DHODH and UCK2 Inhibitor Combination for Viral Replication
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Solution Overview
Problem
Current antiviral therapies face challenges in effectively targeting viral infections due to high mutation rates and toxicity issues when targeting viral proteins, and there is a need for broad-spectrum anti-infectives that can address emerging pathogens without inducing resistance.
Innovation Solution
A combination therapy involving a de novo pyrimidine biosynthesis inhibitor, such as dihydroorotate dehydrogenase (DHODH) inhibitor, and a pyrimidine salvage pathway inhibitor, like UCK2, is administered to inhibit multiple pathways in pyrimidine synthesis and salvage, offering broad-spectrum activity with reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If viral proteins are targeted for therapeutic intervention, then antiviral activity is achieved, but high mutation rates lead to resistance development
Solution Approach 1:
The patent uses host cell enzymes (DHODH and UCK2) as intermediaries to achieve antiviral effect. Instead of directly targeting viral proteins, the invention inhibits host enzymes that are essential for both viral and cellular pyrimidine metabolism, thereby indirectly disrupting viral replication while maintaining broad-spectrum activity against diverse viruses
2Adaptability or versatility
If host cell proteins are targeted for broad-spectrum antiviral activity, then resistance development is reduced, but host cell toxicity increases
Solution Approach 1:
The patent employs parameter changes by using deoxycytidine supplementation to modify the metabolic state of host cells. This supplementation alters the pyrimidine salvage pathway parameters, allowing the combination therapy to achieve broad-spectrum antiviral activity while reducing host cell toxicity through metabolic compensation
Solution Approach 2:
The invention creates a composite therapeutic approach by combining DHODH inhibitor, UCK2 inhibitor, and deoxycytidine supplementation. This multi-component composite strategy enables broad-spectrum antiviral activity while mitigating host cell toxicity through the synergistic effects of the combination
3Reliability
If single agent DHODH inhibitor is administered, then antiviral effect is achieved, but host cell toxicity is increased
Solution Approach 1:
The patent segments the pyrimidine metabolism pathway into two distinct targets: de novo synthesis (DHODH inhibition) and salvage pathway (UCK2 inhibition). This segmentation allows for more precise control of antiviral activity while reducing off-target toxicity by addressing specific metabolic pathways rather than using high doses of single agents
Solution Approach 2:
The invention merges multiple therapeutic agents (DHODH inhibitor, UCK2 inhibitor, and deoxycytidine) into a combination regimen. This merging of therapies creates synergistic antiviral effects while the deoxycytidine supplementation specifically counteracts the toxic effects of DHODH inhibition, reducing host cell toxicity
Data Source
AI summary
Compounds and methods are provided for the treatment of pathogenic virus infections or cancer. The formulations combine an inhibitor of de novo pyrimidine synthesis, and an inhibitor of a pyrimidine salvage pathway enzyme.