Nucleotide analogs
Inventors
Hostetler, Karl Y. • Beadle, James R. • Valiaeva, Nadejda
Assignees
US Department of Veterans Affairs • Office of General Counsel of VA • University of California San Diego UCSD
Publication Number
US-11344555-B2
Publication Date
2022-05-31
Expiration Date
2035-09-15
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Abstract
Disclosed herein, inter alia, are acyclic nucleotide analogs and methods of using an acyclic nucleotide analog for treating and/or ameliorating a papillomavirus infection.
Core Innovation
The invention disclosed provides acyclic nucleotide analogs with antiviral activity against papillomavirus infections, specifically designed to inhibit viral DNA synthesis and/or the production of virions of high-risk human papillomavirus (HPV) types. These compounds can be used alone or in combination therapies for treating or ameliorating papillomavirus infections by selectively targeting viral replication inside host cells.
The invention addresses the problem that there are currently no approved antiviral treatments for early HPV infections before progression to cancer. HPV infections can cause precancerous lesions and several cancers, including cervical cancer caused mainly by high-risk HPV types such as HPV-16 and HPV-18. Existing treatments and vaccines provide limited benefit to individuals already infected, and antiviral nucleoside or nucleotide analogs effective against other viruses have not been applied effectively against HPV.
To solve these challenges, the invention introduces nucleotide analogs represented by Formula (I) and pharmaceutical compositions containing them. These compounds include groups that neutralize the phosphonate charge to improve cell membrane permeation and in vivo stability. Upon uptake, prodrugs convert intracellularly to active diphosphate metabolites that act as chain terminators of DNA synthesis, selectively inhibiting viral DNA replication without significant antiproliferative effects on host cells. The invention includes methods of synthesis, pharmaceutical formulations, and administration regimens, providing a novel approach to treating HPV infections by blocking viral DNA synthesis before oncogenic cellular changes occur.
Claims Coverage
The patent contains multiple independent claims focusing on pharmaceutical compositions with specific nucleotide analog compounds, methods of treatment, and uses for treating papillomavirus infections.
Pharmaceutical composition comprising specified nucleotide analog compounds
A pharmaceutical composition comprising a compound selected from specified nucleotide analogs or their pharmaceutically acceptable salts, formulated for suitable delivery such as topical creams, gels, or suppositories.
Use of nucleotide analogs for treating papillomavirus infections
Use of compounds of Formula (I), or pharmaceutically acceptable salts thereof, characterized by specific substituents and moieties, for the preparation of medicines to ameliorate or treat human papillomavirus by inhibiting viral DNA synthesis and replication.
Methods for ameliorating or treating HPV infection using nucleotide analogs
Methods involving contacting HPV-infected cells or administering an effective amount of compounds of Formula (I) to a subject infected with HPV, where treatment occurs by selective inhibition of viral DNA replication through chain termination.
The independent claims define pharmaceutical compositions comprising the inventive nucleotide analogs, methods of treating human papillomavirus infections with these compounds, and their use in manufacturing medicaments. The main inventive features cover the specified chemical structures of the nucleotide analogs, their selective antiviral mechanism targeting HPV DNA synthesis, and suitable pharmaceutical formulations for administration.
Stated Advantages
Selective inhibition of viral DNA synthesis and virion production of high-risk HPV types without significant antiproliferative effects on host cells.
Potential to eradicate papillomavirus infection early, preventing progression to invasive cancers.
Improved oral bioavailability, cellular penetration, and in vivo stability through phosphonate charge-neutralizing moieties in the compounds.
Flexibility in formulation and administration routes, including topical gels, creams, suppositories, and sustained release approaches.
Potential for reduced treatment duration and dosing frequency compared to existing agents.
Documented Applications
Treatment and amelioration of human papillomavirus infections, including both high-risk (e.g., HPV-16, HPV-18, HPV-31) and low-risk (e.g., HPV-6, HPV-11) types.
Use in pharmaceutical compositions for topical or systemic application to prevent HPV-induced diseases, including cervical intraepithelial neoplasia and HPV-related cancers.
Application in combination therapies for viral infections caused by papillomaviruses by inhibiting viral DNA synthesis.
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