PHOTORNA · Development of photoswitchable ligands for the reversible and selective assembly with RNA
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-10-01 → 2019-12-31
- EU contribution
- €159,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Development of photoswitchable ligands for the reversible and selective assembly with RNA
The ribonucleic acid (RNA) represents an important target for therapy of viral and bacterial infections, a range of genetic diseases and cancer. However, due to the structural diversity of RNA, the rational design of selective RNA binders remains a highly challenging task. Another problem of the development of nucleic acid-targeting drugs is the realization of spatial and temporal control of their activity. From this point of view, manipulation of the drug activity by light is a highly attractive approach. However, the field of photocontrolled RNA-binders has been unexpectedly neglected. Up to now, photoinduced association of small molecules with RNA has been demonstrated only for a few examples. Therefore, the main objective of this project was the development of novel photoswitchable RNA binders whose properties can be reversibly switched and controlled by light. Additionally, the present project was focused on the interactions of photoswitchable ligands with naturally occurring RNAs possessing distinct biological function, so that these studies aimed to reveal novel, medically relevant insights.
Data: CORDIS, © European Union
Project objective
The proposed project aims at the development of novel functional ligands whose association with ribonucleic acid (RNA) is reversibly activated by light. As several RNA forms are essential key elements in physiological processes, the control of their function or malfunction by the reversible binding of photoswitchable ligands possesses a great potential as a tool in anticancer, antiviral and antimicrobial therapy. Surprisingly, this innovative approach towards a controlled reversible generation of RNA binders was mainly neglected in this highly topical research field. Hence, in this project photochromic hemi-indigo and fulgide derivatives are chosen as a platform for the design of photo-responsive RNA ligands, because i) they exhibit general features of RNA binders; ii) their structure can be reversibly modified by light, iii) the core structures are readily synthesized, and iii) the substitution pattern can be easily varied to enable fine-tuning of binding selectivity based on structure-activity relationships. In addition, conjugates that comprise two photoactive RNA-binding units will be obtained and studied because such bifunctional binders are expected to have very high affinity and selectivity toward RNA. An extensive library of derivatives will be synthesized and tested for their photocontrollable association with RNA. As a special method, real-time NMR-spectroscopic studies with direct irradiation of the sample inside a specifically designed spectrometer will be used to assess in detail the dynamics in the course of the photoinduced ligand–RNA interactions. Overall, it is anticipated that this systematic approach will enable the identification and development of lead structures for controllable RNA-targeting drugs with a great pharmacological potential. Moreover, the high interdisciplinary, innovative character of this challenging project gives the researcher an excellent opportunity to achieve professional maturity and open up best career possibilities.
Original text from CORDIS.
Participants
- UNIVERSITAET SIEGEN · SiegenCoordinatorGermany
Links
Data: CORDIS, © European Union