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Self assembly into biofunctional molecules, translating instructions into function

Final Report Summary - BIOFUNCTION (Self assembly into biofunctional molecules, translating instructions into function)

The overall objective of BIOFUNCTION was to develop enabling chemical technologies to address two important problems in biology: detect in a nondestructive fashion gene expression or microRNA sequences in cellulo and, secondly, study the role of multivalency and spatial organization in protein-ligand interaction. Both of these projects harnessed the programmability of nucleic acid hybridization to promote a chemical reaction in the first case or display ligand with define geometrical constrained in the second case.
For nucleic acid sensing and imaging, the nucleic acid sequence to be detected was used to align reagents leading to a reaction yielding a fluorophore. This technology was used to detect messenger and micro RNA associated with cancer in live cells. Furthermore, the same chemistry was used to unmask bioactive drugs opening the door to “smart therapeutics” that could be unleashed in the presence of cancer markers.
The second part of the project used DNA to display diverse molecules (peptides, carbohydrates or drugs) with controlled distance in order to identify the fittest combination of molecules and distance. This technology was first applied to probe the recognition events between HIV’s coat protein (GP120) and antibodies or dendritic cells in order to identify structures that could emulate to epitope of HIV or ligands than could outcompete its interaction with dendritic cells. Furthermore, we demonstrated that large libraries of potential protein ligands could be assembled using smaller libraries of ligand fragments that are combinatorially paired onto a library of DNA template. Following a selection for the fittest library member, the DNA can be amplified to regenerate the library of selected members thus bring the power of reiterative cycles of selection/ amplification to the small molecule realm.