California Sea Grant College Program

Viruses have probably afflicted mankind for millennia, but modem factors such as the booming human population, fast and widespread global travel, and increased ecosystem perturbations have assured viral disease of an even brighter spotlight in the nearfuture. The examples are frightening. HlV infection is still spreading around the globe. Deadly outbreaks of viruses such as Ebola and Lassa fever continue to occur ever more closely to heavily populated regions. Drug resistant strains of familiar pathogens such as herpes simplex virus are beginning to emerge. Clearly, our science is challenged to find new treatments for these diseases.

How will the next generation of antiviral medicines be discovered? A crucial component should continue to be the proven strategy of screening natural products. In the past, structurally diverse metabolites produced by terrestrial microorganisms and plants have shown inhibitory activities against various viral diseases. Unlike their terrestrial counterparts, however, the antiviral potential of secondary metabolites produced by marine organisms is virtually unexplored.

This dissertation describes the discovery of novel antiviral agents produced by marine organisms. Studies involving several important viral targets are presented, and included are chemical investigations that have identified lead compounds for antiviral drug discovery. A series of linear, lipophilic peptides produced by a marine fungus are presented as novel inhibitors of the herpes simplex virus. Evidence suggests that these peptides directly inactivate the virus. Synthetic analogs of the natural substrates were prepared, leading to the development of structure-activity relationships outlining the biological importance of key structural features, and perhaps a greater insight into the possible mechanism of action. The thalassiolins, metabolites isolated from a sea grass Thalassia testudinum, were identified as inhibitors of the HlV enzyme integrase, and also the replication of HIV in cell culture. The marine cyclic peptide sansalvamide is presented as the first natural product inhibitor of the topoisomerase enzyme of the Molluscum contagiosum virus. I believe that the molecules described in this dissertation extend our knowledge and comprehension of viral inactivating agents, and further serve to support the recognition of the marine environment as a future resource for the continued discovery of novel antiviral medicines.