Cyclic Peptide DOS Inhibitors for Immune Rejuvenation
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Solution Overview
Problem
Current strategies to address immune-senescence in older individuals, which increases the risk of infectious diseases and cancer, are inadequate, particularly in restoring long-lasting immune protection and rejuvenating the immune system.
Innovation Solution
Development of cyclic polypeptide inhibitors, known as DOS compounds, which specifically target and inhibit sestrin-MAPK complexes (sMAC), thereby disrupting their activation and promoting immune rejuvenation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mTOR inhibitors are administered continuously for eight weeks before vaccination, then immune response is improved, but treatment complexity and cost increase
Solution Approach 1:
The DOS compound is administered once before vaccination to pre-condition the immune system, eliminating the need for continuous eight-week mTOR inhibitor treatment. This preliminary action achieves immune rejuvenation at a single time point, resolving the contradiction between effective immune response and treatment complexity
Solution Approach 2:
The invention extracts and targets the specific sestrin-MAPK complex pathway responsible for immune suppression in aging, rather than using broad-spectrum mTOR inhibitors. This targeted approach achieves comparable or superior immune response with simplified single-dose treatment, reducing treatment complexity while maintaining reliability
2Reliability
If senolytics are used to kill senescent immune cells, then immune rejuvenation is achieved, but severe immunodeficiency occurs
Solution Approach 1:
Instead of killing senescent T cells (senolytic approach), the DOS compound inverts the strategy by directly inhibiting the sestrin-MAPK complex that causes immune suppression. This approach rejuvenates immune function without eliminating senescent cells, avoiding the harmful immunodeficiency effect while achieving immune rejuvenation
Solution Approach 2:
The DOS compound acts as an intermediary that blocks the pathological interaction between sestrin and MAPK complex, preventing the transmission of immune-suppressive signals. This mediates immune rejuvenation without direct cell death, avoiding the immunodeficiency side effect of senolytics
3Reliability
If small molecule inhibitors target sestrins, then sMAC activation is prevented, but drug development is complicated by lack of catalytic domain
Solution Approach 1:
The invention changes the molecular parameter from small molecule to cyclic peptide structure. Cyclic peptides can effectively target protein-protein interaction interfaces like the sestrin-MAPK complex without requiring catalytic domains, enabling potent sMAC inhibition while simplifying the drug development process compared to small molecule approaches
Solution Approach 2:
The DOS compound uses a cyclic peptide structure that combines the specificity of protein-based inhibitors with the stability of cyclic conformation. This composite approach enables effective targeting of the sestrin-MAPK interface while facilitating easier synthesis and development compared to small molecule inhibitors
Data Source
AI summary
The invention provides a cyclic polypeptide, derivative or analogue thereof, comprising or consisting of an amino acid sequence derived from sestrin, or a truncation thereof. The cyclic polypeptides can be used in treating, preventing or ameliorating infectious diseases (viral and bacterial), and age-related conditions, such as cancer and neurodegenerative disorders, and particularly conditions that are associated with or caused by impairment of the immune system response, which is mediated by T cells.