Indole Derivatives Inhibit NMD to Restore Protein Expression
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Solution Overview
Problem
Current treatments for genetic diseases caused by premature termination codons often result in the degradation of mRNA, leading to the absence of gene expression, even when a functional truncated protein could be translated, highlighting the need for a mechanism to inhibit nonsense-mediated mRNA decay (NMD) to restore protein expression.
Innovation Solution
Specific indole derivatives are developed to inhibit the NMD pathway, allowing the translation of mRNAs with premature termination codons by preventing the interaction between hUPF1 and hSMG5, thereby stabilizing hyperphosphorylated forms of hUPF1 and excluding hSMG5 from processing bodies, which leads to the accumulation of NMD substrates within these structures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NMD mechanism is activated to degrade mRNAs with premature termination codons, then truncated proteins are prevented from being synthesized, but functional truncated proteins are lost and gene expression is absent
Solution Approach 1:
The patent applies parameter changes by using chemical compounds (indole derivatives) that modify the phosphorylation state of hUPF1 protein, shifting it from dephosphorylated to phosphorylated form. This parameter change in protein phosphorylation status alters the interaction between hUPF1 and hSMG5, preventing NMD complex formation and thereby changing the fate of mRNAs with premature termination codons from degradation to stabilization and functional translation
Solution Approach 2:
The patent introduces hUPF1 phosphorylation as an intermediary mechanism that mediates between the NMD pathway and functional protein translation. By controlling the phosphorylation state of hUPF1 through chemical intervention, the system creates a regulatory node that can either promote NMD (when dephosphorylated) or prevent it (when phosphorylated), thus serving as a switch between mRNA degradation and functional protein production
2Productivity
If hUPF1 interacts with hSMG5 to form NMD complex, then mRNA degradation is activated, but functional truncated proteins cannot be translated
Solution Approach 1:
The patent applies preliminary anti-action by using chemical compounds that preemptively phosphorylate hUPF1 before it can interact with hSMG5 to form the NMD complex. This preliminary phosphorylation prevents the formation of the harmful NMD complex in the first place, thereby preventing mRNA degradation and allowing functional truncated proteins to be translated instead
3Quantity of substance
If NMD pathway is inhibited to restore gene expression, then functional truncated proteins can be translated, but mRNA stability must be maintained
Solution Approach 1:
The patent employs feedback mechanisms where the phosphorylation state of hUPF1 serves as a regulatory signal that feeds back to control NMD activity. The chemical compounds induce phosphorylation of hUPF1, which then prevents its interaction with hSMG5, creating a feedback loop that maintains mRNA stability and promotes functional protein translation while preventing degradation
Data Source
AI summary
The invention relates to an indole derivative compound of the formula (II) in which: X is N, CR8 or N+ R8, wherein R8 is a hydrogen atom, a hydroxyl or alkyl or methoxy group optionally substituted by a phenyl group; R2, R3 and R4 are independently a hydrogen atom or a halogen atom or an optionally substituted alkyl, amine, alkene, ester, sulfonamide, ether or benzyl group; R5 is a hydrogen atom or an optionally substituted alkyl, amine, benzyl group; R6 is an optionally substituted C1-C3 alkyl group; R7 is a hydrogen atom or an optionally substituted C1-C3 alkyl group and R7 is absent when the cycle A is at the b position, A representing a cycle; R9 and R10 form together a carbon bond or independently represent a R11, OR11, SR11 group, wherein R11 is hydrogen or a saturated or unsaturated optionally substituted C1-C3 alkyl group that may contain one or more sulphur, oxygen or nitrogen atoms. The invention also relates to the pharmaceutically acceptable salts of said compounds, their isomers and/or a mixture thereof, to a pharmaceutical composition containing such compound, and to the use of said compound in the preparation of a drug for treating a genetic disease resulting from at least one mutation inducing the occurrence of an early termination codon.