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J.D. Kriesel, G. Herpin, B.B. Jones, C. Grissom; Triplex–Forming Oligonucleotides Intended To Eliminate or Disable Latent Hsv–1 Ocular Infections . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2799.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To create drugs with activity against latent herpes simplex virus (HSV) with the goal of eliminating recurrent episodes of herpes keratitis. Methods: Triplex–forming oligonucleotides (TFO's, also called antigenes) form a third DNA strand –– the triplex –– that is bound non–covalently to specific dsDNA target sequences to induce mutations or affect transcription of a gene. Two oligonucleotides 20 and 24 bp in length were selected for their proposed activity against target sequences in the HSV–1 LAT domain. Phosphodiester–backboned, purine motif TFOs were synthesized along with matched control poly–AG oligonucleotides of the same length. Conjugations were confirmed by HPLC and mass spectroscopy. Results: Triplex DNA was demonstrated in vitro using one of the TFOs and its HSV–1 target sequence. This TFO appeared to be concentrated 100–fold in primary rat ganglionic neuron cultures and it specifically inhibited expression in a luciferase–construct system. Intraperitoneal injection of fluorophor–labeled TFOs resulted in detectable drug within mouse trigeminal ganglia 6–24 hours later. The potent virucidal, photactivatable compound pheophorbide has been successfully conjugated to several anti–HSV TFOs. Experiments in the red light activatable system are in progress. Conclusions: These studies offer the prospect of a novel anti–HSV agents that may have activity against latent HSV–1, the cause of recurrent herpes keratitis.
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