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-9801884-B2
Publication Date
2017-10-31
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 discloses acyclic nucleotide analogs and methods for using these analogs to treat and/or ameliorate papillomavirus infections by selectively inhibiting viral replication through inhibition of DNA synthesis. These compounds of Formula (I) and pharmaceutically acceptable salts thereof act as antiviral agents that block viral DNA synthesis and production of virions of high-risk HPV types, thereby eradicating the infection before cellular changes leading to invasive cancer occur.
The invention addresses the lack of approved antiviral treatments for human papillomavirus infection, particularly early HPV infections that have not progressed to cancer. Existing therapies and vaccines provide limited benefit to individuals already infected, and nucleoside or nucleotide analog antiviral drugs have known limitations with oral bioavailability and cellular uptake. The invention offers improved nucleotide analog compounds with moieties that neutralize phosphonate charge to enhance cell membrane penetration, stability, and controlled release of active metabolites, enabling selective inhibition of HPV replication without significant antiproliferative effects on host cells.
Claims Coverage
The patent contains a set of independent claims directed to compounds of specific structural formulas and their use for treating papillomavirus infections. The claims focus on the chemical structures of the nucleotide analogs and their application in antiviral therapy against HPV.
Compounds of Formula (I) with specific substituents for treating papillomavirus
The invention covers compounds of Formula (I) characterized by a guanine or modified guanine base, with varied substitutions where Z1 and Z2 are independently —O— or —NRZ—, and R1 and R2 groups being absent, hydrogen, or optionally substituted alkyl, alkenyl, aryl, heteroaryl, and heterocyclyl moieties, or forming cyclic prodrug structures; the compounds inhibit viral DNA synthesis selectively.
Use of compounds of Formula (I) in medicine preparation for HPV treatment
Application of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, in the manufacture of medicines intended to ameliorate or treat human papillomavirus infections by inhibiting viral replication through DNA synthesis inhibition.
Methods of ameliorating or treating HPV infection by compound administration
Methods involving contacting HPV-infected cells or administering an effective amount of a compound of Formula (I), or its pharmaceutically acceptable salts, to a subject infected with HPV, effectuating selective inhibition of HPV replication by blocking viral DNA synthesis.
The claims collectively cover the chemical entities of nucleotide analog compounds with defined substitutions and prodrug moieties, their pharmaceutical application for the treatment of papillomavirus infection, and their therapeutic methods for selectively inhibiting viral DNA synthesis to treat HPV infections.
Stated Advantages
Selective inhibition of viral DNA synthesis and production of virions of high-risk HPV types leading to eradication before progression to cancer.
Ability to treat early HPV infections lacking currently approved antiviral drugs.
Improved cellular uptake and stability via moieties that neutralize phosphonate charge, enhancing lipophilicity and oral bioavailability.
Separation of antiviral activity from antiproliferative effects on host cells by controlling the intracellular release rate of the active metabolite PMEG diphosphate.
Documented Applications
Treatment or amelioration of human papillomavirus infections, including both high-risk types (e.g., HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, HPV-82) and low-risk types (e.g., HPV-6, HPV-11).
Use of compounds to inhibit viral replication by blocking viral DNA synthesis in HPV-infected subjects.
Pharmaceutical compositions containing the compounds for topical, oral, intravaginal, or targeted drug delivery to treat papillomavirus infections.
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