Antisense technology is a rapidly developing method of chemical biology and a promising tool for therapeutic applications. An antisense agent selectively binds to the target mRNA inside cells and prevents it from being translated into a functional protein. We want to synthesize cell-permeable photoswitchable antisense agents based on artificial oligonucleotides (GPNA) coupled to molecular photoswitches operational under visible light. Then we want to apply such agents to downregulate gene expression in vivo by light.

GPNA oligomers were successfully used as cell-penetrating antisense agents, efficiently downregulating expression of the EGFR receptor in the HNSCC and NSCLC cancer cell lines at the 3µM GPNA concentration.⁴ We want to modify GPNA oligomers with biocompatible photoswitches - either replacing one of the GPNA’s nucleobases or crosslinking its backbone. Photomerization of the photoswitch should cause sufficient conformational changes of the oligomer to destabilize its hybridization with a complementary RNA chain. And that will allow for switching the antisense effect on and off with light.

After initial in vitro validation, the method will be tested on mammalian cell cultures as well as on zebrafish embryos in order to obtain significant light-induced phenotype changes. Overall, we aim to create a practical technique for chemical optogenetics and dissection of complex biological systems (e.g. organism development) with high spatiotemporal precision.

[4] D. Ly, B. Armitage, et.al. ACS Chem. Biol. 2013, 8, 345-352.

Self-replication of genetic information is the characteristic feature of life. All contemporary organisms share the common molecular framework based on DNA storage and enzymatic readout of the information. There are strong evidences that primordial genetic systems were based on RNA with catalytic abilities (“RNA world”). However, up to date no general mechanism for RNA autoreplication was proposed. We want to explore the capability of more robust and structurally simple genetic polymers for self-replication under abiotic conditions and their potential as a hypothetical component of the most primitive protocells. [5]

Our long-term goal is to create self-replicating evolutionary chemical systems that can become a component of an artificial cell and lead to synthetic life. Our research will also contribute to the discussion how likely life could independently develop outside Earth from simple molecules organized in chemical systems.

[5] J.M. Heemstrra, D.R. Liu J. Am. Chem. Soc. 2009, 131, 11347-49; M.R. Ghadiri et.al. Science 2009, 325, 73-77; Y. Brudno, M. E. Birnbaum, R. E. Kleiner, D. R. Liu Nature Chem. Biol. 2010, 6, 148-155