C2'epiAmB Epimer Selective Ergosterol Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Amphotericin B (AmB) is highly toxic, limiting its effective utilization for systemic fungal infections despite its potential as a last-line defense, and existing derivatives have not improved its therapeutic index effectively due to toxicity issues.
Innovation Solution
Development of C2'epiAmB, a derivative with a modified C2' hydroxyl group that preferentially binds ergosterol over cholesterol, reducing toxicity and maintaining antifungal efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amphotericin B is used to treat fungal infections, then antifungal efficacy is improved, but toxicity increases
Solution Approach 1:
The patent applies local quality by modifying only the C2' hydroxyl group on the mycosamine appendage while leaving the rest of the amphotericin B molecule unchanged. This localized modification selectively alters sterol binding properties to reduce toxicity while preserving antifungal efficacy through maintained ergosterol binding capability
Solution Approach 2:
The patent employs parameter changes by epimerizing the C2' hydroxyl group configuration, changing the stereochemical parameter at this specific position. This parameter change fundamentally alters the molecule's interaction with different sterols, reducing affinity for cholesterol (lowering toxicity) while maintaining affinity for ergosterol (preserving antifungal activity)
2Object-affected harmful factors
If amphotericin B derivatives are developed to reduce toxicity, then therapeutic index is improved, but existing derivatives fail to effectively improve toxicity
Solution Approach 1:
The patent applies local quality by modifying only the C2' hydroxyl group on the mycosamine appendage while leaving the rest of the amphotericin B molecule unchanged. This localized modification selectively alters sterol binding properties to reduce toxicity while preserving antifungal efficacy through maintained ergosterol binding capability
Solution Approach 2:
The patent employs parameter changes by epimerizing the C2' hydroxyl group configuration, changing the stereochemical parameter at this specific position. This parameter change fundamentally alters the molecule's interaction with different sterols, reducing affinity for cholesterol (lowering toxicity) while maintaining affinity for ergosterol (preserving antifungal activity)
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
C2'epiAmB demonstrates reduced toxicity and retained antifungal activity, making it a potentially clinically viable alternative to AmB with improved therapeutic index.
Implementation Method 1
C2'epiAmB, a derivative with a modified C2' hydroxyl group that preferentially binds ergosterol over cholesterol, reducing toxicity and maintaining antifungal efficacy
Data Source
Figure 1A~1B
Figure 1C
Figure 2A~2C
AI summary
Disclosed is a derivative of amphotericin B (AmB), denoted C2'epiAmB, with an improved therapeutic index over amphotericin B, pharmaceutical compositions comprising the AmB derivative, methods of making the AmB derivative and the pharmaceutical composition, and their use in methods of inhibiting growth of a yeast or fungus and treating a yeast or fungal infection. C2'epiAmB is an epimer of the parent compound. Specifically, C2'epiAmB differs from the parent compound at the C2' stereogenic center on mycosamine. This difference in structure results in (i) retained capacity to bind ergosterol and inhibit growth of yeast, (ii) greatly reduced capacity to bind cholesterol, and (iii) essentially no toxicity to human cells.