Lysine riboswitches, structure-based compound design with lysine riboswitches, and methods and compositions for use of and with lysine riboswitches

A method of inhibiting gene expression, the method comprising

• (a) bringing into contact a compound and a cell,
• (b) wherein the compound has the structure of Formula I:
• wherein R2 and R3 are each independently positively charged, can serve as a hydrogen bond donor, or both,
• wherein R1 is negatively charged, R4 is negatively charged, or R1 and R4 are in a resonance hybrid with a net negative charge,
• wherein at least one of R1 or R4 is CH2, CH3, NH, O, O−, OH, S, S−, SH, C—R14, CH—R14, or N—R14, wherein R14 is CH2, CH3, O, O−, OH, S, S−, or SH,
• wherein R9 is C, CH, CH2, NH, O, S, C—R5, CH—R5, or N—R5, wherein R5 is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, tert-butyl, sec-butyl, iso-butyl, cyclobutyl, ethenyl, 3-propenyl, 1-propenyl, isopropenyl, 3-butenyl, 4-butenyl, 3-propynyl, 3-butynyl, 4-butynyl, diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, or piperidin-2-onyl (valerolactam),
• wherein R2 is NH2+, NH3+, OH, SH, NOH, NHNH2, NHNH3+, CO2H, SO2OH, B(OH)2, or imidazolium,
• wherein R3 is N, NH, NH2+, NH3+, O, OH, S, SH, C—R13, CH—R13, N—R13, NH—R13, O—R13, or S—R13, wherein R13 is NH2+, NH3+, CO2H, B(OH)2, CH(NH2)2, C(NH2)2+, CNH2NH3+, C(NH3+)3, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxy-1-methylethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1,4 dihydroxybutyl, 2,4-dihydroxybutyl, 1-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-2-methylpropyl, 1-hydroxymethyl-1-methylethyl, trishydroxymethylmethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, 1,2-dithiolethyl, 2-thiol-1-methylethyl, 1-thiolpropyl, 2-thiolpropyl, 3-thiolpropyl, 1,3-dithiolpropyl, 2,3-dithiolpropyl, 1-thiolbutyl, 2-thiolbutyl, 3-thiolbutyl, 4-thiolbutyl, 1,4 dithiolbutyl, 2,4-dithiolbutyl, 1-thiol-2-methylpropyl, 2-thiol-2-methylpropyl, 3-thiol-2-methylpropyl, 1-thiolmethyl-1-methylethyl, tristhiolmethylmethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1,2-diaminoethyl, 2-amino-1-methylethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 1,3-diaminopropyl, 2,3-diaminopropyl, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl, 1,4 diaminobutyl, 2,4-diaminobutyl, 1-amino-2-methylpropyl, 2-amino-2-methylpropyl, 3-amino-2-methylpropyl, 1-aminomethyl-1-methylethyl, trisaminomethylmethyl, or is not present,
• wherein R7 has an S configuration based on a priority of R2>R6>R8,
• wherein R6, R7, R8, R10, and R11 are each independently C, CH, CH2, N, NH, O, or S,
• wherein each independently represent a single or double bond,
• wherein the compound is not lysine, and
• wherein the cell comprises a gene encoding an RNA comprising a lysine-responsive riboswitch, wherein the compound inhibits expression of the gene by binding to the lysine-responsive riboswitch.