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Conformationally Constrained Sialyl Analogues as New Potential Binders of h-CD22.

ABSTRACT: Here, two conformationally constrained sialyl analogues were synthesized and characterized in their interaction with the inhibitory Siglec, human CD22 (h-CD22). An orthogonal approach, including biophysical assays (SPR and fluorescence), ligand-based NMR techniques, and molecular modelling, was employed to disentangle the interaction mechanisms at a molecular level. The results showed that the Sialyl-TnThr antigen analogue represents a promising scaffold for the design of novel h-CD22 inhibitors. Our findings also suggest that the introduction of a biphenyl moiety at position 9 of the sialic acid hampers canonical accommodation of the ligand in the protein binding pocket, even though the affinity with respect to the natural ligand is increased. Our results address the search for novel modifications of the Neu5Ac-α(2-6)-Gal epitope, outline new insights for the design and synthesis of high-affinity h-CD22 ligands, and offer novel prospects for therapeutic intervention to prevent autoimmune diseases and B-cell malignancies.

SUBMITTER: Forgione RE

PROVIDER: S-EPMC9315041 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Conformationally Constrained Sialyl Analogues as New Potential Binders of h-CD22.

Forgione Rosa Ester RE Nieto Ferran Fabregat FF Di Carluccio Cristina C Milanesi Francesco F Fruscella Martina M Papi Francesco F Nativi Cristina C Molinaro Antonio A Palladino Pasquale P Scarano Simona S Minunni Maria M Montefiori Marco M Civera Monica M Sattin Sara S Francesconi Oscar O Marchetti Roberta R Silipo Alba A

Chembiochem : a European journal of chemical biology 20220330 10

Here, two conformationally constrained sialyl analogues were synthesized and characterized in their interaction with the inhibitory Siglec, human CD22 (h-CD22). An orthogonal approach, including biophysical assays (SPR and fluorescence), ligand-based NMR techniques, and molecular modelling, was employed to disentangle the interaction mechanisms at a molecular level. The results showed that the Sialyl-TnThr antigen analogue represents a promising scaffold for the design of novel h-CD22 inhibitors ...[more]

PMID: 35313057

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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.

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Conformationally Constrained Sialyl Analogues as New Potential Binders of h-CD22.

Publications

Conformationally Constrained Sialyl Analogues as New Potential Binders of h-CD22.

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