Compounds and methods for the treatment of viral infection
Inventors
Margolis, Leonid • Balzarini, Jan • McGuigan, Christopher • Lisco, Andrea • Vanpouille, Christophe • Derudas, Marco
Assignees
Katholieke Universiteit Leuven • US Department of Health and Human Services
Publication Number
US-8946243-B2
Publication Date
2015-02-03
Expiration Date
2029-03-27
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Abstract
The invention relates to compounds and methods for treating or preventing a viral infection, by administering a monophosphorylated prodrug of acyclovir or monophosphorylated derivative of an acyclovir prodrug to a subject suffering from or susceptible (to a viral infection, such as HIV infection.
Core Innovation
The invention provides compounds and methods for treating or preventing viral infections by administering monophosphorylated prodrugs of acyclovir or monophosphorylated derivatives of acyclovir prodrugs to subjects suffering from or susceptible to viral infections such as HIV infection. The invention particularly relates to novel compounds represented by a specific chemical formula (Formula I) involving substitutions on the acyclovir molecule to improve activity and cellular penetration.
The invention addresses a key problem with existing antiviral therapies for HIV-1, which is characterized by a high mutation frequency leading to ongoing challenges with drug resistance. Traditional treatments include nucleoside reverse transcriptase inhibitors (NRTIs) that mimic natural nucleosides. Acyclovir (ACV), while effective against herpesviruses via phosphorylation by a viral kinase, has limited activity against HIV since it requires viral kinase activation.
The innovation bypasses the herpesvirus thymidine kinase requirement by synthesizing monophosphorylated prodrugs of acyclovir or its derivatives that can be converted in vivo to the active triphosphate form, which inhibits HIV-1 reverse transcriptase. These prodrugs possess lipophilic ester chains allowing efficient cell penetration and demonstrate potent inhibition of HIV replication at significantly lower concentrations than non-phosphorylated acyclovir or ACV monophosphate. The invention also relates to pharmaceutical formulations, methods of treatment and prevention of viral infections (including HIV), preparation processes, and kits for administration.
Claims Coverage
The claims include two main inventive features focused on specific compounds and pharmaceutical formulations, providing comprehensive coverage of the invention's chemical and therapeutic aspects.
Compounds represented by Formula I
These compounds consist of monophosphorylated prodrugs of acyclovir or derivatives represented by a detailed chemical Formula I, characterized by specific substituents including aryl or heteroaryl groups, and defined configurations and substitutions, with certain provisos regarding substituent combinations.
Pharmaceutical formulations comprising the compounds
Pharmaceutical compositions comprising the compounds of Formula I combined with pharmaceutically acceptable carriers suitable for administration to treat or prevent viral infections such as HIV infection.
The claims collectively cover the novel chemical structures of monophosphorylated acyclovir prodrugs with specific substitutions, as well as their pharmaceutical formulations, emphasizing their utility in treating viral infections, especially HIV, thereby protecting both the compounds themselves and their therapeutic use in formulated forms.
Stated Advantages
The monophosphorylated prodrugs of acyclovir readily penetrate cells due to their lipophilic ester chains, making them active at concentrations 3 to 100 times lower than monophosphorylated acyclovir or acyclovir itself.
At low concentrations, these prodrugs effectively suppress HIV-1 replication where non-phosphorylated acyclovir shows no effect.
The compounds have potential for preventing HIV transmission through topical application as microbicides to reduce HIV viral load in mucosal compartments.
Given their structural similarity to acyclovir, a low-toxicity drug for herpesvirus infections, the prodrugs likely have low toxicity and minimal side effects in vivo.
They may be used alone or in combination with other anti-HIV therapies to enhance treatment efficacy.
Documented Applications
Treatment or prevention of viral infections, particularly HIV infection, by administering monophosphorylated prodrugs of acyclovir or derivatives thereof to subjects.
Use as topical microbicides to reduce HIV viral load in mucosal tissues of HIV-infected or HIV-negative individuals to prevent transmission.
Systemic administration to control HIV viral load and slow disease progression.
Combination therapy with other anti-HIV agents including nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 inhibitors, and others.
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