N4-Hydroxy Citicoline Prodrug for Antiviral Bioactivation
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Solution Overview
Problem
Current antiviral drugs, such as molnupiravir, require hydrolysis to become active, with the conversion to the monophosphate being a rate-limiting step, which can hinder their effectiveness.
Innovation Solution
The use of a diphosphate-choline prodrug, where β-D-N4-hydroxycytidine 5′-diphosphate is formed after cleavage of choline, bypassing the rate-limiting step and improving bioactivation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If molnupiravir is used as an antiviral drug, then antiviral activity is achieved, but the rate-limiting hydrolysis step and monophosphate conversion reduce bioactivation efficiency
Solution Approach 1:
The invention applies preliminary action by pre-forming the diphosphate bond in the citicoline prodrug structure before administration. This allows the compound to bypass the rate-limiting monophosphate conversion step that occurs with molnupiravir, as the diphosphate bond is already present and only requires cleavage of the choline moiety to release the active N4-hydroxycytidine diphosphate, thereby accelerating bioactivation while maintaining antiviral efficacy
Solution Approach 2:
The invention uses citicoline as an intermediary prodrug structure that mediates between the administered compound and the active antiviral agent. The citicoline moiety serves as a carrier that protects the N4-hydroxycytidine diphosphate during circulation and facilitates its delivery to target cells, where it is cleaved to release the active form, thus improving bioactivation efficiency compared to direct administration of molnupiravir
2Ease of operation
If citicoline is used as a dietary supplement, then high oral bioavailability and low toxicity are achieved, but no antiviral activity is present
Solution Approach 1:
The invention applies local quality by introducing a specific hydroxy group at the N4-position of the cytosine base in the citicoline structure. This localized modification at a specific position of the molecule confers antiviral activity to the otherwise biologically inert citicoline, while preserving the favorable pharmacokinetic properties of the citicoline backbone including high oral bioavailability and low toxicity
Solution Approach 2:
The invention uses parameter changes by modifying the chemical structure of citicoline through hydroxylation at the N4-position of cytosine. This structural parameter change transforms citicoline from a compound with only metabolic functions to one that also possesses antiviral activity, while the citicoline portion maintains its favorable pharmacokinetic parameters including high oral bioavailability and low toxicity
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
This approach results in improved permeability and sustained high concentrations of the active nucleoside analogs in plasma over a long period, enhancing antiviral efficacy.
Implementation Method 1
the diphosphate-choline prodrug, where β-D-N4-hydroxycytidine 5′-diphosphate is formed after cleavage of choline
Implementation Method 2
These enzymes convert the nucleoside analog via the mono-and diphosphate to the ultimately active nucleoside analog triphosphate
Data Source
AI summary
The present disclosure relates to the medical use of citicoline analogs with a N4-hydroxycytidine moiety and a solvate or pharmaceutically acceptable salt thereof. The compounds can be used as antiviral drug for treatment of e.g. Covid-19, human rhinovirus (HRV), influenza and respiratory syncytial virus (RSV).