Title: Combinatorial Selections of Structure-Specific Nucleic Acid Binding Ligands
Keywords: Bioorganic chemistry, Split-and-pool synthesis, DNA-encoded library, affinity selection, PCR amplification, Molecular interaction
Supervisor: Thomas Lavergne, Ph.D., CNRS Researcher, ResearchID N-8896-2013, Webpage
Duration of the position: 18 months
Deadline for application: March 15, 2017
Post-doc starts: April-May 2017
Funding program: ANR Tremplin-ERC
Host-institution: Université Grenoble Alpes – CNRS, Département de Chimie Moléculaire
The development of selective probes and drugs to detect and disturb nucleic acid related processes is of importance to fundamental biology, clinical diagnostics and therapeutics. In the past decade, there has been growing evidence that the formation of unusual nucleic acid structures, such as G-quadruplexes (G4), profoundly influences cell regulation. Those motifs are suspected to form in key regulatory regions of human cells and their occurrences in human and pathogens have been compellingly associated with diseases such as cancers, viral infections and degenerative disorders. Through an interdisciplinary program, at the crossroads of synthetic chemistry, combinatorial chemistry, molecular biology and biophysical organic chemistry, we ambition to design, synthesize and exploit molecular ligands with the ability to specifically recognize and affect distinct G4 structures of biological interest.
The goal of this project is to assemble and screen a thoughtfully designed library of branched small-molecules equipped with an optimum chemical diversity to engage in high affinity and specific binding with distinct G4 structures. This focused library will be generated by the split and pool association of notorious nucleic acid binding motifs with functionally diverse molecular fragments. Each member of the library will be barcoded, according to DNA encoding technology, to allow for the rapid and cost-efficient identification of the highly specific ligands that will be isolated through iterative selection procedures. Ligands selections will be performed against topologically controlled and stabilized G4 mimicking structures already assembled in the host laboratory.
After deconvolution (DNA deep-sequencing), the binding parameters of the most promising ligands will be determined in the lab against all available targets using biophysical methods (SPR, BLI, ITC, CD). Additional biophysical/ biochemical characterizations and cellular evaluations will be performed through collaborations.
Candidates should have a strong background in the synthesis and characterization of biomolecules (preferably nucleic acids and their conjugates) and be highly motivated and interested in working on multidisciplinary projects. Knowledge and skills in molecular biology (PCR, enzymatic ligation) will be appreciated but is not mandatory. Knowledge and skills in molecular recognition and biophysical organic chemistry will be appreciated but is not mandatory.
Please email your CV (with the contact details of, at least, two referees) and a short cover letter describing your research interests and career goal(s), in FR or EN, at firstname.lastname@example.org
Standard salary for postdoctoral positions at the institution (~2k€/month net salary)
Bât NanoBio, 570 rue de la Chimie 38041 GRENOBLE