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-10213430-B2
Publication Date
2019-02-26
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 discloses acyclic nucleotide analogs and methods of using these analogs for treating and ameliorating papillomavirus infections. Specifically, it provides antiviral agents that selectively inhibit or block viral DNA synthesis and production of virions of high risk human papillomavirus (HPV) types, thereby eradicating the infection before cellular changes lead to invasive cancers.
The problem solved by the invention is the lack of approved antiviral treatments for human papillomavirus infections, particularly early infections that have not progressed to cancer. Existing HPV vaccines have limited efficacy in sexually active women already infected by HPV, and there is currently no pharmaceutical drug that effectively treats productive HPV replication. The invention addresses this unmet medical need by offering compounds with antiviral activity against papillomaviruses without significant antiproliferative effects on host cells.
Claims Coverage
The claims include one independent claim directed to a compound of Formula (I) with various substituents and prodrugs and several pharmaceutical compositions containing such compounds. The main inventive features involve specific structural features of the nucleotide analog compounds and their pharmaceutical uses.
Nucleotide analog compound with specific structural formula
A compound of Formula (I) having a defined base moiety B1, chemical substituents Z1, Z2, R1, R2, R3, and other substituents as specified, including prodrug forms with groups that neutralize the charge of the phosphonate to improve bioavailability and selective inhibition of viral DNA synthesis.
Pharmaceutical compositions comprising the compound
Pharmaceutical compositions that contain an effective amount of the compound of Formula (I) or pharmaceutically acceptable salts thereof, formulated for administration with pharmaceutically acceptable carriers.
Use of the compound for treating papillomavirus infection
Use of the compound of Formula (I) in the preparation of a medicine or medicament for ameliorating or treating human papillomavirus infection by inhibiting viral replication through inhibition of viral DNA synthesis.
Methods of treating HPV infection with the compound
Methods of ameliorating or treating a host infected with human papillomavirus by contacting infected cells or administering an effective amount of the compound of Formula (I) or its salt to the subject to selectively inhibit viral replication and DNA synthesis.
The claims collectively cover the chemical compounds characterized by Formula (I), pharmaceutically acceptable salts and prodrugs thereof, pharmaceutical compositions containing such compounds, and their use and methods to treat human papillomavirus infections by targeting viral DNA synthesis selectively.
Stated Advantages
The compounds selectively inhibit viral DNA synthesis and virion production of high risk HPV types without significant antiproliferative effects on host cells.
Early inhibition of HPV replication can eradicate infection before cellular changes lead to invasive cancers, representing an advance over current treatments.
The prodrug moieties improve oral bioavailability, aqueous stability, and reduce toxicity risks compared to parent nucleotide analogs.
The antiviral activity can be separated from the antiproliferative activity by moderating the release rate of the active metabolite in cells.
Documented Applications
Treatment or amelioration of human papillomavirus infection, including both high-risk HPV types (e.g., HPV-16, HPV-18, HPV-31, etc.) and low-risk types (e.g., HPV-6, HPV-11).
Preparation of medicines or medicaments for preventing or treating viral diseases caused by papillomavirus.
Therapeutic administration of the compounds in pharmaceutical compositions for treating HPV infections potentially including topical, oral, intravaginal, and other routes of administration.
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