Title page for ETD etd-01212009-071834


Type of Document Dissertation
Author Rybachuk, Galena V.
URN etd-01212009-071834
Title Antiviral Chemotherapeutic Agents against Equine Herpesvirus Type 1: The Mechanism of Antiviral Effects of Porphyrin Derivatives
Degree Doctor of Philosophy (Ph.D.)
Department Pathobiological Sciences (Veterinary Medical Sciences)
Advisory Committee
Advisor Name Title
Konstantin Gus Kousoulas Committee Chair
Inder Sehgal Committee Member
John C. Larkin Committee Member
Rustin Moore - honorary member Committee Member
Shafiqul Chowdhury Committee Member
Lane D. Foil Dean's Representative
Keywords
  • glycoprotein
  • antiviral
  • tetrasulfonated phenylporphyrin
  • membrane fusion
  • porphyrin
  • EHV-1
  • virus
  • herpes
  • equine
Date of Defense 2008-12-16
Availability unrestricted
Abstract
Equine Herpesvirus-1 (EHV-1) is an important ubiquitous enzootic equine pathogen, causing significant economic losses to the horse industry. Despite extensive vaccination protocols, EHV-1 continues to be a major cause of epidemic abortion, perinatal mortality, respiratory disease and neurologic disease. EHV-1 infections are usually dealt with by using management practices that limit spread of the disease and secondary complications, providing symptomatic relief to infected horses, but no specific treatment is available. New therapeutic or virucidal agents could have great utility in slowing both the progression and spread of the disease in an epidemic situation.

A number of porphyrins and their derivatives have been tested to have activity against HIV, vaccinia, and coronavirus. Porphyrin based compounds were suggested to inhibit virus infection by reducing the fusogenic potential of the virus (Vzorov et al., 2002). However, the mechanism of action of porphyrin-based compounds is not well understood. While current antiherpetic agents target viral DNA replication, interference with the upstream replicative events such as fusion would not adversely affect the host cell metabolism, and makes them important targets for chemotherapeutic intervention of virus dissemination.

We screened a number of porphyrin and platinum compounds for EHV-1 antiviral activity by testing their ability to interfere with EHV-1 infection of rabbit kidney and equine cell cultures during the entry and post entry events of the viral life cycle in order to determine if compounds act at the level of binding, penetration, replication, or egress. We identified Cu (III) tetrasulfonated phenylporphyrin and Fe (II) tetrasulfonated phenylporphyrin as lead candidate antiviral compounds on the basis of their in vitro efficacy, cytotoxicity and therapeutic index.

These compounds exhibited high antiviral potency during virus-to-cell fusion events, as well as no apparent cytotoxicity in cell culture assays at EHV-1 inhibitory concentrations. Specifically, selected porphyrin compounds inhibited free virus, gB-mediated virus entry, reduced the extent of virus spread, and cell-to-cell fusion in the virus-free cell fusion system. The EHV-1 antiviral properties and other pharmacological characteristics make porphyrins auspicious candidates for the treatment of EHV-1 infections and may promote understanding of membrane fusion events of EHV-1 life cycle.

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