Didehydro Nucleotide Analogs for Broad-Spectrum Chain Termination
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Solution Overview
Problem
There is a need for targeted active compounds to treat viral and microbial infections and inhibit cancer cell proliferation, as existing nucleotide/nucleoside analogs have limited structural diversity and potential side effects.
Innovation Solution
Development of novel 3,4-didehydro and 3'-deoxy-3,4-didehydro compounds, synthesized using prokaryotic viperin enzymes (pVips), which produce diverse nucleotide derivatives with enhanced antiviral, antibacterial, and anti-tumoral activities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing nucleotide/nucleoside analogs are used to treat viral and microbial infections, then antiviral activity is achieved, but structural diversity is limited and side effects occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleotide analogs through systematic variations at multiple positions: substituting the sugar moiety (ribose, deoxyribose, arabinoose, xyloose), changing the base (A, G, C, T, U, and modified bases), varying the phosphate groups (mono-, di-, tri-phosphates), and introducing different substituents (halogens, alkyl groups, functional groups). This comprehensive structural parameter variation generates diverse analogs with improved antiviral activity and reduced side effects while maintaining the core mechanism of action.
2Reliability
If existing nucleotide/nucleoside analogs are used to treat viral infections, then antiviral effects are obtained, but the therapeutic spectrum is narrow
Solution Approach 1:
The patent achieves universality by designing a comprehensive series of nucleotide analogs that can target multiple viral families and types simultaneously. The systematic structural variations enable the analogs to interfere with different viral replication mechanisms (RNA-dependent RNA polymerase, reverse transcriptase, DNA polymerase) across diverse viruses including influenza, HIV, hepatitis, herpes, and coronaviruses, thereby expanding the therapeutic spectrum while maintaining reliable antiviral effects.
3Adaptability or versatility
If existing nucleotide/nucleoside analogs are used, then treatment of viral infections is possible, but potential side effects occur
Solution Approach 1:
The patent applies local quality by introducing specific substituents at particular positions of the nucleotide structure to enhance selectivity and reduce off-target effects. For example, adding halogen atoms (fluoro, chloro, bromo) at specific carbon positions, introducing alkyl groups at nitrogen positions, or adding functional groups (carboxyl, hydroxyl, amino) at strategic locations. These localized modifications improve the analogs' affinity for viral enzymes while reducing interaction with host cellular components, thereby minimizing side effects.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The novel compounds effectively terminate polynucleotide chain synthesis, conferring viral resistance and inhibiting cancer cell proliferation, offering a broader therapeutic spectrum with reduced side effects.
Implementation Method 1
prokaryotic viperin enzymes (pVips), which produce diverse nucleotide derivatives
Implementation Method 2
ddhCTP acts as a chain terminator for certain viral RNA-dependent RNA polymerases, leading to inhibition of viral replication
Data Source
AI summary
Disclosed herein are 3,4-didehydro- and 3′-deoxy-3,4-didehydro-compounds and pharmaceutical compositions thereof. Methods of use of these pharmaceutical compositions include those for treating diseases including virus-induced diseases, cancer, autoimmune diseases, immune disorders, and bacterial-associated diseases or infections, or combinations thereof. Examples of viral-induced diseases include viral infections by RNA or DNA viruses, for example SAR-CoV-2, EBV, BKV, JCV and HCMV.