Antiviral Compounds via CRAC Pathway Activation
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Solution Overview
Problem
Current antiviral therapies for viral infections, particularly those caused by RNA viruses like influenza and coronaviruses, face challenges such as high mutational rates leading to viral resistance, lengthy vaccine development processes, unpredictable responses, and increased infectivity of off-target viral strains, necessitating the need for new therapies with reduced vulnerability to resistance and improved applicability.
Innovation Solution
The use of compounds that activate the Ca2+ release-activated Ca2+ (CRAC) entry pathway, specifically thapsigargin and its derivatives, which induce a potent and sustained antiviral host innate immune response by activating store-operated Ca2+ entry (SOCE), effectively reducing virus production and replication across various cell types, including human respiratory epithelial cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antiviral drugs directly target the virus (e.g., M2 channel inhibitors, neuraminidase inhibitors, polymerase inhibitors), then viral replication is inhibited, but viral resistance develops rapidly
Solution Approach 1:
The patent uses host cellular pathways (autophagy, interferon response, apoptosis) as intermediaries to achieve antiviral effects. Instead of directly targeting viral proteins, the compounds modulate host cell processes that naturally combat viral infection, thereby preventing resistance while maintaining efficacy against diverse RNA viruses including influenza and coronaviruses
2Reliability
If sub-type specific vaccines are developed to target particular viral strains, then protection against specific strains is achieved, but the process is too protracted for rapid response to pandemic strains
Solution Approach 1:
The patent employs compounds that activate universal host defense mechanisms (autophagy, interferon response, apoptosis) that are effective against multiple RNA virus families simultaneously. This multi-functional approach provides broad-spectrum protection against influenza, coronaviruses, and other RNA viruses without requiring strain-specific development, enabling rapid response to emerging pandemics
Solution Approach 2:
The compounds prepare host cells in advance by activating constitutive antiviral pathways (autophagy and interferon response). This preliminary activation of host defenses creates a pre-existing state of resistance that immediately protects against viral infection upon exposure, eliminating the time lag associated with vaccine development and deployment
3Reliability
If antibodies are generated through vaccination against a particular viral strain, then immunity to that strain is achieved, but antibodies can unexpectedly enhance infectivity of other viral strains
Solution Approach 1:
The patent uses host cellular pathways (autophagy, interferon response, apoptosis) as intermediaries to achieve antiviral effects. Instead of directly targeting viral proteins, the compounds modulate host cell processes that naturally combat viral infection, thereby preventing resistance while maintaining efficacy against diverse RNA viruses including influenza and coronaviruses
4Reliability
If compounds are administered at higher doses to ensure antiviral effect, then viral replication is more effectively inhibited, but cytotoxicity increases
Solution Approach 1:
The patent optimizes compound parameters (chemical structure, dosage, administration regimen) to achieve maximum antiviral effect at minimal cytotoxic doses. By modifying molecular structures and adjusting dosing parameters, the compounds activate host defense pathways effectively while maintaining a wide therapeutic window that prevents cell damage even 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 compounds demonstrate a surprising antiviral effect by inducing prolonged host resistance, reducing viral output, and blocking replication of influenza and coronaviruses without significant cytotoxicity, even at non-toxic doses, offering a viable solution for treating viral infections with enhanced efficacy and safety.
Implementation Method 1
the brief cellular activation of a host Ca2+ signalling pathway, Ca2+ release-activated Ca2+ (CRAC) entry, induces a potent and sustained antiviral host innate immune response
Implementation Method 2
CRAC entry operated store operated Ca2+ entry (SOCE) induces prolonged host resistance that dramatically reduces virus production
Data Source
AI summary
The invention provides an agent for the treatment or prevention of viral infection in a subject. The agent is preferably a compound of Formula (I) or (Ia) wherein R1-R4, A and B are as defined herein. Also provided are pharmaceutical compositions and combinations comprising such agents.