Alpha O-Conotoxin Peptide Selective Receptor Blocking
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Solution Overview
Problem
Current treatments for neuralgia and cancers lack selective and effective medications that can specifically target α9α10 nicotinic acetylcholine receptors (nAChRs) and NMDA receptors, leading to inadequate analgesia and limited therapeutic options for neuralgia and cancer management.
Innovation Solution
Development of a new αO-superfamily conotoxin peptide, specifically designed to block α9α10 nAChRs and NMDA receptors, which is synthesized through a method involving precursor peptides, oxidative folding, and fusion proteins, offering high specificity and potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If common non-selective nAChR agonists such as nicotine are used to treat neuralgia and related diseases, then symptoms can be relieved, but strong side-effects occur on heart and gastrointestinal tract and addiction is caused
Solution Approach 1:
The patent applies local quality by designing conotoxin peptides with specific amino acid sequences that target particular nAChR subtypes (such as α9α10-containing receptors) rather than acting on all nAChR subtypes uniformly. This subtype-specific binding provides localized therapeutic action on neuralgia while avoiding side effects on other physiological systems mediated by different nAChR subtypes.
Solution Approach 2:
The patent segments the broad nAChR receptor family into distinct subtypes and develops selective ligands for each subtype. By creating peptides that specifically bind to certain subtypes (e.g., α9α10) while excluding others, the therapy can be segmented to affect only the desired physiological pathways involved in neuralgia without triggering unwanted responses in heart, gastrointestinal tract, or addiction pathways.
2Reliability
If selective ligand compounds for various subtypes of nAChRs are developed, then high selectivity on various subtypes can be achieved, but the complexity of obtaining and characterizing selective compounds increases
Solution Approach 1:
The patent employs preliminary action by using phage display technology to pre-select and enrich conotoxin variants with high affinity and selectivity for target nAChR subtypes before detailed characterization. The phage display library is subjected to multiple rounds of selection against purified nAChR subtypes, preliminarily filtering out non-specific binders and enriching for high-selectivity candidates, thereby simplifying subsequent validation processes.
Solution Approach 2:
The patent uses phage display to create copies of conotoxin sequences with variations, allowing high-throughput screening of many variants simultaneously. By copying and displaying numerous conotoxin sequences on phage surfaces, the system can rapidly identify selective binders through competitive binding assays, reducing the complexity of finding selective ligands compared to traditional one-by-one characterization methods.
3Reliability
If α9α10 nAChR blocking agents are used for treatment of neuralgia, then analgesia and acceleration of neuronal recovery can be achieved, but the availability of such specific medications is limited
Solution Approach 1:
The patent achieves universality by developing a platform technology (phage display library of conotoxins) that can generate selective ligands for multiple different nAChR subtypes. The same phage display approach used to identify α9α10-selective conotoxins can be applied to other nAChR subtypes, making the methodology universally applicable for creating subtype-specific therapeutics across different neurological conditions.
Data Source
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AI summary
The present invention pertains to fields of biochemistry and molecular biology, relates to an αO-superfamily conotoxin peptide, pharmaceutical composition thereof, preparation method and use thereof. The present invention further relates to a propeptide of the conotoxin peptide, nucleic acid construct thereof, expression vector and transformed cell thereof, and fusion protein thereof. The present invention further relates to a method for blocking acetylcholine receptors as well as a use of the conotoxin peptide in the manufacture of a medicament. The new αO-superfamily conotoxin peptide of the present invention is capable of specifically blocking acetylcholine receptor (nAChRs) (e.g., α9α10 nAChR), and NMDA receptor (e.g., NR2C NMDAR), and has activity for treatment of neuralgia, addiction, and activity for treatment of chemotherapy of cancers, breast cancer, lung cancer, wound healing, epilepsia, ischemia, and thus is promising in the manufacture of analgesic, a medicament for treatment of addiction, and a tool drug for neuroscience.