Developing Cathepsin Inhibitors as Therapeutics for Emerging Viral Infections

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Abstract There is an urgent need for effective remedies for many newly emergent viruses. Therapeutics capable of inhibiting multiple emerging viruses would be ideal. Recent evidence demonstrates an essential role for cellular cathepsins L and B in viral glycoprotein processing and cellular entry for the highly pathogenic viruses Ebola, NipahIHendra and SARS Coronavirus. For Ebola and SARS CoV, inhibitors of the cellular cathepsin enzymes effectively block viral entry and replication in cell culture. In contrast, inhibition of cellular cathepsin function, by either by pharmacologic or genetic methods, is well tolerated in mice strongly suggesting that these enzymes are good targets for antiviral drug development. This proposal will test compounds identified through a biochemical high throughput screen against human cathepsins B and L as inhibitors of Ebola virus entry using retroviral pseudotypes. A novel filamentous viruslike particle system will be employed to confirm the ability of lead compounds to block Ebola infection. Finally, promising candidates will be tested for efficacy against "live" Ebola infection. Given that Ebola, NipahIHendra and SARS viruses all require the cellular cathepsins, these studies will identify new lead compounds for development of therapeutics effective for multiple emerging viral threats. To accomplish this goal we propose the following aims: Specific Aim 1) Utilize a biochemical-based high throughput screen of diverse libraries to identify cathepsin B and Cathepsin L inhibitors. Perform structure activity analysis to improve efficacy and alter the specificity of an identified CatL inhibitor. Specific Aim 2) Test the candidate cathepsin B and L inhibitor compounds for inhibition of viral entry using pseudotype, filamentous virus-like particle and "live" Ebola assays.