Our long-term objectives are to further develop and exploit a new class of antiviral agents with """"""""broadspectrum"""""""" activity. In addition to a variety of medically important viruses, the list of targeted viruses includes several NIAID Categories A and B viruses making these compounds valuable potential drugs for this nation's biodefense. The first successful prototype viral target for this novel antiviral strategy was human hepatitis D virus (HDV). This application now seeks to leverage the expertise and reagents available with HDV to begin to expand the therapeutic spectrum of this novel antiviral strategy to combat bunyaviruses. Prenylation, a type of sequence-specific post-translational modification of proteins involves the covalent addition of a prenyl lipid to a sequence motif, termed a """"""""CXXX box."""""""" A wide variety of viruses also encode CXXX box-containing proteins, and like HDV are suspected of using prenylation in key aspects of their life cycles, indicating they are prime targets for prenylation inhibition-based antiviral therapy. Excitingly, prenylation inhibitors are surprisingly well tolerated in vivo. We propose to first synthesize sufficient quantities of proven as well as novel agents with prenylation-inhibiting activity, and to then use these compounds in the HDV prototype model to evaluate a novel regimen designed to increase the antiviral potency of prenylation inhibitors. Next we will better characterize the prenylation status of a selected bunyavirus substrate that produces a Dengue-like illness for which no effective therapy exists to date. Finally we will evaluate the latter's sensitivity to the optimized anti-prenylation regimen.
Our specific aims are to: 1) synthesize known and improved prenylation inhibitors; 2) determine the synergy potential of combination therapy with HMG-CoA reductase and prenylation inhibitors; 3) characterize the prenylation efficiency and specificity of the absolutely conserved CXXX box-containing protein in a bunyavirus; 4) evaluate the optimized antiprenylation regimen determined from the above aims against a specific bunyavirus target. Together with our collaborators, using our expertise in peptidomimetic design of prenyltransferase inhibitors, molecular virology, and recently developed in vitro and in vivo models for testing prenylation inhibition-based antiviral therapies, we anticipate that successful accomplishment of our aims will yield an invaluable weapon for this nation's biodefense arsenal.
| Glenn, Matthew P; Chang, Sung-Youn; Horney, Carrie et al. (2006) Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites. J Med Chem 49:5710-27 |
