Conformationally-Constrained 3CLpro Inhibitors for Broad-Spectrum Antiviral Activity
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Solution Overview
Problem
Current antiviral compounds targeting 3C-like proteases have limited specificity, making broad-spectrum antivirals rare and ineffective against coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2, which lack effective FDA-approved vaccines or therapeutics.
Innovation Solution
Development of non-deuterated and deuterated 3CLpro inhibitors with conformationally-constrained moieties that leverage spatial orientation to enhance binding with the 3CL protease, incorporating bicyclic and tricyclic cycloalkane derivatives and heterocycles, which are potent against multiple coronaviruses, including SARS-CoV and SARS-CoV-2, and are designed to reduce isomerization and improve pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional protease inhibitors are used, then they can inhibit viral protease activity, but they have short range of specificity and are genus-, species-, or strain-specific
Solution Approach 1:
The patent designs inhibitors with a conformationally-constrained peptidomimetic backbone that can bind to the active sites of diverse 3C-like proteases across multiple virus families (coronaviruses, picornaviruses, caliciviruses). The inhibitor structure incorporates a P1 glutamine surrogate and P2 leucine residue that recognize conserved features of the protease active site, enabling broad-spectrum activity against genetically diverse viruses while maintaining potent inhibition.
2Reliability
If protease inhibitors are designed to target specific viral proteases, then they can achieve potent inhibition, but broad-spectrum antivirals remain rare and elusive
Solution Approach 1:
The inhibitor incorporates a conformationally-constrained peptidomimetic backbone with specific local features (P1 glutamine surrogate, P2 leucine residue) that target the conserved catalytic triad and substrate-binding pocket of 3C-like proteases. This localized optimization of binding interactions at the active site enables the inhibitor to achieve both potent inhibition and broad-spectrum activity against viruses with varying protease sequences.
3Adaptability or versatility
If flexible inhibitor structures are used, then they can adapt to different protease conformations, but conformational variability reduces binding precision
Solution Approach 1:
The inhibitor employs a conformationally-constrained peptidomimetic backbone that is pre-organized in the bioactive conformation required for binding to the protease active site. This pre-constraint of the backbone structure, along with fixed stereocenters at the P1 and P2 positions, eliminates unproductive conformations and ensures precise orientation of the reactive warhead group for optimal interaction with the catalytic Cys-His dyad.
Data Source
AI summary
Compounds and treatment methods with compounds exhibiting antiviral activity and/or inhibition of viral replication against viruses, particularly those belonging to the picornavirus-like supercluster, including coronavirus.