Enzymatic modification of nucleic acids

A method of substituting a guanine with a PreQ1 analog within an RNA molecule, comprising

• (i) contacting the PreQ1 analog with an RNA molecule in the presence of a transglycosylase;
• and
• (ii) allowing the transglycosylase to substitute a guanine moiety from a guanine within the RNA sequence with the PreQ1 analog thereby forming a modified RNA molecule,
• wherein the PreQ1 analog is the compound of formula II:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• L1 is R5-substituted alkylene, R5-substituted or unsubstituted heteroalkylene, a detectable moiety, R5-substituted or unsubstituted cycloalkylene, R5-substituted or unsubstituted heterocycloalkylene, R5-substituted or unsubstituted arylene, or R5-substituted or unsubstituted heteroarylene;
• R5 is independently oxo, halogen, —CF3, —CN, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R6-substituted or unsubstituted alkyl, R6-substituted or unsubstituted heteroalkyl, R6-substituted or unsubstituted cycloalkyl, R6-substituted or unsubstituted heterocycloalkyl, R6-substituted or unsubstituted aryl, or R6-substituted or unsubstituted heteroaryl;
• R6 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R7-substituted or unsubstituted alkyl, R7-substituted or unsubstituted heteroalkyl, R7-substituted or unsubstituted cycloalkyl, R7-substituted or unsubstituted heterocycloalkyl), R7-substituted or unsubstituted aryl, or R7-substituted or unsubstituted heteroaryl;
• L2 is R8-substituted alkylene, R8-substituted or unsubstituted heteroalkylene, a detectable moiety, R8-substituted or unsubstituted cycloalkylene, R8-substituted or unsubstituted heterocycloalkylene, R8-substituted or unsubstituted arylene, or R8-substituted or unsubstituted heteroarylene;
• R8 is independently oxo, halogen, —CF3, —CN, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R9-substituted or unsubstituted alkyl, R9-substituted or unsubstituted heteroalkyl, R9-substituted or unsubstituted cycloalkyl, R9-substituted or unsubstituted heterocycloalkyl, R9-substituted or unsubstituted aryl, or R9-substituted or unsubstituted heteroaryl;
• R9 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R10-substituted or unsubstituted alkyl, R10-substituted or unsubstituted heteroalkyl, R10-substituted or unsubstituted cycloalkyl R10-substituted or unsubstituted heterocycloalkyl, R10-substituted or unsubstituted aryl, or R10-substituted or unsubstituted heteroaryl;
• R3 is a detectable moiety, a biomolecule, hydrogen, halogen, —CN, R11-substituted or unsubstituted alkyl, R11-substituted or unsubstituted heteroalkyl, R11 substituted or unsubstituted cycloalkyl, R11-substituted or unsubstituted heterocycloalkyl, R11-substituted or unsubstituted aryl, or R11-substituted or unsubstituted heteroaryl;
• R11 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl;
• R12 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R13-substituted or unsubstituted alkyl, R13-substituted or unsubstituted heteroalkyl, R13-substituted or unsubstituted cycloalkyl, R13-substituted or unsubstituted heterocycloalkyl, R13-substituted or unsubstituted aryl, or R13-substituted or unsubstituted heteroaryl;
• R7, R10, and R13 are independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
• and
• R4 is hydrogen.

A method of screening for a transglycosylase inhibitor comprising:

• (i) contacting a detectable PreQ1 analog with an RNA molecule in the presence of a transglycosylase and a test transglycosylase inhibitor;
• and
• (ii) determining whether the transglycosylase substitutes a guanine moiety from a guanine within the RNA molecule with the detectable PreQ1 analog,
• wherein the PreQ1 analog is the compound of formula II:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• L1 is R5-substituted alkylene, R5-substituted or unsubstituted heteroalkylene, a detectable moiety, R5-substituted or unsubstituted cycloalkylene, R5-substituted or unsubstituted heterocycloalkylene, R5-substituted or unsubstituted arylene, or R5-substituted or unsubstituted heteroarylene;
• R5 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R6-substituted or unsubstituted alkyl, R6-substituted or unsubstituted heteroalkyl, R6-substituted or unsubstituted cycloalkyl, R6-substituted or unsubstituted heterocycloalkyl, R6-substituted or unsubstituted aryl, or R6-substituted or unsubstituted heteroaryl;
• R6 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R7-substituted or unsubstituted alkyl, R7-substituted or unsubstituted heteroalkyl, R7-substituted or unsubstituted cycloalkyl, R7-substituted or unsubstituted heterocycloalkyl), R7-substituted or unsubstituted aryl, or R7-substituted or unsubstituted heteroaryl;
• L2 is R8-substituted alkylene, R8-substituted or unsubstituted heteroalkylene, a detectable moiety, R8-substituted or unsubstituted cycloalkylene, R8-substituted or unsubstituted heterocycloalkylene, R8-substituted or unsubstituted arylene, or R8-substituted or unsubstituted heteroarylene;
• R8 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R9-substituted or unsubstituted alkyl, R9-substituted or unsubstituted heteroalkyl, R9-substituted or unsubstituted cycloalkyl, R9-substituted or unsubstituted heterocycloalkyl, R9-substituted or unsubstituted aryl, or R9-substituted or unsubstituted heteroaryl;
• R9 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R10-substituted or unsubstituted alkyl, R10-substituted or unsubstituted heteroalkyl, R10-substituted or unsubstituted cycloalkyl R10-substituted or unsubstituted heterocycloalkyl, R10-substituted or unsubstituted aryl, or R10-substituted or unsubstituted heteroaryl;
• R3 is a detectable moiety, a biomolecule, hydrogen, halogen, —CN, R11-substituted or unsubstituted alkyl, R11-substituted or unsubstituted heteroalkyl, R11 substituted or unsubstituted cycloalkyl, R11-substituted or unsubstituted heterocycloalkyl, R11-substituted or unsubstituted aryl, or R11-substituted or unsubstituted heteroaryl;
• R11 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R12-substituted or unsubstituted alkyl, R12-substituted or unsubstituted heteroalkyl, R12-substituted or unsubstituted cycloalkyl, R12-substituted or unsubstituted heterocycloalkyl, R12-substituted or unsubstituted aryl, or R12-substituted or unsubstituted heteroaryl;
• R12 is independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, R13-substituted or unsubstituted alkyl, R13-substituted or unsubstituted heteroalkyl, R13-substituted or unsubstituted cycloalkyl, R13-substituted or unsubstituted heterocycloalkyl, R13-substituted or unsubstituted aryl, or R13-substituted or unsubstituted heteroaryl;
• R7, R10, and R13 are independently oxo, halogen, —CF3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O) NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
• and
• R4 is hydrogen.