Peptides having tetrahedral mimicking groups as inhibitors of rhomboid proteases

Patent metadata

Field	Value
Publication number	US-11518783-B2
Application number	US-201716307068-A
Country	US
Kind code	B2
Filing date	Jun 6, 2017
Priority date	Jun 6, 2016
Publication date	Dec 6, 2022
Grant date	Dec 6, 2022

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Univ Johns Hopkins

Inventors

• Urban Sinisa
• Gandhi Shiv
• Cho Sangwoo

Classifications

• C07K2319/50

  containing protease site · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K2/00

  Peptides of undefined number of amino acids; Derivatives thereof · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• C07K5/101 Primary

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title