Compositions, methods of treating and preventing fungal infections, and methods of inhibiting prp8 intein expression

A method, comprising:

• administering to a subject a Prp8 intein splicing inhibitor of formula (I)
• wherein R1, R2, R3, R4, and R5 are independently selected from the group consisting of halogen, trifluoromethyl, hydrogen, amine, amide, nitrogen oxide, C1-C23 alkyl, aryl, heteroaryl, carbocycle, heterocycle, and oxygen, wherein one or more of the halogen, trifluoromethyl, amine, amide, nitrogen oxide, C1-C23 alkyl, aryl, heteroaryl, carbocycle, heterocycle, and oxygen optionally can be independently substituted with one or more halogen, hydrogen, C1-C3 alkyl, trifluoromethyl, or nitrogen oxide;
• wherein R6 and R7 are independently selected from oxygen and hydrogen;
• wherein A is independently selected from:
• wherein
• in A represent a point of attachment and wherein X1, X2, and X3 are independently selected from carbon, nitrogen, sulfur, and oxygen;
• and
• wherein in formula (I) represents a point of attachment to at least one of:
• wherein X4 is carbon or nitrogen;
• wherein R8, R9, R10, R11, and R12 are independently selected from hydrogen, halogen, trifluoromethyl, alkyl, and nitrogen oxide,
• wherein the subject has an infection, or is at risk of developing an infection, with a fungus.

A method of inhibiting Prp8 intein expression or activity in a cell or tissue, said method comprising:

• contacting the ell or tissue with a compound of formula (I):
• wherein R1, R2, R3, R4, and R5 are independently selected from the group consisting of halogen, trifluoromethyl, hydrogen amine, amide, nitrogen oxide, C1-C23 alkyl, aryl, heteroaryl, carbocycle, heterocycle, and oxygen, wherein one or more of the halogen, trifluoromethyl, amine, amide, nitrogen oxide, C1-C23 alkyl, aryl, heteroaryl, carbocycle, heterocycle, and oxygen optionally can be independently substituted with one or more halogen, hydrogen, C1-C3 alkyl, trifluoromethyl, or nitrogen oxide;
• wherein R6 and R7 are independently selected from oxygen and hydrogen;
• wherein A is independently selected from:
• wherein
• in A represent a point of attachment and wherein X1, X2, and X3 are independently selected from carbon, nitrogen, sulfur, and oxygen;
• and
• wherein in formula (I) represents a point of attachment to at least one of:
• wherein X4 is carbon or nitrogen;
• wherein R8, R9, R10, R11, and R12 are independently selected from hydrogen, halogen, trifluoromethyl, alkyl, and nitrogen oxide, under conditions effective to inhibit Prp8 intein expression or activity in a cell or tissue.

A method for screening for compounds that inhibit Prp8 intein splicing comprising an assay, said assay comprising:

• providing a GFP-Prp8 fusion protein;
• treating said GFP-Prp8 fusion protein with an intein splicing buffer;
• reacting the treated GFP-Prp8 fusion protein with one or more reagent;
• and
• detecting Prp8 intein splicing activity in a compound.