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High affinity binding of conformationally constrained synthetic oligomers to an antigen-specific antibody: Discovery of a diagnostically useful synthetic ligand for murine Type 1 diabetes autoantibodies.

ABSTRACT: 'Antigen surrogates' are synthetic, non-natural molecules that recognize the antigen-binding sites of antibodies. These molecules are of interest as replacements for native antigens as antibody 'capture agents' in ELISA-like assays of potential diagnostic utility, for example when the antibody is indicative of a disease state. Antigen surrogates for disease-related antibodies can be mined from one-bead one-compound (OBOC) libraries by first denuding the library of ligands for antibodies present in the serum of control patients or animals, followed by screening the remainder of the library against serum from individuals with a particular disease of interest. Most of the work in this area has been done with peptoids (oligomers of N-alkylated glycine), which provide antibody ligands with only modest affinity and selectivity. Here, we explore the hypothesis that this is due to the 'floppiness' of the peptoid backbone by creating libraries of peptoid-like molecules that have conformation-restricting structural elements inserted into their backbones. Indeed, we show here that these libraries can provide high affinity and selectivity antigen surrogates and that this much-improved binding is completely dependent on conformational restriction of the oligomer chain.

SUBMITTER: Doran TM

PROVIDER: S-EPMC4607566 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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High affinity binding of conformationally constrained synthetic oligomers to an antigen-specific antibody: Discovery of a diagnostically useful synthetic ligand for murine Type 1 diabetes autoantibodies.

Doran Todd M TM Gao Yu Y Simanski Scott S McEnaney Patrick P Kodadek Thomas T

Bioorganic & medicinal chemistry letters 20150527 21

'Antigen surrogates' are synthetic, non-natural molecules that recognize the antigen-binding sites of antibodies. These molecules are of interest as replacements for native antigens as antibody 'capture agents' in ELISA-like assays of potential diagnostic utility, for example when the antibody is indicative of a disease state. Antigen surrogates for disease-related antibodies can be mined from one-bead one-compound (OBOC) libraries by first denuding the library of ligands for antibodies present ...[more]

PMID: 26067174

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Project description:Photosynthetic reaction centers convert excitation energy from absorbed sunlight into chemical potential energy in the form of a charge-separated state. The rates of the electron transfer reactions necessary to achieve long-lived, high-energy charge-separated states with high quantum yields are determined in part by precise control of the electronic coupling among the chromophores, donors, and acceptors and of the reaction energetics. Successful artificial photosynthetic reaction centers for solar energy conversion have similar requirements. Control of electronic coupling in particular necessitates chemical linkages between active component moieties that both mediate coupling and restrict conformational mobility so that only spatial arrangements that promote favorable coupling are populated. Toward this end, we report the synthesis, structure, and photochemical properties of an artificial reaction center containing two porphyrin electron donor moieties and a fullerene electron acceptor in a macrocyclic arrangement involving a ring of 42 atoms. The two porphyrins are closely spaced, in an arrangement reminiscent of that of the special pair in bacterial reaction centers. The molecule is produced by an unusual cyclization reaction that yields mainly a product with C(2) symmetry and trans-2 disubstitution at the fullerene. The macrocycle maintains a rigid, highly constrained structure that was determined by UV-vis spectroscopy, NMR, mass spectrometry, and molecular modeling at the semiempirical PM6 and DFT (B3LYP/6-31G**) levels. Transient absorption results for the macrocycle in 2-methyltetrahydrofuran reveal photoinduced electron transfer from the porphyrin first excited singlet state to the fullerene to form a P(•+)-C(60)(•-)-P charge separated state with a time constant of 1.1 ps. Photoinduced electron transfer to the fullerene excited singlet state to form the same charge-separated state has a time constant of 15 ps. The charge-separated state is formed with a quantum yield of essentially unity and has a lifetime of 2.7 ns. The ultrafast charge separation coupled with charge recombination that is over 2000 times slower is consistent with a very rigid molecular structure having a small reorganization energy for electron transfer, relative to related porphyrin-fullerene molecules.

Dataset Information

High affinity binding of conformationally constrained synthetic oligomers to an antigen-specific antibody: Discovery of a diagnostically useful synthetic ligand for murine Type 1 diabetes autoantibodies.

Publications

High affinity binding of conformationally constrained synthetic oligomers to an antigen-specific antibody: Discovery of a diagnostically useful synthetic ligand for murine Type 1 diabetes autoantibodies.

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