Cyclic Peptides Stimulate Proteasome Degradation

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Solution Overview

Problem

Current proteasome stimulators lack potency and selectivity, limiting their effectiveness in treating diseases associated with insufficient protein degradation by the proteasome system.

Innovation Solution

A pharmaceutical composition comprising a cyclic peptide of formula (I), which includes at least one aromatic amino acid, a polar amino acid, and an arginine, is developed to stimulate proteasomal degradation of disordered proteins while sparing ordered proteins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecules and peptides are used to stimulate the proteasome, then proteasome activity is enhanced, but potency and selectivity are insufficient

Engineering Contradiction:

Improveproteasome stimulation effectivenessVSAvoidselectivity between disordered and ordered proteins

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The cyclic peptide is designed with specific local amino acid properties: aromatic amino acids (Phe, Tyr, Trp) at positions 3-5 interact with hydrophobic pockets in the proteasome gate, while polar amino acids (Ser, Thr) at positions 1-2 provide hydrogen bonding capability. This localized functional differentiation enables selective stimulation of disordered protein degradation while sparing ordered proteins

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention changes the molecular parameters of proteasome stimulators by using a cyclic hexapeptide structure with specific amino acid composition and stereochemistry. The cyclic conformation and specific residue arrangement create optimal binding parameters for the proteasome gate, achieving both potency and selectivity that small molecules and linear peptides lack

Inventive Principle:

Principle #35Parameter changes

2Reliability

If existing proteasome stimulators are used, then some proteasome activation is achieved, but potency is insufficient for effective treatment

Engineering Contradiction:

Improveproteasome activationVSAvoidstimulation potency

Core Design Contradiction:

ReliabilityVSPower

Solution Approach 1:

The cyclic peptide combines multiple amino acid types (aromatic, polar, and charged residues) in a specific sequence and configuration to create a composite molecular structure. This composite approach integrates hydrophobic interactions, hydrogen bonding, and electrostatic interactions, resulting in high potency that exceeds individual small molecule stimulators

Inventive Principle:

Principle #40Composite materials

3Adaptability or versatility

If proteasome stimulators are developed for treating proteinopathies, then disease treatment potential is improved, but selectivity between disordered and ordered proteins is insufficient

Engineering Contradiction:

Improvedisease treatment applicabilityVSAvoidprotein substrate selectivity

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

Instead of designing inhibitors that block the proteasome, the invention uses stimulators that enhance proteasome activity toward disordered proteins. The cyclic peptide inverts the normal substrate selection process by inducing conformational changes in the proteasome gate that specifically favor disordered protein entry, achieving both therapeutic applicability and substrate selectivity

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS20250073302A1Cyclic peptides as proteasome stimulators

Publication Date: 2025.03.06 PURDUE RES FOUND

AI summary

Cyclic peptides that are proteasome stimulators, compositions comprising the same, and their use for stimulating proteasomal degradation of proteins.