Chimeric Conjugates Degrade Viral Proteases
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Solution Overview
Problem
Current antiviral compounds targeting coronaviral proteases and non-structural proteins like PLpro and Mpro are not sufficiently potent, leading to only partial inhibition of viral replication and infectivity, necessitating the development of more effective therapeutics to combat COVID-19 and other coronavirus infections.
Innovation Solution
The use of chimeric conjugates, or proteolysis targeting chimeras (PROTACs), which combine a viral or host protein targeting moiety with a protein degradation-inducing moiety to specifically degrade essential viral proteins such as PLpro, Mpro, NSP9, NSP12, or host proteins like BRD2/3/4, thereby enhancing p53-mediated suppression of viral replication and pathogenesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antiviral compounds are used to inhibit coronaviral proteases and non-structural proteins, then partial inhibition of viral replication is achieved, but the potency is insufficient to fully block viral replication and infectivity
Solution Approach 1:
Instead of using conventional inhibitors that block protease activity, the patent employs PROTACs that recruit cellular degradation machinery to destroy the viral proteases and non-structural proteins. This inverted approach shifts from functional inhibition to complete protein degradation, achieving more reliable and complete suppression of viral replication and infectivity.
Solution Approach 2:
The patent introduces E3 ubiquitin ligases as intermediary proteins that facilitate the degradation of viral targets. The PROTAC molecules act as bridges, connecting viral proteases/NSPs to host E3 ligases, thereby mediating their ubiquitination and proteasomal degradation. This intermediary mechanism overcomes the limitations of direct inhibition by leveraging the cell's own degradation machinery.
2Productivity
If conventional inhibitors are used to target viral proteins, then some viral replication is blocked, but the inhibition is not sufficiently potent requiring higher doses or combination therapies
Solution Approach 1:
The patent fundamentally changes the mechanism of action parameter from reversible binding inhibition to irreversible protein degradation. PROTACs induce sustained target protein degradation, maintaining low concentrations of functional viral proteins over time. This parameter change allows achieving high anti-viral productivity at lower compound concentrations compared to conventional inhibitors that require continuous presence at higher doses.
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
These chimeric conjugates effectively degrade targeted viral and host proteins, enhancing the host's ability to combat viral infections by increasing p53 levels and inhibiting viral replication and pathogenesis, providing a synergistic increase in anti-viral activity.
Implementation Method 1
The second moiety binds to a second protein, wherein the second protein is, or recruits, a protein degrader
Implementation Method 2
target the degradation of viral proteins... such chimeras can be used to degrade an essential viral protein
Data Source
AI summary
The present application describes chimeras which target and degrade essential viral proteins or host proteins involved in viral pathogenesis. In particular, the chimeras of this application combine a moiety that binds to a target protein (such as a coronaviral papain-like protease (PLpro), main protease (Mpro), or other non-structural proteins (e.g., NSP9 or NSP12); or a host protein, such as bromodomain 2, bromodomain 3, or bromodomain 4)), with a moiety that recruits a protein degrader, thereby degrading the target protein. In some instances, the chimera simultaneously induces p53, which itself has anti-viral activity, by engaging HDM2 as the protein degrader. The disclosure also relates to methods of using such chimeras in the prevention and treatment of viral infections, particularly viral infections (such as COVID-19) caused by coronaviruses (such as SARS-CoV-2).