Proximitetsligering som ett nytt verktyg för selektion av kombinationer av reagens för diagnostik och terapi

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https://uu.diva-portal.org/smash/project.jsf?pid=project:4807

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Project

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Title [sv]

Proximity ligation-based selection of combinatorial diagnostic and therapeutic reagents

Title [en]

Proximitetsligering som ett nytt verktyg för selektion av kombinationer av reagens för diagnostik och terapi

Abstract [sv]

Efficient identification of molecules specifically binding proteins is of central importance in future medicine. Accordingly, effective means to construct, select and optimize affinity reagents can enable personalized diagnostic assays and new, effective therapies. This project builds on our experience in developing molecular tools, which will now for the first time be applied for efficient selection of low-molecular weight compounds for use in diagnostics and in therapy. We propose to establish a new form of the proximity ligation assay (PLA) that will allow efficient selection of individual or combinations of candidate compounds, binding specific target proteins. We will combine libraries of low-molecular weight compounds and target proteins, where both classes of molecules have been modified by conjugation to DNA strands. Thereby DNA molecules attached to specifically interacting pairs of compounds and target proteins can be joined by ligation and identified via next generation sequencing of ligation products for high-throughput identification of affinity reactions. We will use the same mechanism to identify pairs, trios or more compounds capable of binding the same protein molecule. Selected combinations of binding reagents are expected to exhibit improved affinity through avidity effects, as well as greater target specificity, leading to enhanced diagnostic or therapeutic performance. We will establish the method by developing kinase inhibitors of enhanced performance.

Principal InvestigatorLandegren, Ulf Uppsala University

Coordinating organisation

Uppsala University

Funder

Vetenskapsrådet

Period

2012-01-01 － 2016-12-31

National Category

Medicinal ChemistryCell and Molecular BiologyMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)