Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide.

IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions.

A Semisynthetic Strategy Leads to Alteration of the Backbone Amidate Ligand in the NiSOD Active Site.

Computational investigations have implicated the amidate ligand in nickel superoxide dismutase (NiSOD) in stabilizing Ni-centered redox catalysis and in preventing cysteine thiolate ligand oxidation. To test these predictions, we have used an experimental approach utilizing a semisynthetic scheme that employs native chemical ligation of a pentapeptide (HCDLP) to recombinant S. coelicolor NiSOD lacking these N-terminal residues, NΔ5-NiSOD.

Novel alpha,alpha-difluorohomophthalimides via copper-catalyzed tandom cross-coupling-cyclization of 2-halobenzamides with alpha,alpha-difluoro Reformatskii reagent.

Novel alpha,alpha-difluorohomophthalimides 2 were prepared by reacting N-substituted 2-halobenzamides with the alpha,alpha-difluoro Reformatskii reagent BrZnCF2CO2Et (3) in the presence of CuBr at room temperature. The synthesis involves a CuBr-mediated cross-coupling of 3 with aryl iodides or activated aryl bromides, followed by a spontaneous cyclization of the ethyl 2-benzamido-alpha,alpha-difluoroacetate intermediates at room temperature. N-unsubstituted alpha,alpha-difluorohomophthalimides 2 (R' = H), bearing an acidic imide proton capable of acting as a carboxylic acid bioisostere, were also prepared by reacting 3 equiv of 3 with the parent 2-iodobenzamides.

Site-specific polymer attachment to a CCL-5 (RANTES) analogue by oxime exchange.

A synthetic strategy that allows for the site-specific attachment of polymers such as poly(ethylene glycol) (PEG) to protein pharmaceuticals is described. PEG was attached to a 67-amino acid fully synthetic CCL-5 (RANTES) analogue at its GAG binding site both to reduce aggregation and to increase the circulating lifetime. Effective protection of an Aoaa chemoselective linker during peptide assembly, total chemical protein synthesis, and protein folding was achieved with an isopropylidene group.

A new approach to the chemical synthesis of keto-proteins.

To increase the versatility of protein-conjugation, an orthogonal protection strategy is described, which enables the efficient synthesis of keto-proteins bearing a reactive ketone functionality using Boc, Fmoc, and chemical ligation methodologies. A 1,3-dithiolane group was used to protect the ketone function of levulinate- and pyruvate-derivatized peptides during solid-phase synthesis, acidolytic cleavage, and purification. When required, the 1,3-dithiolane group could be cleanly removed using aqueous silver or mercuric solutions to regenerate the reactive keto-protein at ambient temperature.