The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition

J Med Chem. 2009 Sep 10;52(17):5520-30. doi: 10.1021/jm9007856.

Abstract

Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated. ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types -1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyclovir / chemistry*
  • Acyclovir / pharmacology*
  • Amides / chemistry*
  • Amino Acids / chemistry
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Benzene / chemistry
  • Catalytic Domain
  • Cathepsin A / chemistry
  • Cathepsin A / metabolism
  • Cell Line
  • Enzyme Activation / drug effects
  • Esters / chemistry
  • HIV-1 / drug effects*
  • Humans
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism
  • Phosphoric Acids / chemistry*
  • Simplexvirus / drug effects

Substances

  • Amides
  • Amino Acids
  • Anti-HIV Agents
  • Esters
  • HINT1 protein, human
  • Nerve Tissue Proteins
  • Phosphoric Acids
  • phosphoramidic acid
  • Cathepsin A
  • Benzene
  • Acyclovir