Polypeptide Inhibitors Targeting LDH Tetramerization Interface
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current pharmacological approaches to inhibit lactate dehydrogenase (LDH) in cancer therapy face challenges such as poor selectivity over other dehydrogenases, suboptimal physicochemical properties, and high intracellular concentrations of LDH, making it difficult to achieve therapeutic inhibition.
Innovation Solution
Development of polypeptides that inhibit the tetramerization of LDH subunits, targeting the oligomeric interface instead of the active site, which can disrupt protein self-assembly and reduce intracellular LDH concentration, thereby inhibiting its activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If active-site LDH inhibitors are used, then LDH catalytic activity is inhibited, but selectivity over other dehydrogenases is poor and ADME properties are suboptimal
Solution Approach 1:
Instead of targeting the active site of LDH (the conventional approach), the invention targets the tetrameric interface of LDH subunits. This inverted approach of targeting protein-protein interaction interfaces rather than catalytic sites enables selective inhibition of LDH tetramerization and activity while avoiding off-target effects on other dehydrogenases that share common NAD-binding domains.
Solution Approach 2:
The invention uses polypeptides as intermediary molecules that specifically bind to and disrupt the tetrameric interface of LDH subunits. These polypeptide intermediaries prevent the formation of functional LDH tetramers by interfering with subunit assembly, thereby inhibiting catalytic activity without directly competing for the active site, thus achieving selectivity and improved pharmacological properties.
2Reliability
If high concentrations of LDH inhibitors are used to overcome high intracellular LDH concentration, then more LDH activity can be inhibited, but toxicity and off-target effects increase
Solution Approach 1:
The invention employs polypeptides with specific local structural features that are tailored to recognize and bind to the unique tetrameric interface of LDH subunits. This local specificity in the polypeptide structure enables high-affinity binding to the target interface while maintaining selectivity, allowing effective inhibition at lower concentrations without causing systemic toxicity or off-target effects.
3Reliability
If selective LDH-5 inhibition is pursued, then cancer pathogenesis can be targeted, but compensation by LDH-1 can sustain the Warburg phenotype
Solution Approach 1:
The invention develops polypeptides that target the conserved tetrameric interface common to both LDH-1 and LDH-5 isoenzymes. This universal targeting approach ensures simultaneous inhibition of multiple LDH isoenzymes, preventing metabolic compensation and sustaining the Warburg phenotype. The polypeptides are designed to recognize interface features shared across LDH isoenzymes, providing broad-spectrum inhibition relevant to cancer therapy.
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 effectively inhibit the tetramerization of LDH subunits, leading to reduced LDH activity and potentially enhanced therapeutic efficacy in cancer treatment by targeting both LDH-1 and LDH-5 isoenzymes.
Implementation Method 1
targeting the oligomeric interface instead of the active site, which can disrupt protein self-assembly and reduce intracellular LDH concentration
Data Source
AI summary
A polypeptide including the amino acid sequence of formula (I): GX1MMX2LQHGSX3X4X5QTP. These polypeptides modulate the activity of the native tetrameric lactate dehydrogenase LDH-1, by inhibiting the tetramerization of its subunits. Also, the therapeutic use of these polypeptides as a medicament, in particular for the prevention and/or the treatment of cancer.