Key result
C2-modified guanines such as N2-acetylguanine rival guanine in binding affinity but completely disrupt a key Watson-Crick pairing interaction between the ligand and RNA.
Why the study?
Riboswitches encapsulate effector ligands, limiting chemical space for RNA-targeting therapeutics, and understanding how C8, C6, and C2 modified guanine derivatives interact with the guanine riboswitch remains needed.
C2-modified guanines disrupt key RNA interactions while maintaining high binding affinity, opening new chemical space for antimicrobial agents targeting purine riboswitches.
Answers are grounded in this paper and cite their sources.
C2-modified guanines rival native affinity despite pocket disruption; leaves open whether they yield selective antimicrobials targeting purine riboswitches.
Riboswitches are important model systems for the development of approaches to search for RNA-targeting therapeutics. A principal challenge in finding compounds that target riboswitches is that the effector ligand is typically almost completely encapsulated by the RNA, which severely limits the chemical space that can be explored. Efforts to find compounds that bind the guanine/adenine class of riboswitches with a high affinity have in part focused on purines modified at the C6 and C2 positions. These studies have revealed compounds that have low to sub-micromolar affinity and, in a few cases, have antimicrobial activity. To further understand how these compounds interact with the guanine riboswitch, we have performed an integrated structural and functional analysis of representative guanine derivatives with modifications at the C8, C6 and C2 positions. Our data indicate that while modifications of guanine at the C6 position are generally unfavorable, modifications at the C8 and C2 positions yield compounds that rival guanine with respect to binding affinity. Surprisingly, C2-modified guanines such as N2-acetylguanine completely disrupt a key Watson–Crick pairing interaction between the ligand and RNA. These compounds, which also modulate transcriptional termination as efficiently as guanine, open up a significant new chemical space of guanine modifications in the search for antimicrobial agents that target purine riboswitches.
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Matyjasik et al. (2020) studied this question. Guanine derivatives with modifications at the C8, C6 and C2 positions vs. Guanine was evaluated on Binding affinity and structural interaction with the guanine riboswitch. C2-modified guanines such as N2-acetylguanine rival guanine in binding affinity but completely disrupt a key Watson-Crick pairing interaction between the ligand and RNA.
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