US 2017/0246196 A1 · COMPOSITION AND METHODS OF USE OF SMALL MOLECULES AS BINDING LIGANDS FOR THE MODULATION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9(PCSK9) PROTEIN ACTIVITY

Abstract

This invention is related to the field of PCSK9 biology and the composition and methods of use of small molecule ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small molecule compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small molecule ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL-cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small molecule ligands that can raise LDL levels.

Claims24

Dependent claims

A method, comprising:

a) providing;
i) a PCSK9 protein, wherein said protein comprises a binding site that induces allosteric modulation and a low density lipoprotein receptor binding site;
ii) a small molecule ligand capable of binding to said binding site;
iii) a plurality of hepatocyte cells comprising a low density lipoprotein receptor and low density lipoproteins;
b) binding said small molecule ligand to said binding site, wherein said small molecule ligand induces a conformational shift of said protein;
and
c) modulating the affinity of said low density lipoprotein receptor binding site for said low density lipoprotein receptor by said conformational shift.

4 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/505,017Filed 20 Aug 2015

Priority

21 Aug 2014

Published

31 Aug 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

A61K 31/675
Phosphorus compounds: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
A61K 31/41
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with two or more ring hetero atoms, at least…
A61K 31/4245
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxadiazoles
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone

Composition and methods of use of small molecules as binding ligands for the modulation of proprotein convertase subtilisin/kexin type 9(pcsk9) protein activity

Life of this patent

Composition and methods of use of small molecules as binding ligands for the modulation of proprotein convertase subtilisin/kexin type 9(pcsk9) protein activity

Life of this patent

Abstract

Claims24