A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions

Han Chen, Molly Coseno, Scott B. Ficarro, My Sam Mansueto, Gloria Komazin-Meredith, Sandrine Boissel, David J. Filman, Jarrod A. Marto, James M. Hogle, Donald M. Coen

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Human cytomegalovirus DNA polymerase comprises a catalytic subunit, UL54, and an accessory subunit, UL44, the interaction of which may serve as a target for the development of new antiviral drugs. Using a high-throughput screen, we identified a small molecule, (5-((dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo[c]thiophen-4(5H)-one), that selectively inhibits the interaction of UL44 with a UL54-derived peptide in a time-dependent manner, full-length UL54, and UL44-dependent long-chain DNA synthesis. A crystal structure of the compound bound to UL44 revealed a covalent reaction with lysine residue 60 and additional noncovalent interactions that cause steric conflicts that would prevent the UL44 connector loop from interacting with UL54. Analyses of the reaction of the compound with model substrates supported a resonance-stabilized conjugation mechanism, and substitution of the lysine reduced the ability of the compound to inhibit UL44-UL54 peptide interactions. This novel covalent inhibitor of polymerase subunit interactions may serve as a starting point for new, needed drugs to treat human cytomegalovirus infections.

Original languageEnglish (US)
Pages (from-to)112-118
Number of pages7
JournalACS Infectious Diseases
Volume3
Issue number2
DOIs
StatePublished - Feb 10 2017

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

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