US 9453061 B2 - Method And Compositions For Treatment Of Calcineurin-related Diseases - The Lens

Method And Compositions For Treatment Of Calcineurin-related Diseases

Published: Sep 27, 2016
Earliest Priority: Aug 06 2014
Family: 2
Cited Works: 71
Cited by: 0
Cites: 0
Sequences: 19
Additional Info: Cited Works Full text Published Sequence

Abstract

Therapeutic compositions for treatment of protein serine/threonine phosphatase-related diseases are obtained by engineering amino acid sequences that disrupt interaction between the protein serine/threonine phosphatase and a protein inhibitor and are provided herein. Calcineurin and PPI are examples of protein serine/threonine phosphatases. RCAN1 is an inhibitor of calcineurin and is overexpressed in patients with serious diseases, such as Down syndrome and Alzheimer's disease. Molecules that bind RCAN1 at regions that interact with calcineurin selectively modulate functions of calcineurin to treat these diseases. Methods of treating a subject for a protein serine/threonine phosphatase-related disease by administering a molecule having an amino acid sequence selected from the group of SEQ ID NOs: 1-19 are further provided.

Claims

A method for treating a protein serine/threonine phosphatase-related disease, the method comprising the steps of:
administering to the subject a composition that disrupts interaction between a protein inhibitor RCAN1 (SEQ ID NO:1) and a protein serine/threonine phosphatase calcineurin in the subject, wherein the protein inhibitor inhibits at least one function of the calcineurin protein serine/threonine phosphatase, wherein the composition comprises a peptide comprising an amino acid sequence selected from the group of SEQ ID nos: 3, 5, 7, 8, 13, and 14;

increasing the function of the calcineurin protein serine/threonine phosphatase compared to the function prior to the administering and decreasing a symptom of the calcineurin protein serine/threonine phosphatase-related disease;

thereby treating the subject for the disease wherein the disease is Down syndrome or type II diabetes.
The method according to claim 1, wherein the protein inhibitor is not a substrate for phosphatase function of the protein serine/threonine phosphatase.
The method according to claim 1, further comprising prior to administering, formulating the composition to include at least one portion of calmodulin and Ca²⁺ ions, and the portion having affinity to bind the calcineurin thereby disengaging the calcineurin autoinhibitory domain to expose a catalytic site of the calcineurin and increasing the function of the calcineurin.
The method according to claim 1, wherein the composition comprises at least one of a targeting protein or a scaffolding protein.
A method of disrupting the interaction between calcineurin and an inhibitor, the method comprising:
synthesizing a molecule comprising at least one amino acid sequence selected from the group consisting of: SEQ ID NOs 3, 5, 7, 8, 13, and 14 and

disrupting by the molecule an interaction between calcineurin and a protein inhibitor.