TY - JOUR
T1 - A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions
AU - Chen, Han
AU - Coseno, Molly
AU - Ficarro, Scott B.
AU - Mansueto, My Sam
AU - Komazin-Meredith, Gloria
AU - Boissel, Sandrine
AU - Filman, David J.
AU - Marto, Jarrod A.
AU - Hogle, James M.
AU - Coen, Donald M.
N1 - Funding Information:
This work was supported by NIH Grant AI019838 to D.M.C. and J.M.H., a sponsored research agreement from Biota Holdings Limited to D.M.C., and the Dana-Farber Strategic Resources Initiative to J.A.M.
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2017/2/10
Y1 - 2017/2/10
N2 - 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.
AB - 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.
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U2 - 10.1021/acsinfecdis.6b00079
DO - 10.1021/acsinfecdis.6b00079
M3 - Article
C2 - 28183184
AN - SCOPUS:85017497019
SN - 2373-8227
VL - 3
SP - 112
EP - 118
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 2
ER -
