Gesellschaft Deutscher Chemiker
Keine Benachrichtigungen
Sie haben noch keine Lesezeichen
Abmelden

Artikel

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

Von Wiley-VCH zur Verfügung gestellt

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.


Abstract

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.

Zum Volltext

Überprüfung Ihres Anmeldestatus ...

Wenn Sie ein registrierter Benutzer sind, zeigen wir in Kürze den vollständigen Artikel.