title: Alkoxyalkyl esters of (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine are potent inhibitors of the replication of wild-type and drug-resistant human immunodeficiency virus type 1 in vitro.
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.
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0676, USA. khostetl@ucsd.edu
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Aldern
authors.forename: William B
authors.initials: WB
authors.lastname: Wan
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Ciesla
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002452:Cell Count; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000235:genetics; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009154:Mutation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004279:DNA, Viral; D004952:Esters; D063065:Organophosphonates; C530757:octadecyloxyethyl 9-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine