Ribose Linker Compounds for NAD+ Biosynthesis
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Solution Overview
Problem
Current nicotinamide riboside (NR) and its derivatives face challenges such as enzymatic degradation and limited oral availability due to hydrolytic decay, which hampers their effectiveness in increasing NAD+ levels.
Innovation Solution
Development of novel ribose linker compounds of Formula I, II, and III, which can be functionalized with biologically active agents or prodrugs, designed to bypass enzymatic degradation and enhance cellular uptake for incorporation into NAD biosynthetic pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If nicotinamide riboside is used as a NAD+ precursor, then NAD+ levels can be increased, but enzymatic degradation and hydrolytic decay reduce oral availability
Solution Approach 1:
The patent introduces a ribose linker compound as an intermediary substance that bridges the gap between oral administration and intracellular NAD+ production. This linker compound resists enzymatic degradation in the gut and serves as a stable precursor that cells can uptake and convert to NAD+, thereby solving the reliability issue of oral availability while maintaining the NAD+ boosting effect
Solution Approach 2:
The patent modifies the chemical structure of nicotinamide riboside by changing parameters such as adding hydrophobic groups or modifying the ribose moiety. These structural parameter changes reduce enzymatic degradation and improve oral bioavailability, allowing the compound to survive gastrointestinal conditions and reach cells intact
2Reliability
If nicotinamide riboside is modified to bypass degradation processes, then intracellular NAD+ boosting is enabled, but transport limitations across cell membranes remain
Solution Approach 1:
The patent changes physical and chemical parameters of the ribose linker compound, such as adjusting hydrophobicity, molecular size, or charge distribution. These parameter modifications optimize both enzymatic stability and membrane permeability, allowing the compound to resist degradation while facilitating efficient cellular uptake through passive diffusion or transporter mechanisms
Solution Approach 2:
The patent creates a composite molecular structure combining the nicotinamide riboside core with hydrophobic moieties or fatty acid chains. This composite structure provides enzymatic protection while the hydrophobic portions enhance membrane penetration, simultaneously addressing both stability and uptake challenges
3Reliability
If the ribose moiety is modified to prevent degradation, then oral availability improves, but the highly polar species still face transport limitations
Solution Approach 1:
The patent systematically adjusts key physicochemical parameters including hydrophobicity (log P), molecular weight, and hydrogen bonding capacity. By optimizing these parameters, the compound achieves hydrolytic resistance while reducing polarity-related transport barriers, balancing stability and bioavailability without excessive structural complexity
Data Source
AI summary
The present disclosure provides a compound of Formula I: A-R1-A′ wherein A and A′ are independently H or [Formula I], wherein A, A′, and R1 are as described herein. Also provided are methods of making the compounds described herein, and use of the compounds, e.g., in NAD-increasing compositions.