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Exploiting conformational dynamics to inhibit human herpesvirus proteases


The human herpesviruses (HHVs) make up one of the most prevalent families of human viral pathogens. Infection with HHV is associated with several serious illnesses, including oral/genital herpes, chickenpox/shingles, infectious mononucleosis, cancer and neurodegeneration. In patients who are immunocompromised, including HIV/AIDs patients, organ transplant recipients and newborn infants, HHV infection can be life threatening and lead to serious complications. The current antiviral treatments for HHV infection almost exclusively target the viral DNA polymerase, and these drugs suffer from toxicity and emergent resistance. To develop new routes to managing HHV infection, there is a critical need for the identification and validation of new viral therapeutic targets. We seek to pharmacologically validate the viral maturational protease as a new therapeutic target. The human herpesvirus protease (HHV Pr) is essential for viral replication and infectivity, and inhibition of proteolysis arrests the viral replication cycle and disrupts infection. All HHV Prs are obligate homodimers, and undergo significant allosteric rearrangement that causes a disorder-to-order conformational switch within the dimer interface and active site, leading to catalytic activation. Here we present new methods for exploiting the HHV Pr monomer/dimer equilibrium to isolate HHV Pr in various conformational states that are catalytically inactive. These methods present routes for HHV Pr inhibitor development and have produced new tools for managing HHV infection.

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