Description:
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Novel lipid-amino acid prodrug platform enhances delivery of nucleoside phosphonate antivirals for SARS-CoV-2 treatment.
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Conjugates amino acid promoieties to antiviral compounds to improve solubility, permeability, metabolic activation, and tissue targeting.
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Evaluated using an immunosuppressed Syrian hamster model that closely reflects severe COVID-19 in vulnerable patient populations.
Abstract
This technology utilizes a novel prodrug platform to significantly improve the oral bioavailability and antiviral potency of nucleoside phosphonate antivirals against SARS-CoV-2. It achieves this by conjugating lipid-modified amino acid promoieties, such as tyrosinamide or homoserinamide, to the phosphonate group of active compounds like GS-441524 and cidofovir. This chemical modification is designed to enhance the compounds' solubility, permeability, metabolic activation, and targeted delivery, particularly to lung tissues. The synthesized prodrugs undergo rigorous in vitro evaluation for antiviral activity and cytotoxicity, followed by in vivo assessment of their efficacy, toxicity, and maximum tolerated dose in an immunosuppressed Syrian hamster model of COVID-19.
This approach is highly differentiated by overcoming critical limitations of current treatments. Unlike remdesivir, which requires intravenous administration and has limited oral bioavailability, this platform aims for effective oral delivery, enabling outpatient use and prophylaxis. It leverages a unique, previously validated prodrug strategy that has shown superior oral efficacy and potency in adenovirus models, offering a versatile and non-toxic amino acid scaffold for optimization. Furthermore, the use of an immunosuppressed Syrian hamster model provides a more relevant and naturally susceptible system for evaluating severe COVID-19, directly addressing the needs of vulnerable patient populations.
Benefit
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Enables oral administration, overcoming limitations of intravenous-only antivirals.
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Enhances antiviral potency against SARS-CoV-2.
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Improves targeted delivery of the drug to lung tissues.
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Supports both prophylactic (preventative) and therapeutic (treatment) use.
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Expands accessibility to a broader patient population, including outpatients and vulnerable groups.
Applications
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Oral COVID-19 treatment
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COVID-19 prophylaxis
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Outpatient COVID-19 therapy
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Immunosuppressed patient treatment
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Lung-targeted antiviral delivery