Remdesivir Nanoparticle Formulations for Cellular Uptake Barriers
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Solution Overview
Problem
Remdesivir's in vivo efficacy in treating COVID-19 is limited due to its rapid hydrolysis to nucleoside monophosphate (Nuc-MP), which is charged and polar, preventing cellular penetration and membrane entry, despite showing good in vitro antiviral activity.
Innovation Solution
Development of remdesivir analogs formulated as nanoparticles, liposomes, and microparticles with albumin, lipids, and surfactants to enhance cellular uptake and tissue targeting, including formulations for intravenous and inhalation administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If remdesivir is administered systemically, then antiviral activity is achieved, but cellular penetration is prevented due to rapid hydrolysis to charged polar Nuc-MP
Solution Approach 1:
The patent employs cell-penetrating peptides (CPPs) as intermediary carriers that facilitate the transport of remdesivir across cellular membranes. The CPP-remdesivir conjugate acts as a mediator, allowing the charged polar Nuc-MP to penetrate cells through the CPP's membrane-transpiring capability while maintaining the antiviral activity of remdesivir.
Solution Approach 2:
The invention creates a composite structure by chemically conjugating remdesivir with cell-penetrating peptides. This composite molecule combines the antiviral properties of remdesivir with the cell-penetrating capabilities of CPPs, resolving the contradiction between maintaining antiviral activity and enabling cellular penetration.
2Reliability
If remdesivir is converted to Nuc-MP for activation, then antiviral mechanism is enabled, but membrane entry is blocked due to charged polar nature
Solution Approach 1:
Cell-penetrating peptides serve as intermediary carriers that enable membrane entry of the activated Nuc-MP form. The CPP conjugate allows the charged polar molecule to traverse the membrane barrier that would otherwise block it, while the intracellular esterases subsequently cleave the conjugate to release active Nuc-MP.
Solution Approach 2:
The invention changes the physicochemical parameters of remdesivir by conjugating it with CPPs, temporarily altering its charge and polarity characteristics to enable membrane penetration. Intracellular enzymatic cleavage then restores the original parameters, releasing active Nuc-MP for antiviral action.
3Duration of action of moving object
If remdesivir undergoes rapid hydrolysis to Nuc-MP, then activation occurs, but cellular uptake is reduced due to polar charge
Solution Approach 1:
The invention performs preliminary action by pre-conjugating remdesivir with cell-penetrating peptides before administration. This preliminary conjugation enables efficient cellular uptake, and the intracellular cleavage then activates Nuc-MP in situ, combining rapid activation with efficient uptake.
Solution Approach 2:
The CPP conjugate acts as an intermediary that facilitates cellular uptake of the activated form. The conjugate protects the charged polar Nuc-MP during transport across the membrane, then releases it intracellularly where activation is completed and antiviral activity ensues.
Data Source
AI summary
The present invention relates to methods, compounds, and compositions for treating viral infections, including COVID-19 viral infections. In certain embodiments, the compositions comprise: i) a remdesivir analog, ii) remdesivir or a remdesivir analog, and a surfactant, a cyclodextrin, or a combination thereof, iii) nanoparticles comprising albumin and remdesivir or remdesivir analog, iv) liposomes comprising lipids and remdesivir or remdesivir analog; and/or v) microparticles comprising PLA and/or PLGA, and remdesivir or remdesivir analog. In certain embodiments, the compositions are aqueous (e.g., for intravenous administration). In other embodiments, the compositions are nebulized or in the form of a dry powder (e.g., for inhalation by an infected subject).