Hybridization of an Aß-specific antibody fragment with aminopyrazole-based ß-sheet ligands displays striking enhancement of target affinity.

Determining Aß levels in body fluids remains a powerful tool in the diagnostics of Alzheimer's disease. This report delineates a new supramolecular strategy which increases the affinity of antibodies towards Aß to make diagnostic procedures more sensitive. A monoclonal antibody IC16 was generated to an N-terminal epitope of Aß and the variable regions of the heavy and light chains were cloned as a recombinant protein (scFv). A 6 × histidine tag was fused to the C-terminus of IC16-scFv allowing hybridization with a small organic ß-sheet binder via Ni-NTA complexation. On the other hand, a multivalent nitrilotriacetic acid (NTA)-equipped trimeric aminopyrazole (AP) derivative was synthesized based on a cyclam platform; and experimental evidence was obtained for efficient Ni(2+)-mediated complex formation with the histidine-tagged antibody species. In a proof of principle experiment the hybrid molecule showed a strong increase in affinity towards Aß. Thus, the specific binding power of recombinant antibody fragments to their ß-sheet rich targets can be conveniently enhanced by non-covalent hybridization with small organic ß-sheet binders.

A Synthetic Methodology Toward Pyrrolo[2,3- b]pyridones for GC Base Pair Recognition.

Flexible synthetic access to a novel biarylic GC binding motif is presented, consisting of a pyridone connected to a fused pyrrolo[2,3- b]pyridone. Extensive molecular modeling led to an optimized design with perfect complementarity to the Hoogsteen site inside DNA's major groove. A wide range of functional elements can be introduced by minor modifications of the synthetic strategy. Our approach relies on mild Pd-catalyzed coupling reactions, featuring a triple heterohalogenated orthogonally addressable pyridine as a key intermediate.

Interactions of calix[n]arenes with nucleic acids.

DNA interaction with artificial binders is of great interest, especially in light of the broad range of possible biomedical applications. The growing understanding of replication, transcription and translation opened the path for new approaches to target pathological effects at a very early stage. Meanwhile, the competitive binding to nucleic acids by designed molecules, which, for example, block certain sequences for natural binders, such as transcription factors, has become a promising concept in the context of gene therapy. On the other extreme, the transport of nucleic acids over the cell membrane into the nucleus by transfection agents opens the possibility to reprogram protein biosynthesis within host cells. In the past decades several substance classes have been developed for a noncovalent specific DNA binding with predictable biological effects, such as peptide nucleic acids or polyamide ligands. Calixarenes have not received so much attention, although they consist of a compact aromatic core tuneable in size, and allow the introduction of cationic functionalities at their upper and lower rims. Formerly being utilized as receptor moieties due to the possibility of complexating guests in their cavities, calixarenes are now also used as molecular scaffolds for multivalent ligands and are, therefore, suitable tools for cooperative DNA complexation. This review surveys specific supramolecular interactions between calixarene derivatives and nucleic acids, with an emphasis on structural elements in the calixarenes and the biological consequences of their complex formation with DNA strands.