Heteroleptic (S

Despite the increasingly widespread clinical impact of adenovirus (HAdV) infections in healthy individuals and the associated high morbidity in immunosuppressed patients, particularly among the paediatric population, a specific treatment for this virus has yet to be developed. In this study, we report the anti-HAdV activity of sub-micromolar concentrations of four heteroleptic (C^S)-cycloaurated complexes bearing a single thiophosphinamide [Au(dpta)Cl2, Au(dpta)(mrdtc), and Au(dpta)(dedtc)] or thiophosphonamide [Au(bpta)(dedtc)] chelating ligand and a dithiocarbamate moiety. In addition to their low cytotoxicity, the findings of mechanistic assays revealed that these molecules have antiviral activity by targeting stages of the viral replication cycle subsequent to DNA replication. Additionally, all four compounds showed a significant inhibition of human cytomegalovirus (HCMV) DNA replication, thereby providing evidence for potential broad-spectrum antiviral activity.

Antiviral activity of immunosuppressors alone and in combination against human adenovirus and cytomegalovirus.

Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC50) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC50=0.05 µM and 0.3 µM, respectively) and HCMV (IC50=10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI50) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI50=0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI50=0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human Cmax values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections.

Inhibition of adenovirus transport from the endosome to the cell nucleus by rotenone.

Regardless of the clinical impact of human adenovirus (HAdV) infections in the healthy population and its high morbidity in immunosuppressed patients, a specific treatment is still not yet available. In this study, we screened the CM1407 COST Action's chemical library, comprising 1,233 natural products to identify compounds that restrict HAdV infection. Among them, we identified rotenolone, a compound that significantly inhibited HAdV infection. Next, we selected four isoflavonoid-type compounds (e.g., rotenone, deguelin, millettone, and tephrosin), namely rotenoids, structurally related to rotenolone in order to evaluate and characterized in vitro their antiviral activities against HAdV and human cytomegalovirus (HCMV). Their IC50 values for HAdV ranged from 0.0039 µM for rotenone to 0.07 µM for tephrosin, with selective indices ranging from 164.1 for rotenone to 2,429.3 for deguelin. In addition, the inhibition of HCMV replication ranged from 50% to 92.1% at twice the IC50 concentrations obtained in the plaque assay for each compound against HAdV. Our results indicated that the mechanisms of action of rotenolone, deguelin, and tephrosin involve the late stages of the HAdV replication cycle. However, the antiviral mechanism of action of rotenone appears to involve the alteration of the microtubular polymerization, which prevents HAdV particles from reaching the nuclear membrane of the cell. These isoflavonoid-type compounds exert high antiviral activity against HAdV at nanomolar concentrations, and can be considered strong hit candidates for the development of a new class of broad-spectrum antiviral drugs.