A small molecule exerts selective antiviral activity by targeting the human cytomegalovirus nuclear egress complex

• DOI: 10.1371/journal.ppat.1011781
• Publication Date: 2023-11-17T18:40:21Z
• Authors: Han Chen; Ming F. Lye; Christoph Gorgulla; Scott B. Ficarro; Gregory D. Cuny; David A. Scott; Fan Wu; Paul W. Rothlauf; Xiaoou Wang; Rosio Fernandez; Jean M. Pesola; Sorin Draga; Jarrod A. Marto; James M. Hogle; Haribabu Arthanari; Donald M. Coen
• Keywords: Docking (animal)

Human cytomegalovirus (HCMV) is an important pathogen for which new antiviral drugs are needed. HCMV, like other herpesviruses, encodes a nuclear egress complex (NEC) composed of two subunits, UL50 and UL53, whose interaction crucial viral replication. To explore whether small molecules can exert selective activity by inhibiting NEC subunit interactions, we established homogeneous time-resolved fluorescence (HTRF) assay these interactions used it to screen >200,000 compound-containing wells. Two compounds, designated GK1 GK2, selectively inhibited this in the HTRF with also active co-immunoprecipitation assay, exhibited more potent anti-HCMV than cytotoxicity or against another herpesvirus. At doses that substantially reduced HCMV plaque formation, GK2 had little no effect on expression proteins co-localization UL53 at rim subset cells. contain acrylamide moiety predicted covalently interact cysteines, analog without potential lacked activity. Mass spectrometric analysis showed binding multiple cysteines UL53. Nevertheless, substitution cysteine 214 serine (C214S) ablated detectable inhibitory vitro, C214S engineered into conferred resistance GK1, inhibitors. Thus, exerts targeting NEC. Docking studies suggest tethers one end C214 within pocket permitting molecule sterically hinder prevent formation. Our results prove concept block Such compounds could serve as foundation development chemical tools studying HCMV.