Stabilizing non-native excited states as a therapeutic strategy for targeting RNA

Abstract Regulatory RNAs transiently morph into non-native high-energy ‘excited’ conformational states that remodel the native ground state secondary structure needed for function. For two HIV-1 regulatory RNAs, we show that stabilizing excited states using point substitution mutations leads to potent conformation-dependent inhibition of RNA cellular activity to a degree that correlates with the extent of excited state stabilization. Stabilizing non-native excited states potentially provides a general therapeutic strategy for targeting RNA.