NPM-Binding Polypeptides Inhibit Renal Cell Death
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Solution Overview
Problem
Acute Kidney Injury (AKI) lacks effective therapies, with high mortality rates, particularly in cardiac surgery patients, due to the lack of targeted treatments that inhibit renal cell death caused by ischemia.
Innovation Solution
Development of novel renally-targeted polypeptides that bind to nucleophosmin (NPM) and inhibit the formation of NPM:Bax complexes, which are administered to prevent and treat AKI by reducing kidney cell death.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used for AKI, then treatment options are limited, but mortality rates remain high due to lack of effective intervention
Solution Approach 1:
The patent introduces NPM-binding polypeptides as intermediary substances that interfere with the interaction between NPM and Bax proteins. These polypeptides act as mediators to prevent the formation of the NPM:Bax complex, thereby blocking the apoptotic pathway without directly affecting the cell death process itself. This intermediary approach resolves the contradiction by providing a targeted intervention point in the molecular pathway leading to renal cell death.
Solution Approach 2:
The invention applies preliminary anti-action by administering NPM-binding polypeptides before ischemic injury progresses to irreversible cell death. The polypeptides preemptively block the NPM:Bax complex formation that would otherwise lead to apoptotic activation during ischemia-reperfusion injury. This preliminary intervention prevents the harmful cascade before it fully develops, improving treatment reliability while reducing renal cell death.
2Reliability
If targeted therapies are developed to inhibit renal cell death, then treatment effectiveness improves, but device and therapy complexity increases
Solution Approach 1:
The patent extracts the critical binding interface between NPM and Bax proteins and creates synthetic polypeptides that specifically target this interaction. By isolating and targeting only the NPM-binding domain, the therapy achieves high specificity for preventing renal cell death without requiring complex multi-component systems. This extraction approach simplifies the therapy while maintaining high effectiveness in improving kidney cell survival rates.
Solution Approach 2:
The invention employs parameter changes by modifying polypeptide sequences to optimize NPM-binding affinity and specificity. Through systematic variation of amino acid sequences (as shown in the multiple SEQ ID NOs provided), the therapy achieves enhanced binding parameters that maximize protective effect. This parameter optimization allows effective therapy with relatively simple polypeptide structures, balancing treatment effectiveness with therapeutic simplicity.
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
The polypeptides significantly improve kidney cell survival rates during ischemic stress, providing a therapeutic option for AKI, particularly in cardiac surgery patients, by inhibiting regulated cell death and reducing the risk of post-operative complications.
Implementation Method 1
Polypeptides and polypeptide derivatives of the invention bind to the cell protein nucleophosmin (NPM) and inhibit the formation of NPM:Bax complexes
Data Source
AI summary
Described herein are polypeptides comprising at least one nucleophosmin-binding domain, including engineered polypeptides, and methods of using such polypeptides to treat or prevent acute kidney injury and/or kidney ischemia.