Abstract
(S)-9-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA], is an effective broad-spectrum antiviral against many DNA viruses but has been reported to be inactive against human immunodeficiency virus (HIV). We synthesized several alkoxyalkyl esters of (S)-HPMPA and now report that hexadecyloxypropyl-(S)-HPMPA [HDP-(S)-HPMPA] and octadecyloxyethyl-(S)-HPMPA [ODE-(S)-HPMPA]had 50% effective concentrations of 0.4 to 7.0 nanomolar and were nearly fully active against HIV variants having reverse transcriptase mutations M184V and K103N and against a zidovudine-resistant variant with mutations D67N, K70R, T215Y, and K219Q. Resistance to HDP-(S)-HPMPA and ODE-(S)-HPMPA was noted for a mutant with mutation K65R. HDP-(S)-HPMPA is also active against herpes simplex virus type 1, human cytomegalovirus, hepatitis B virus, adenoviruses, and orthopoxviruses and is worthy of further evaluation as a possibly therapy for HIV infection.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemical synthesis
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Adenine / chemistry
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Adenine / pharmacology
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Cell Count
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Cell Line
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Cell Survival / drug effects
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DNA, Viral / genetics
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DNA, Viral / metabolism
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Drug Resistance, Viral / genetics
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Esters / chemical synthesis
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Esters / chemistry
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Esters / pharmacology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Genetic Variation
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HIV Infections / drug therapy
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HIV-1 / drug effects*
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HIV-1 / genetics
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HIV-1 / physiology*
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Humans
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In Vitro Techniques
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Microbial Sensitivity Tests
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Molecular Structure
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Mutation
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Organophosphonates / chemical synthesis
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Organophosphonates / chemistry
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Organophosphonates / pharmacology*
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Virus Replication / drug effects*
Substances
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Anti-HIV Agents
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Antiviral Agents
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DNA, Viral
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Esters
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Organophosphonates
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octadecyloxyethyl 9-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
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9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
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Adenine