The Principal Investigator proposes a high risk/high impact project for identifying novel structural leads for inhibiting the human cytomegalovirus (HCMV) serine protease. HCMV is an opportunistic infection agent which can cause serious consequences in immune compromised patients. Although drugs against HCMV are available, including ganciclovir and acyclovir, they are nucleotide analogs and have serious side effects. HCMV protease is essential for the viral infectivity and therefore is a target for drug development. HCMV protease is a serine protease. Three crystal structures of this enzyme have been determined. The Investigator proposes to (i) develop a detailed three-dimensional model for the ligand-bound active site of the HCMV serine protease, (ii) identify potential peptide, peptidomimetic, and small molecule inhibitors of the enzyme, (iii) synthesize and evaluate the antiviral profiles of the lead compounds obtained from (ii), and (iv) refine the lead structure by utilizing the active site model to prioritize second generation targets that will be synthesize and evaluated for their anti-HCMV activities.
