Macrocyclic HCV Protease Inhibitors Resisting Drug Resistance
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Solution Overview
Problem
Current HCV NS3/4A protease inhibitors are susceptible to drug resistance, particularly due to mutations at residues like Arg155, Ala156, and Asp168, limiting their effectiveness across different genotypes and leading to treatment failures.
Innovation Solution
Development of novel macrocyclic HCV NS3/4A protease inhibitors with flexible quinoxalines at the P2 position that interact with evolutionarily constrained regions of the protease, avoiding contacts with non-essential residues, and extending into the substrate envelope to improve resistance profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current HCV NS3/4A protease inhibitors are used, then they show therapeutic efficacy against HCV infection, but they are susceptible to drug resistance due to mutations at residues like Arg155, Ala156, and Asp168
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific structural modifications at critical positions (P2 quinoxaline region) to interact with evolutionarily constrained regions of the protease. This localized optimization ensures that the inhibitor maintains strong binding to essential catalytic residues while avoiding contacts with variable residues that confer resistance, thereby resolving the contradiction between efficacy and resistance susceptibility
Solution Approach 2:
The patent employs preliminary action by pre-designing inhibitors with extended substrate envelope coverage that anticipates and prevents resistance mutations. The macrocyclic structure is configured in advance to occupy the substrate envelope space, creating a steric barrier that prevents the formation of resistance-conferring mutations at Arg155, Ala156, and Asp168 before they can occur during treatment
2Adaptability or versatility
If existing protease inhibitors are used, then they target essential viral proteins, but most are not efficacious against other genotypes, especially GT3
Solution Approach 1:
The patent applies universality by designing a macrocyclic inhibitor structure that can accommodate variations across different HCV genotypes. The extended substrate envelope and optimized P2 quinoxaline region create a versatile binding interface that maintains efficacy against multiple genotypes including GT1 and GT3, making the inhibitor broadly applicable rather than genotype-specific
3Measurement precision
If current DAAs are used, then they show high SVR rates against GT1, but they are susceptible to drug resistance except for sofosbuvir
Solution Approach 1:
The patent applies the principle of flexible shells by incorporating a macrocyclic structure with flexible quinoxaline regions that can adapt to the protease active site while maintaining a rigid overall framework. This flexibility allows the inhibitor to maintain high binding affinity and SVR rates against GT1 while the extended envelope provides resistance to mutation-driven resistance mechanisms
Data Source
AI summary
The invention provides novel classes of HCV therapeutics that are orally available, safe and effective HCV NS3/4A protease inhibitors and are less susceptible to drug resistance than existing therapeutics. The invention also relates to pharmaceutical composition of these compounds and methods of preparation and use thereof.