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MIH-01 INHIBITION OF VIRAL STD INFECTION BY PEPTIDES CONTAINING PROTEIN TRANSDUCTION MOTIFS Brandt, Curtis R. Protein-protein interactions are fundamental in biology. Because of their importance, interfering with these interactions is a potentially powerful strategy for drug development. In the past few years, a number of publications have shown that peptides that match the sequence of a protein-protein interface will compete for the interaction and disrupt the complex. Such peptides have also been used to map protein-protein interaction sites. One problem with the use of peptide inhibitors is their inefficient entry into cells. However, the use of peptides to block activities at the cell surface does not suffer this limitation. During studies to improve the delivery of antiviral peptides into cells, we discovered that peptides that contain membrane-transiting motifs (e.g., tat, homeodomain, FGF4 signal sequence) were potent antivirals. We have identified peptides that inhibit Herpes simplex virus Type 1, Influenza virus, Human Immunodeficiency virus, Human Papilloma virus, and Vaccinia virus. Studies in animals show the peptides block HSV-induced disease and Influenza virus even post-exposure. We will briefly discuss the evidence showing that some of these peptides are virucidal, rendering virions permanently non-infectious. In studies where virions were added to cells at 4°C followed by peptide addition and subsequent shift to 37°C, we showed that the peptides inhibited viral entry. Finally, we will discuss more extensively new data showing that some of the peptides induce a state in cells whereby they are resistant to viral infection. Toxicity studies showing the peptides are non-toxic in vivo after corneal or vaginal instillation will also be discussed. The fact that we can prevent infection of cells by the three major viral STDs with only one or two peptides represents a novel approach for microbicide development. Curtis R. Brandt, Ph.D |
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