Peptides having tetrahedral mimicking groups as inhibitors of rhomboid proteases
The present invention describes rhomboid protease inhibitors having high specificity and inhibition characteristics providing novel antibiotics, anti-malarial pharmaceutical agents, and provides a strategy for designing RiBns (rhomboid-inhibiting boronates) to target rhomboid selectively in unrelated organisms.
1. A compound comprising a tetrahedral mimicking group attached to a first end of a rhomboid protease substrate,
wherein the rhomboid protease substrate comprises either KRFRSMQYSA (SEQ ID NO: 3) or KRFRSNQYSA (SEQ ID NO: 4), and
wherein the rhomboid protease is PfROM4.
2. The compound of claim 1 , wherein the rhomboid protease substrate is selected from the group consisting of: Ac-KRFRSMQYSA (SEQ ID NO: 3) and Ac-KRFRSNQYSA (SEQ ID NO: 4),
wherein Ac is an N-terminal acetyl moiety, and wherein the tetrahedral mimicking group is attached to the C-terminal end of the rhomboid protease substrate.
3. The compound of claim 1 , wherein the tetrahedral mimicking group is B(OH) 2 , or trifluoromethylketone.
4. The compound of claim 1 , wherein the rhomboid protease substrate has an acetyl group attached to a second end.
5. A method for inhibiting PfROM4 comprising the steps of providing a compound of claim 1 and applying it to PfROM4.
6. A method of inhibiting PfROM4 in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of claim 1 and inhibiting PfROM4.
7. The method of claim 6 , wherein the subject is a human.
8. A method of treating malaria in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of claim 1 .
9. The method of claim 8 , wherein the subject is a human.
10. The method of claim 8 , wherein the malaria is antibiotic resistant.