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Rational design of multivalent ligands as new RNA binders based on functionalized polyketides scaffolds

English title Rational design of multivalent ligands as new RNA binders based on functionalized polyketides scaffolds
Applicant Gerber Sandrine
Number 116117
Funding scheme Project funding (Div. I-III)
Research institution Institut des sciences et ingénierie chimiques EPFL - SB - ISIC
Institution of higher education EPF Lausanne - EPFL
Main discipline Organic Chemistry
Start/End 01.04.2007 - 30.09.2008
Approved amount 42'150.00
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Keywords (10)

aminoalcohol fragments; aminoglycosides mimetics; aminopolyol dimers; docking; dynanic combinatorial chemistry; electrostatic interactions; dynamic combinatorial chemistry; functionalized polyketides; RNA binding; stacking interactions

Lay Summary (English)

Lay summary
Targeting biopolymers with small molecules has appeared as a major issue in the search for new potential therapeutic systems. In our laboratory, enzymes such as alpha-mannosidases involved in the biosynthesis of glycoproteins have been identified as potential interesting targets in the development of new anti-cancer agents. We reported that high affinity ligands of these enzymes display promising activities as anti-proliferative agents against glioblastoma and melanoma cells. Among the panel of biopolymers representing relevant therapeutic targets, RNA molecules also constitute fascinating molecular hosts in view of their distinctive architecture, as well as the electrostatic field generated by their fold that create potential binding pockets for small molecules. The large family of aminoglycoside antibiotics, containing subarrays of aminoalcohols and diamines, have been particularly studied for their ability to interact with diverse RNA molecules and to block the binding of specific proteins to their viral RNA targets. Recently, we disclosed the synthesis of polyketides functionalized by amino groups, from 3,3'-methylenebis{[6-(benzyloxy)methoxy]cyclohept-3-en-1-ol} We suggest that the aminoalcohol subunits thus introduced on linear and cyclic skeletons should provide recognition elements for RNA molecules. In the present project, we aim at using different approaches for the rational design and synthesis of new high affinity ligands for these biopolymers and to evaluate their potential therapeutic applications. The amino-functionalized polyketides developed in our group and further analogues are envisaged as the central core for the building of new ligands for bacterial ribosomal RNA and other relevant RNA targets. In fact, various tools such as dynamic combinatorial chemistry, click-chemistry and peptide couplings will be used to combine them into dimeric species (enhancement of the affinity for the biopolymer) or with other binding molecules (aromatic fragments) to benefit from both polar and stacking interactions with RNA molecules. Computational predicting tools are also envisaged for the determination of the best geometry, the adequate number of amino groups and the nature of other binding fragments that should be introduced on our systems for reaching the highest affinity for the studied RNA fragments.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants


Associated projects

Number Title Start Funding scheme
107532 A) Synthesis of pyrrolidine derivatives as growth inhibitors of cancer cells. B) An efficient combinatorial method for the discovery of new RNA ligands. Total asymmetric synthesis of long chain polyols and aminopolyols 01.04.2005 Project funding (Div. I-III)