2. Academic Validation
  3. Metal binding 6-arylthio-3-hydroxypyrimidine-2,4-diones inhibited human cytomegalovirus by targeting the pUL89 endonuclease of the terminase complex

Metal binding 6-arylthio-3-hydroxypyrimidine-2,4-diones inhibited human cytomegalovirus by targeting the pUL89 endonuclease of the terminase complex

  • Eur J Med Chem. 2021 Oct 15:222:113640. doi: 10.1016/j.ejmech.2021.113640.
Lei Wang 1,  Tiffany C Edwards 2,  Rajkumar Lalji Sahani 2,  Jiashu Xie 2,  Hideki Aihara 3,  Robert J Geraghty 2,  Zhengqiang Wang 4
Affiliations

Affiliations

  • 1 Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA; Department of Pharmaceutical Science, School of Chemical Engineering, Dalian University of Technology, 116024, Dalian, China.
  • 2 Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 3 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 4 Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: wangx472@umn.edu.
PMID: 34147908 DOI: 10.1016/j.ejmech.2021.113640
Abstract

The genome packaging of human cytomegalovirus (HCMV) requires a divalent metal-dependent Endonuclease activity localized to the C-terminus of pUL89 (pUL89-C), which is reminiscent of RNase H-like Enzymes in active site structure and catalytic mechanism. Our previous work has shown that metal-binding small molecules can effectively inhibit pUL89-C while conferring significant Antiviral activities. In this report we generated a collection of 43 metal-binding small molecules by repurposing analogs of the 6-arylthio-3-hydroxypyrimidine-2,4-dione chemotype previously synthesized for targeting HIV-1 RNase H, and by chemically synthesizing new N-1 analogs. The analogs were subjected to two parallel screening assays: the pUL89-C biochemical assay and the HCMV Antiviral assay. Compounds with significant inhibition from each assay were further tested in a dose-response fashion. Single dose cell viability and PAMPA cell permeability were also conducted and considered in selecting compounds for the dose-response Antiviral testing. These assays identified a few analogs displaying low μM inhibition against pUL89-C in the biochemical assay and HCMV replication in the Antiviral assay. The target engagement was further evaluated via a thermal shift assay using recombinant pUL89-C and molecular docking. Overall, our current work identified novel inhibitors of pUL89-C with significant Antiviral activities and further supports targeting pUL89-C with metal-binding small molecules as an Antiviral approach against HCMV.

Keywords

Human cytomegalovirus; Metal-binding compounds; Terminase complex; pUL89-C; thermal shift assay.

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