Peptide Modulators of δPKC-F1Fo ATP Synthase Interaction
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Solution Overview
Problem
Current therapies for heart attacks are inadequate in minimizing cardiac cell death during reperfusion, as excessive inhibition of the F1Fo ATP synthase by δPKC leads to inefficient ATP production, exacerbating cardiac injury, particularly in diabetic patients.
Innovation Solution
Development of peptides derived from the 'd' subunit of F1Fo ATP synthase to interfere with or enhance δPKC modulation of F1Fo ATP synthase activity, facilitating rapid return of aerobic ATP synthesis and reducing ischemic tissue damage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Power
If δPKC activates F1Fo ATP synthase, then ATP production increases, but excessive inhibition occurs leading to inefficient ATP production and cardiac injury
Solution Approach 1:
The patent uses peptides derived from the d subunit of F1Fo ATP synthase as intermediary molecules to modulate the δPKC-F1Fo interaction. These peptides act as mediators that can either enhance or inhibit the binding between δPKC and the d subunit, thereby controlling F1Fo activity and ATP production to prevent excessive inhibition while maintaining efficient energy synthesis.
Solution Approach 2:
The patent changes the functional state of the δPKC-F1Fo interaction by introducing peptide modulators that alter the binding affinity and interaction dynamics. By modifying this key parameter (interaction strength), the system achieves optimal F1Fo activity without excessive inhibition, resolving the contradiction between ATP production and harmful over-inhibition.
2Productivity
If conventional heart attack therapies are used, then blood flow is restored, but cardiac cell death increases during reperfusion
Solution Approach 1:
The patent applies preliminary action by administering F1Fo-derived peptides before or during reperfusion therapy to pre-establish protective modulation of the δPKC-F1Fo interaction. This preliminary intervention prevents excessive inhibition from occurring during the harmful reperfusion phase, thereby reducing cardiac cell death while maintaining blood flow restoration benefits.
Solution Approach 2:
The patent converts the harmful effect of δPKC-mediated F1Fo inhibition during reperfusion into a beneficial controlled interaction. By using peptide modulators, the system transforms the previously harmful excessive inhibition into a regulated and optimal F1Fo activity state, turning the harmful reperfusion process into a beneficial recovery phase with reduced cell death.
3Reliability
If δPKC interacts with d subunit of F1Fo, then F1Fo activity is inhibited, but this exacerbates cardiac injury in diabetic patients
Solution Approach 1:
The patent applies local quality by using peptides that specifically target the d subunit of F1Fo ATP synthase, creating a localized modulation effect at the critical δPKC-F1Fo interaction site. This localized approach allows precise control of F1Fo activity in the mitochondrial membrane where the harmful interaction occurs, without affecting other cardiac functions, thereby reducing cardiac injury specifically at the site of pathology.
Data Source
AI summary
The present invention provides isolated or synthetic peptides derived from the d subunit of mammalian F1Fo ATP synthase (dF1Fo) protein for the purposes of tissue protection and improved energy production following acute injury from ischemia/reperfusion or other toxic insults, or in chronic diseases such as diabetes and cancer. The major focus of the patent protection will be 2 peptides comprising an amino acid sequence having at least 75% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2 and pharmaceutical compositions thereof. However, additional peptide sequences within the dF1Fo protein may also have efficacies in these disease states and therefore all peptides shown in the Figures of this application (combined with the human immunodeficiency virus (HIV)-Tat protein transduction, cytochrome oxidase subunit IV (COIV) mitochondrial targeting and Flag domains) are included for their efficacies in these conditions.