Methods and compostions for specific inhibition of protein splicing by small molecules

A method for activating the function of a protein, the method comprising:

• a) providing a protein which is interrupted by an intein wherein the intein renders the protein inactive, the protein being provided in the presence of a small-molecule inhibitor of protein splicing at an effective concentration, the effective concentration being sufficient to inhibit excision of the intein;
• and
• b) thereafter enabling excision of the intein by reducing the inhibitor to a level below the effective concentration, the excision thereby activating the function of the protein to a significant degree.

A method for controlling the activity of an intein, the method comprising:

• a) providing an intein with its N-terminus or its C-terminus or both being fused to a protein, the intein fusion being provided in the presence of a small-molecule inhibitor of protein splicing at an effective concentration, the effective concentration being sufficient to inhibit activity of the intein;
• and
• b) thereafter enabling cleavage of the intein at its N-terminus or its C-terminus or both by reducing the inhibitor to a level below the effective concentration, thereby controlling the activity of the intein.

A composition comprising a compound of formula 1 in a pharmaceutically acceptable carrier wherein the compound of formula 1 is:

• or pharmaceutical salt thereof, wherein X is selected from the group consisting of oxygen and sulfur, and R is an aromatic group.

A composition comprising a compound of formula 2 in a pharmaceutically acceptable carrier wherein the compound of formula 2 is:

• or pharmaceutical salt thereof, wherein R is selected from the group consisting of hydrogen and methyl, and Ar is a phenyl group which may be substituted with halogen or trifluoromethyl.

A composition comprising a compound of formula 3 in a pharmaceutically acceptable carrier wherein the compound of formula 3 is:

• or pharmaceutical salt thereof, wherein R1 is an aromatic or aromatic carboxamide group;
• R2 is an aromatic sulfone or sulfoxide group or an aromatic ester.

A composition comprising a compound of formula 4 in a pharmaceutically acceptable carrier wherein the compound of formula 4 is:

• or pharmaceutical salt thereof, wherein X is H or an alkyl group.

A composition comprising a compound of formula 5 in a pharmaceutically acceptable carrier wherein the compound of formula 5 is:

• or pharmaceutical salt thereof, wherein R is an alkyl or acyl ester group and Ar is an aromatic group.

A composition comprising a compound of formula 6 in a pharmaceutically acceptable carrier wherein the compound of formula 6 is:

• or pharmaceutical salt thereof, wherein R1 is a methyl or aromatic group, R2 is H, nitrile or an acyl group, R3 is H, an alkyl or an aromatic group and R4 is H or an ester group.

A composition comprising a compound of formula 7 in a pharmaceutically acceptable carrier wherein the compound of formula 7 is:

• or pharmaceutical salt thereof, wherein R1 is nitrile or an aliphatic ketone group and R2 is an aromatic group.

A composition comprising a compound of formula 8 in a pharmaceutically acceptable carrier wherein the compound of formula 8 is:

• or pharmaceutical salt thereof, wherein Ar is an aromatic group.

A composition comprising a compound of formula 9 in a pharmaceutically acceptable carrier wherein the compound of formula 9 is:

• or pharmaceutical salt thereof, wherein R is an alkyl group.

A composition comprising a compound of formula 10 in a pharmaceutically acceptable carrier wherein the compound of formula 10 is:

• or pharmaceutical salt thereof, wherein X is O or S and R is Br or a CHO group with Schiff base with p-F-aniline.

A composition comprising a small-molecule compound in a pharmaceutically acceptable carrier, the small-molecule compound selected from the group consisting of compounds of formulas 11-69 as recited in FIG. 8-15, or pharmaceutical salts thereof.

A method for treating tuberculosis, the method comprising administering a small molecule inhibitor of protein splicing to a human in need of such treatment.

A small-molecule inhibitor of protein splicing in a pharmaceutically acceptable carrier, wherein the inhibitor is an organic compound with the ability to specifically interact with an intein-containing protein.