Structural studies of how synthetic compounds stabilise G-quadruplex DNA structures

Dnr:

SNIC 2017/1-234

Type:

SNAC Medium

Principal Investigator:

Erik Chorell

Affiliation:

Umeå universitet

Start Date:

2017-06-01

End Date:

2018-06-01

Primary Classification:

10405: Organisk kemi

Secondary Classification:

10499: Annan kemi

Webpage:

http://www.chemistry.umu.se/english/research/group-leaders/erik-chorell/?languageId=1

Allocation

Abstract

G-quadruplexes or G4 structures of DNA or RNA are abundant in both eukaryotes and prokaryotes. Their biological roles have over the last years started to be uncovered with links to various aspects of genome maintenance and regulation but also to human diseases. However, there are still large gaps in the knowledge of the structure, regulation, and the biological interplay of these systems. Development of compounds that selectively interact with specific G4 structures is therefore of tremendous importance to uncover the details of their biological functions and to discover their potentially unknown functions at different genomic locations. Furthermore, such selective compounds are also highly interesting from a pharmaceutical perspective. There are today compounds reported that bind all types of G4 structures, but the big challenge in the field is to be able to target specific G4 conformations. We have designed three different approaches with the aim to identify compounds that selectively target individual G4 structures to uncover their biological roles and investigate their potential as therapeutics. 1) We use structure-based design and synthetic method development of selective G4 binding derivatives based on our recently developed 2,2'-diindolylmethanes. (M. Livendahl, et al., Chem. Eur. J., 2016, 22, 13004.) 2) We have performed a high-throughput screen that identified G4 selective compounds. (J. Jamroskovic, et al., Chem. Eur. J., 2016, 22, 18932.) We are currently improving these compounds activity and selectivity by synthesizing new derivatives based on the original hit compounds. 3) We have designed of a completely new strategy to achieve individual G4 structure selectivity based on a modified oligonucleotide “recognition sequence” tethered to a G4 stabilizing compound. To achieve selectivity, it is of great importance to get structural information of how the compounds are interacting with the G4 so that new chemical groups can be introduced to find selective interactions. In classical medicinal chemistry, crystallography or NMR studies in combination with computational studies are normally used to get this type of information. We have performed NMR (in collaboration with NMR for life) but have not been able to get any detailed information. Crystallography has proven difficult with G4 structures, as these structures tend to change their overall conformation upon crystallization. As a consequence, we are in great need of performing computational studies of our compounds and their interactions with G4 structures. The NMR studies have given us information about the area where our compounds interact with the G4 structure (see for example M. Livendahl, et al., Org. Biomol. Chem., 2017 DOI: 10.1039/C7OB00300E.) and we would now like to for example perform MD simulations of how the compounds interact with the G4 structure in the area defined by the NMR studies. I have reqruited a post doc that will work with this and I have also discussed the project with prof Anna Linusson (department of chemistry , UmU) and she is willing to assist us in the project.