Modified Polypeptide Ultra-Tight ACE2 Binding
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Solution Overview
Problem
Current strategies for addressing COVID-19, including vaccines and drugs, face challenges in effectively blocking the entry of SARS-CoV-2 into host cells, particularly due to the virus's high infectivity and potential for severe symptoms, especially in older adults and those with underlying conditions.
Innovation Solution
Development of a polypeptide with modified amino acid sequences that bind to the SARS-CoV-2 receptor-binding domain (RBD) with significantly higher affinity than the wild-type, engineered to have ultra-tight binding properties, potentially inhibiting viral entry into cells and providing broad specificity against future strains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type RBD is used to bind ACE2, then the binding affinity is sufficient for viral entry, but the binding affinity is not tight enough to effectively block viral entry and provide protection against severe symptoms
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid positions (358, 484, 498, 501) in the RBD sequence to alter the binding parameters. These mutations change the chemical and structural properties of the RBD-ACE2 interface, resulting in ultra-tight binding with Kd < 10 pM, which provides effective viral entry blocking and protection against severe symptoms.
2Reliability
If current vaccines and drugs are used, then some level of protection is achieved, but they face challenges in effectively blocking viral entry due to the virus's high infectivity and potential for severe symptoms
Solution Approach 1:
The patent uses the viral RBD itself as a therapeutic agent, creating a copy of the viral protein that functions as a blocking agent. The engineered RBD polypeptide binds to ACE2 with ultra-tight affinity, effectively competing with the viral spike protein for ACE2 binding sites, thereby blocking viral entry and providing protection against severe symptoms.
3Reliability
If the polypeptide is engineered with ultra-tight binding properties, then viral entry is effectively inhibited, but the complexity of the polypeptide sequence modifications increases
Solution Approach 1:
The patent applies local quality by making specific point mutations at critical positions (358, 484, 498, 501) in the RBD sequence rather than completely redesigning the protein. These localized changes at specific amino acid positions are sufficient to achieve ultra-tight binding (Kd < 10 pM) and effective viral entry blocking, maintaining relative sequence simplicity while dramatically improving binding affinity.
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 modified polypeptide achieves a >1000-fold tighter binding to the ACE2 receptor, potentially inhibiting viral entry effectively and offering protection against severe symptoms and future strains of COVID-19, with the potential for use in treating COVID-19 and other coronavirus infections.
Implementation Method 1
the polypeptide binds soluble, monomeric angiotensin-converting enzyme 2 (ACE2) receptor when expressed on the surface of yeast cells with at least 50 fold higher affinity than the wild-type RBD
Data Source
AI summary
A polypeptide comprising an amino acid sequence of SARS CoV-2 receptor-binding domain (RBD) is disclosed, wherein said amino acid sequence comprises a modification at position 358 and at least two additional modifications at two positions selected from the group consisting of 484, 498 and 501, wherein the polypeptide binds soluble, monomeric angiotensin-converting enzyme 2 (ACE2) receptor. Uses thereof are further disclosed.