AT2R Agonists Modulate Receptor Activity for Neuroprotection
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Solution Overview
Problem
Current treatments for diseases related to cardiovascular and neurodegenerative disorders often fail to adequately modulate the activity of the Angiotensin II Type 2 Receptor (AT2R), leading to insufficient therapeutic effects due to suppressed AT2R activity and excessive AT1R activity, which contributes to metabolic and renal diseases.
Innovation Solution
Development of specific small agonists, such as polypeptides with the sequence Lys-Pro-Leu-Lys-Pro-Trp, that bind to AT2R to activate the receptor, thereby promoting therapeutic effects by increasing AT2R activity and reducing AT1R activity, which are used in pharmaceutical compositions for treating various diseases characterized by insufficient AT2R activity or excessive AT1R activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for cardiovascular and neurodegenerative disorders, then general therapeutic effects are achieved, but AT2R activity remains suppressed and AT1R activity remains excessive, leading to insufficient therapeutic outcomes
Solution Approach 1:
The patent segments the renin-angiotensin system into two distinct receptor targets: AT1R (which mediates harmful effects) and AT2R (which mediates protective effects). By developing selective AT2R agonists rather than broad RAS inhibitors, the treatment can specifically enhance protective pathways while avoiding suppression of beneficial AT2R signaling, thereby resolving the contradiction between achieving therapeutic effects and maintaining proper receptor activity balance.
Solution Approach 2:
The invention changes the pharmacological parameter from non-selective RAS inhibition to selective AT2R activation. This parameter change allows the treatment to specifically increase AT2R activity (improving adaptability) while achieving therapeutic effects through enhanced vasodilation, anti-inflammatory, and neuroprotective pathways, thereby resolving the insufficiency of current therapies.
2Reliability
If AT2R activity is increased through specific agonists, then therapeutic effects are enhanced including neuroprotection and cardiovascular improvement, but this requires development of new specific agonist molecules
Solution Approach 1:
The patent uses peptide-based AT2R agonists as intermediary molecules that specifically bind to and activate the AT2R receptor. These peptide intermediaries (such as those containing Lys-Pro-Leu-Lys-Pro-Trp sequences) serve as the bridge between the administered drug and the receptor target, enabling selective AT2R activation. This approach balances the need for specific therapeutic effects with the feasibility of peptide synthesis and manufacturing.
3Object-affected harmful factors
If AT2R activation is used to treat diseases, then neuroprotective and anti-inflammatory effects are achieved, but current treatments fail to adequately modulate AT2R activity
Solution Approach 1:
The patent converts the previously underutilized AT2R pathway into a therapeutic benefit. By developing selective AT2R agonists, the treatment harnesses the naturally protective and anti-inflammatory signaling of AT2R to counterbalance the harmful effects of excessive AT1R activity. This transforms the imbalance in the renin-angiotensin system from a pathological state into a therapeutic opportunity, reducing inflammation and providing neuroprotection through enhanced AT2R activation.
Data Source
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AI summary
New polypeptide agonists of AT2R are disclosed, as well as pharmaceutical compositions comprising the agonists, methods of their use in the treatment of diseases, conditions or disorders characterized by insufficient AT2R activity or excessive AT1R activity, and methods of their use as laboratory reagents for research purposes.