Selective PLpro Inhibitors With Reduced Human Protein Off-Targeting
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Solution Overview
Problem
Existing treatments for viral infections, particularly those caused by coronaviruses like SARS-CoV-1 and SARS-CoV-2, lack selective inhibitors for papain-like protease (PLpro) that minimize off-target effects on human proteins such as hERG and CYP, which are crucial for viral replication.
Innovation Solution
Development of novel compounds that inhibit PLpro activity with high specificity, formulated as enzyme inhibitors, particularly targeting PLpro to prevent viral replication while minimizing off-target interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for viral infections, then viral replication can be inhibited, but off-target effects on human proteins such as hERG and CYP occur
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (substituents at positions R2, R3, R4, R5 on the phenyl ring, and R6-R9 on the piperidine ring) that optimize interaction with the PLpro active site while avoiding off-target binding to human proteins like hERG and CYP enzymes. This localized optimization of molecular properties at specific positions achieves selective inhibition
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters including the type of substituent groups (halo, alkyl, alkoxy, nitro, cyano, etc.), their positions on the molecular scaffold, and the length of linker chains (L1, L2) to fine-tune the compound's binding affinity for PLpro while minimizing interactions with human proteins, thereby achieving selective inhibition
2Reliability
If selective PLpro inhibitors are developed, then specificity towards PLpro is improved, but compound structure complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the inhibitor molecule into distinct functional segments: a core structure (phenyl-piperidine framework), substituent groups (R1-R10) that provide selectivity, and linker chains (L1, L2) that connect functional elements. This modular design allows systematic optimization of selectivity while managing structural complexity
Solution Approach 2:
The patent employs universality by designing a core molecular scaffold (the phenyl-piperidine structure) that can serve multiple functions: binding to the PLpro active site, providing structural stability, and serving as a platform for attaching various substituent groups that fine-tune selectivity. This universal core structure simplifies the overall design while achieving high selectivity
Data Source
AI summary
This invention relates to compounds that can be used to treat viral infections. The compounds are papain-like protease (PLpro) inhibitors.