8‐Hydroxy‐1,6‐naphthyridine‐7‐carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease

• Published in: ChemMedChem 2022-09, Vol.17 (17), p.e202200334-n/a
• Main Authors: Jung, Eunkyung, Majima, Ryuichi, Edwards, Tiffany C., Soto‐Acosta, Ruben, Geraghty, Robert J., Wang, Zhengqiang
• Format: Article
• Language: English
• Subjects: 8-hydroxy-1,6-naphthyridine-7-carboxamide; Amides - pharmacology; Analogs; Antiviral activity; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Assaying; Chelation; Cytomegalovirus; Endodeoxyribonucleases - chemistry; Endonuclease; Endonucleases; Genomes; human cytomegalovirus; Humans; inhibitor; Inhibitors; Molecular docking; Molecular Docking Simulation; Molecular modelling; Naphthyridines - pharmacology; Packaging; pUL89-C; Viral Proteins - chemistry
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202200334

Human cytomegalovirus (HCMV) replication requires a metal‐dependent endonuclease at the C‐terminus of pUL89 (pUL89‐C) for viral genome packaging and cleavage. We have previously shown that pUL89‐C can be pharmacologically inhibited with designed metal‐chelating compounds. We report herein the synthesis of a few 8‐hydroxy‐1,6‐naphthyridine subtypes, including 5‐chloro (subtype 15), 5‐aryl (subtype 16), and 5‐amino (subtype 17) variants. Analogs were studied for the inhibition of pUL89‐C in a biochemical endonuclease assay, a biophysical thermal shift assay (TSA), in silico molecular docking, and for the antiviral potential against HCMV in cell‐based assays. These studies identified eight analogs of 8‐hydroxy‐1,6‐naphthyridine‐7‐carboxamide subtypes for further characterization, most of which inhibited pUL89‐C with single‐digit μM IC50 values, and conferred antiviral activity in μM range. TSA and molecular modeling of selected analogs corroborate their binding to pUL89‐C. Collectively, our biochemical, antiviral, biophysical and in silico data suggest that 8‐hydroxy‐1,6‐naphthyridine‐7‐carboxamide subtypes can be used for designing inhibitors of HCMV pUL89‐C. The replication of human cytomegalovirus (HCMV) requires a metal‐dependent endonuclease at the C‐terminus of pUL89 (pUL89‐C), which bears an RNase H / integrase‐like active site, structurally and catalytically. We report herein the synthesis and biochemical, antiviral, biophysical and in silico characterization of a few metal‐binding 8‐hydroxy‐1,6‐naphthyridine subtypes. Synthesized analogs feature structural variations at R1 and R2.