Alternative-Binding MPro Inhibitors Against Resistant Virus Variants
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Solution Overview
Problem
Current MPro inhibitors, such as Paxlovid, are not accessible to all patients due to drug contraindications and have limitations in patients with severe renal and hepatic impairment, and there is a risk of emerging virus variants resistant to current treatments.
Innovation Solution
Development of novel MPro inhibitors, SM141 and SM142, which exhibit a unique binding mode in the active site of MPro, inhibiting both MPro and CatL, leading to potent antiviral activity with IC50 values of 8.2 and 14.7 nM, respectively, and reducing viral replication and lung damage in SARS-CoV2-infected mice.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current MPro inhibitors like Paxlovid are used, then antiviral treatment is provided, but accessibility is limited due to drug contraindications and renal/hepatic impairment restrictions
Solution Approach 1:
The patent develops novel MPro inhibitors (SM141 and SM142) with modified chemical structures and binding modes compared to existing inhibitors like nirmatrelvir. These structural parameter changes result in different pharmacokinetic and pharmacodynamic properties, enabling effective treatment in patient populations previously excluded from standard therapy, including those with renal or hepatic impairment.
2Reliability
If current MPro inhibitors are used, then viral replication is suppressed, but resistance may emerge from virus variants
Solution Approach 1:
The patent employs an alternative binding mode for MPro inhibition that differs from conventional inhibitors. By inverting the typical interaction mechanism and targeting different residues in the MPro active site, the novel compounds achieve viral suppression while reducing the likelihood of cross-resistance with existing treatments, providing a backup therapy against resistant variants.
3Reliability
If novel MPro inhibitors with unique binding mode are developed, then antiviral potency is improved, but selectivity against other coronaviruses may be reduced
Solution Approach 1:
The patent describes MPro inhibitors that maintain high potency against SARS-CoV-2 while preserving activity against other coronaviruses. The molecular design incorporates features that interact with conserved regions of the MPro enzyme across different coronavirus species, achieving multi-functionality where a single compound class can target multiple viral pathogens effectively.
Data Source
AI summary
The invention provides novel compounds that are potent inhibitors of main protease (MPro) and pharmaceutical compositions and methods thereof for treating MPro-associated or mediated diseases and conditions, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2).