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

Antimicrob Agents Chemother. 2006 Aug;50(8):2857-9. doi: 10.1128/AAC.01223-05.

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

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacology
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Count
  • Cell Line
  • Cell Survival / drug effects
  • DNA, Viral / genetics
  • DNA, Viral / metabolism
  • Drug Resistance, Viral / genetics
  • Esters / chemical synthesis
  • Esters / chemistry
  • Esters / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Genetic Variation
  • HIV Infections / drug therapy
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Humans
  • In Vitro Techniques
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mutation
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Virus Replication / drug effects*

Substances

  • Anti-HIV Agents
  • Antiviral Agents
  • DNA, Viral
  • Esters
  • Organophosphonates
  • octadecyloxyethyl 9-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
  • 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
  • Adenine