Esculentin Derivatives for Mutated CFTR Chloride Secretion
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Solution Overview
Problem
Current treatments for cystic fibrosis, such as correctors and potentiators, fail to restore the complete functionality of the mutated CFTR chloride channel, leading to impaired chloride ion secretion and dehydration of airway epithelia, which results in chronic pulmonary infections and lung damage.
Innovation Solution
The use of Esculentin-1a(1-21)NH2 and its diastereomer Esc(1-21)-1c peptides, which act as modulators to improve the functionality of mutated CFTR by enhancing chloride ion flow and restoring the balance of periciliary liquid.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If correctors and potentiators are used to treat cystic fibrosis, then CFTR functionality is partially restored, but complete functionality is not achieved and chloride ion secretion remains impaired
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of esculentin-1a through specific substitutions (Lys16→Arg, Lys18→Arg, Lys20→Arg, Lys22→Arg) to create derivatives with enhanced CFTR modulating activity. These structural parameter changes result in peptides that more effectively restore CFTR chloride channel function compared to the parent compound, directly addressing the incomplete restoration problem.
Solution Approach 2:
The patent employs composite materials by combining esculentin-1a derivatives with other CFTR modulators or formulating them in specific pharmaceutical compositions. This composite approach allows the peptides to work synergistically with other compounds to achieve complete CFTR functionality restoration, overcoming the limitation of using single agents.
2Reliability
If CFTR functionality is not fully restored, then chloride ion secretion is impaired, but this leads to dehydration of airway epithelia and chronic pulmonary infections
Solution Approach 1:
The patent applies preliminary action by using esculentin-1a derivatives to proactively restore CFTR function before pathological consequences occur. The peptides prevent the development of dehydrated mucus and subsequent bacterial infections by ensuring adequate chloride ion secretion, rather than treating infections after they establish.
Solution Approach 2:
The patent converts the harmful effect of impaired chloride secretion into a beneficial outcome by using esculentin-1a derivatives that specifically target and correct the CFTR defect. The peptides transform the pathological state of depleted periciliary liquid into a healthy state with proper hydration and ion balance, preventing infections rather than merely treating them.
3Object-affected harmful factors
If conventional antibiotics are used to treat pulmonary infections, then bacterial growth is inhibited, but resistance development occurs
Solution Approach 1:
The patent converts the harmful bacterial infection into a beneficial situation by using esculentin-1a derivatives that restore the host's natural defense mechanism (CFTR function). By re-establishing proper chloride ion secretion and periciliary liquid hydration, the peptides enable the respiratory epithelium to naturally clear bacteria, transforming the infection problem into an opportunity to strengthen host immunity.
Solution Approach 2:
The patent applies self-service by enabling the patient's own CFTR channels to perform the protective function of clearing bacteria. Rather than relying on external antibiotics that bacteria can resist, the restored CFTR function allows the body's natural mechanisms to independently defend against infections, creating a sustainable long-term solution.
Data Source
Figure 1A~1B
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AI summary
Are disclosed pharmaceutical compositions comprising as active ingredients Esculentin-1a(1-21)NH2 and/or Esculentin diastereomer Esc(1-21)-1c for use for restoring dysregulation of water and/or ions content and/or composition of the periciliary liquid due to mutations of the CFTR gene encoding for Cystic fibrosis transmembrane conductance regulator (CFTR) and for use for the treatment of cystic fibrosis.