Structure-guided engineering of peptide-based NLRP3 inflammasome inhibitors for myelodysplastic syndromes (MDS)

Patent metadata

Field	Value
Publication number	US-12565523-B2
Application number	US-202017608021-A
Country	US
Kind code	B2
Filing date	May 1, 2020
Priority date	May 1, 2019
Publication date	Mar 3, 2026
Grant date	Mar 3, 2026

Abstract

Disclosed are compositions and methods for engineered peptide inhibitors of NLRP3 infiammasome and methods of their use in the treatment of Myelodysplastic Syndromes. In one aspect, disclosed herein are engineered inhibitors of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome comprising a Helix 2 of POP1 comprising one or more substitutions at residues 18, 21, 22, 25, 26, 28, 29, and/or 30 of POP1 as set forth in SEQ ID NO:1.

First claim

What is claimed is:

1 . An engineered inhibitor of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, comprising a Helix 2 peptide of POP 1, wherein the Helix 2 peptide comprising one or more substitutions with different amino acid at residues E18, K21, K22, M25, K26, G28, T29, and/or V30 of POP1 as set forth in SEQ ID NO: 1, wherein the first residue of SEQ ID NO: 1 corresponds to residue L15 of POP1.

2 . The engineered inhibitor of claim 1 , wherein the amino acid at residue 18 comprises glycine, lysine, glutamine, or arginine.

3 . The engineered inhibitor of claim 1 , wherein the amino acid at residue 21 comprises leucine, methionine, glutamine, or arginine.

4 . The engineered inhibitor of claim 1 , wherein the amino acid at residue 22 comprises leucine, methionine, glutamine, or arginine.

5 . The engineered inhibitor of claim 1 , wherein the amino acid at residue 25 comprises aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, methionine, asparagine, glutamine, tyrosine, valine, or leucine.

6 . The engineered inhibitor of claim 1 , wherein the amino acid at residue 26 comprises glutamic acid, glycine, leucine, methionine, glutamine, valine, or arginine.

7 . The engineered inhibitor of claim 1 , wherein the amino acid at residue 28 comprises aspartic acid, histidine, isoleucine, leucine, asparagine, or valine.

8 . The engineered inhibitor of of claim 1 , wherein the amino acid at residue 29 comprises cysteine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, leucine, asparagine, arginine, serine, valine, or tyrosine.

9 . The engineered inhibitor of claim 1 , wherein the amino acid at residue 30 comprises alanine, aspartic acid, histidine, isoleucine, leucine, asparagine, praline, threonine, or valine.

Assignees

• H Lee Moffitt Cancer Ct & Res

Inventors

• List Alan
• Ji Haitao
• Luca Vincent

Classifications

• C12N15/102

  Mutagenizing nucleic acids · CPC title

• A61P35/02

  specific for leukemia · 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

• C07K14/4703 Primary

  Inhibitors; Suppressors · CPC title

• C07K14/475 Primary

  Growth factors; Growth regulators · CPC title