Stapled Peptide E1 Inhibitors That Bypass ATP-Site Resistance
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Solution Overview
Problem
Existing cancer treatments targeting ubiquitin and ubiquitin-like activating enzymes face resistance due to mutations in the ATP binding sites of these enzymes, necessitating the development of alternative modes of inhibition.
Innovation Solution
Structurally stabilized alpha-helical peptides, such as stapled peptides, are designed to mimic the E2 helix A domain, competing with the E1-E2 interaction and inhibiting the ubiquitin activating enzymes, including UBA1, UBA3, and UBA2, by binding to the E1 UFD and potentially forming covalent bonds with cysteine residues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ATP binding site inhibitors (e.g., MLN7243) are used to inhibit UBA1, then cancer cell proliferation is suppressed, but resistance develops through point mutations in the ATP binding site
Solution Approach 1:
The patent uses stapled peptides as intermediary molecules that bind to the E1 enzyme's ubiquitin fold domain (UFD), serving as a mediator to block E2 enzyme binding. This intermediary approach avoids direct competition at the ATP binding site, thereby preventing resistance through ATP site mutations while maintaining inhibition efficacy.
Solution Approach 2:
The stapled peptides are designed to mimic the structural features of the E2 enzyme's helix A domain, creating a copy that can bind to the E1 UFD. This structural copying allows the peptide to occupy the binding site and prevent actual E2 enzymes from binding, achieving inhibition without affecting the ATP binding site and thus avoiding resistance mutations.
2Measurement precision
If structurally stabilized peptides are designed to mimic E2 helix A, then binding affinity to E1 increases, but peptide stability and cellular penetration become challenges
Solution Approach 1:
The patent applies chemical stapling modifications to the peptide sequence, changing the physical and chemical parameters of the peptide structure. This stapling creates rigid, stable helical structures that maintain their conformation in cellular environments, thereby improving structural stability while preserving high binding affinity to the E1 enzyme's UFD.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These peptides effectively inhibit the E1-E2 interaction and thioester transfer, offering a potential solution to cancer resistance and providing therapeutic options for E1-dependent cancers and other diseases of pathologic cell survival.
Implementation Method 1
structurally stabilized alpha-helical peptides, such as stapled peptides, are designed to mimic the E2 helix A domain, competing with the E1-E2 interaction
Implementation Method 2
binding to the E1 UFD and potentially forming covalent bonds with cysteine residues
Data Source
AI summary
This disclosure features structurally-stabilized and/or warhead-bearing structurally stabilized peptide inhibitors for targeting ubiquitin activating enzymes (E1). Also disclosed are methods of using such structurally-stabilized and warhead-bearing structurally stabilized peptides in the treatment of E1-expressing or -dependent cancers or diseases. Also provided are combination therapies comprising such structurally-stabilized and/or warhead-bearing structurally stabilized peptide for the treatment of E1-expressing or -dependent diseases.