In vivo programming of endogenous antibodies via oral administration of adaptor ligands.

Vaccination is a reliable method of prophylaxis and a crucial measure for public health. However, the majority of vaccines cannot be administered orally due to their degradation in the harsh gut environment or inability to cross the GI tract. In this study, we report the first proof-of-concept study of orally producible chemically programmed antibodies via specific conjugation of adaptor ligands to endogenous antibodies, in vivo. Pre-immuniztion with 2,4-dinitrophenyl (DNP), or the reactive hapten, 1,3-diketone (DK), or a novel reactive hapten, vinyl sulfone (VS) in mice, followed by oral administration of adaptor ligands composed of the hapten and biotin to the pre-immunized mice resulted in successful in vivo formation of the biotin-hapten-antibody complexes within 2h. Pharmacokinetic evaluations revealed that apparent serum concentrations of programmed antibodies were up to 144nM and that the serum half-lives reached up to 34.4h. These findings show promise for the future development of orally bioavailable drug-hapten-antibody complexes asa strategy to quickly and easily modulate immune targets for aggressive pathogens as well as cancer.

A chemically programmed antibody is a long-lasting and potent inhibitor of influenza neuraminidase.

Programming an anti-flu strategy: A new and potent neuraminidase inhibitor that maintains long-term systemic exposure of an antibody and the therapeutic activity of the neuraminadase inhibitor zanamivir has been created. This strategy could provide a promising new class of influenza A drugs for therapy and prophylaxis, and validates enzyme inhibitors as programming agents in synthetic immunology.

Synthesis of an enantiopure isoxazolidine monomer for ß-aspartic acid in chemoselective ß-oligopeptide synthesis.

The synthesis of an enantiopure isoxazolidine monomer for the incorporation of ß(3)-apartic acid residues into ß(3)-oligopeptides via chemoselective α-ketoacid-hydroxylamine amide formation. This route involves nitrone cycloaddition of 3-thiophenylpropanal and circumvents limitations of other potential starting materials.

Iterative, aqueous synthesis of beta3-oligopeptides without coupling reagents.

The chemoselective synthesis of amides by decarboxylative couplings of alpha-ketoacids and isoxazolidines makes possible an iterative approach to poly-beta3-peptides. Peptide assembly occurs under aqueous conditions and requires no coupling reagents. The requisite isoxazolidine monomers are prepared in enantiopure form by a convenient two-step protocol starting from the appropriate aldehydes.