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Demonstration that Small Molecules can Bind and Stabilize Low-abundance Short-lived RNA Excited Conformational States.

ABSTRACT: Many promising RNA drug targets have functions that require the formation of RNA-protein complexes, but inhibiting RNA-protein interactions can prove difficult using small molecules. Regulatory RNAs have been shown to transiently form excited conformational states (ESs) that remodel local aspects of secondary structure. In some cases, the ES conformation has been shown to be inactive and to be poorly recognized by protein binding partners. In these cases, specifically targeting and stabilizing the RNA ES using a small molecule provides a rational structure-based strategy for inhibiting RNA activity. However, this requires that a small molecule discriminates between two conformations of the same RNA to preferentially bind and stabilize the short-lived low-abundance ES relative to the long-lived more abundant ground state (GS). Here, we tested the feasibility of this approach by designing a mutant that inverts the conformational equilibrium of the HIV-1 transactivation response element (TAR) RNA, such that the native GS conformation becomes a low-abundance ES. Using this mutant and NMR chemical shift mapping experiments, we show that argininamide, a ligand mimic of TAR's cognate protein binding partner Tat, is able to restore a native-like conformation by preferentially binding and stabilizing the transient and low-populated ES. A synthetic small molecule optimized to bind the TAR GS also partially stabilized the ES, whereas an aminoglycoside molecule that binds RNAs nonspecifically did not preferentially stabilize the ES to a similar extent. These results support the feasibility of inhibiting RNA activity using small molecules that preferentially bind and stabilize the ES.

SUBMITTER: Ganser LR

PROVIDER: S-EPMC7054137 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Demonstration that Small Molecules can Bind and Stabilize Low-abundance Short-lived RNA Excited Conformational States.

Ganser Laura R LR Kelly Megan L ML Patwardhan Neeraj N NN Hargrove Amanda E AE Al-Hashimi Hashim M HM

Journal of molecular biology 20191218 4

Many promising RNA drug targets have functions that require the formation of RNA-protein complexes, but inhibiting RNA-protein interactions can prove difficult using small molecules. Regulatory RNAs have been shown to transiently form excited conformational states (ESs) that remodel local aspects of secondary structure. In some cases, the ES conformation has been shown to be inactive and to be poorly recognized by protein binding partners. In these cases, specifically targeting and stabilizing t ...[more]

PMID: 31863746

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Project description:A series of cationic heteroleptic iridium(III) complexes bearing tris-diimine ligands [Ir(phen)2(R-phen)]3+ (R-phen = phenanthroline (1), 3,8-diphenylphenanthroline (2), 3,8-dipyrenylphenanthroline (3), 3-phenylphenanthroline (4), 3-pyrenylphenanthroline (5), and 3,8-diphenylethynylphenanthroline (6)) were synthesized and characterized. These complexes possessed phen ligand-localized 1?,?* transitions below 300 nm, and charge transfer (1CT) and/or 1?,?* transitions between 300 and 520 nm. In 1, 2, 4, and 6, the low-energy bands were mixed 1CT/1?,?*. However, the increased ?-donating ability of the pyrenyl substituent(s) in 3 and 5 split the low-energy bands into a pyrene-based 1?,?* transition at 300-380 nm and an intraligand charge transfer (1ILCT) transition at 380-520 nm. All complexes were emissive at room temperature in CH3CN, but the parentage of the emitting state varied depending on the R substituent(s). Complex 1 exhibited predominantly phen ligand-localized 3?,?* emission mixed with metal-to-ligand charge transfer (3MLCT) character, whereas the emission of 2, 4, and 6 was predominantly from the excited-state with 3?,?*/3ILCT/3MLCT character. The emission from 3 and 5 was dominated by pyrene-based 3?,?* states mixed with 3ILCT character. The different natures of the lowest triplet excited states were also reflected by the different spectral features and lifetimes of the triplet transient absorption of these complexes. Complexes 3 and 5 had singlet oxygen quantum yields as high as 81 and 72%, respectively. Both gave submicromolar phototoxicities toward cancer cells (SK-MEL-28 human melanoma) and bacteria ( S. aureus and S. mutans) with visible-light activation (and marginal to no photobiological activity with red light). Their visible-light phototherapeutic indices (PIs) toward SK-MEL-28 cells were 248 for 3 and >435 for 5; PIs were lower in bacteria (?62) because of their inherent antimicrobial activities. Both complexes were shown to produce substantial amounts of intracellular reactive oxygen species (ROS), which may account for their photobiological activities.

Dataset Information

Demonstration that Small Molecules can Bind and Stabilize Low-abundance Short-lived RNA Excited Conformational States.

Publications

Demonstration that Small Molecules can Bind and Stabilize Low-abundance Short-lived RNA Excited Conformational States.

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