st century to the present stage. The recent launch of the heterofoldamer concept has further fuelled activity in this area, essentially because the conformational space that is available for foldamer design can be enormously augmented by developing oligomers that feature a variety of building blocks in the backbone. Despite offering considerable promise because of the enormous structural diversity, a breakthrough in applications of the foldamers in material science, in particular in molecular machines, is yet to be realized. The technique of using foldamers as dynamic receptors for rod-like guest molecules was first described by Moore and coworkers. In their interesting study, it was demonstrated that m-phenylene ethynylene oligomers fold into macromolecular receptors and adopt a helical architecture that binds to hydrophobic guests. In the helical conformation, these oligomers bind nonpolar ligands within the tubular hydrophobic cavity. Along this line, Huc and co-workers recently reported a fascinating finding that conveys clear indications that the time has come to scan the wide repertoire of foldamers for the purpose of developing molecular machines and nanodevices. This idea is valid because foldamers of any desired shape/architecture can be engineered by using delicate and flexible noncovalent interactions, among which the highly directional hydrogen-bonding interaction assumes prime importance. In their classic paper, Huc and coworkers demonstrated that double helical foldamers that are coiled around rod-shaped guest molecules can perform a screw-type motion, which is an unusual phenomenon that is not observed in other molecular machines (Figure 1a). The heterofoldamers described by Huc and co-workers, called

Solid‐Phase Methodology for Synthesis of O‐Alkylated Aromatic Oligoamide Inhibitors of α‐Helix‐Mediated Protein–Protein Interactions

Rapid access to rigid rods: A method is described for the synthesis of 3-O-alkylated aromatic oligobenzamide foldamers that could be used for assembly of libraries of α-helix mimetic inhibitors of protein-protein interactions (see scheme; Fmoc=9-fluorenylmethoxycarbonyl).

Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA

Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein–DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double-stranded DNA are not known. Here, we report the design, synthesis and structural characterization of aromatic oligoamides that fold into single helical conformations and display a double helical array of negatively charged residues in positions that match the phosphate moieties in B-DNA. These molecules were able to inhibit several enzymes possessing non-sequence-selective DNA-binding properties, including topoisomerase 1 and HIV-1 integrase, presumably through specific foldamer–protein interactions, whereas sequence-selective enzymes were not inhibited. Such modular and synthetically accessible DNA mimics provide a versatile platform to design novel inhibitors of protein–DNA interactions.Molecules that mimic the charge surface of B-DNA could enable the inhibition of DNA processive enzymes. Now, helically folded aromatic oligoamide scaffolds have been synthesized that display anions at positions similar to that of B-DNA phosphates. These foldamer mimics can recognize some DNA binding proteins and inhibit enzymes such as HIV integrase and topoisomerase 1.

1,8-Bis(4-meth­oxy-3-nitro­phen­yl)naphthalene

Molecules of the title compound, C24H18N2O6, are located on a twofold rotation axis passing through through the central C—C bond of the naphthalene ring system. The molecular conformation is characterized by a roughly coplanar arrangement of the two substituted phenyl rings [dihedral angle 18.53 (5)°]. These two aryl rings are each twisted by 65.40 (5)° from the plane of the naphthyl unit.