Broad-spectrum non-nucleoside inhibitors of human herpesviruses

Abstract

Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of ‘quiescent’ HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo.

Preliminary Study of Fourteen AIDS-Associated Lung Complications from Imaging,Pathology and Microbiology

“…Patients of HIV-associated herpes virus infection have distinctive features in the clinical, such as a number of skin lesions, bullae of lungs, blood blisters, systemic symptoms, long course of ill, high incidence of pneumonia and encephalitis and other serious complications [30,31]. A high-incidence of herpes infection is observed in the AIDS patients, 26.4% occurred in the stage of HIV infection, 73.6% of them in the AIDS stage [32].…”

Comparison of three cell-based drug screening platforms for HSV-1 infection

“…After 4 days, CHIR99021, forskolin, and dorsomorphin were withdrawn and cells cultured for additional 25 days. Vero cells were cultured as previously described (McClain et al, 2015). Infection protocols used a modified KOS HSV-1 strain that expresses enhanced green fluorescent protein (EGFP) from the viral immediate early ICP0 promoter and monomeric red fluorescent protein (mRFP) from the promoter of the true late regulated Glycoprotein C (gC) (McClain et al, 2015).…”

“…Vero cells were cultured as previously described (McClain et al, 2015). Infection protocols used a modified KOS HSV-1 strain that expresses enhanced green fluorescent protein (EGFP) from the viral immediate early ICP0 promoter and monomeric red fluorescent protein (mRFP) from the promoter of the true late regulated Glycoprotein C (gC) (McClain et al, 2015). Infections of Vero cells and NPCs were approximately 1 pfu/cell for the multiplicity of infection (MOI), whilst neurons were infected with 0.3 pfu/cell.…”

“…1). We recently described the efficacy of lysosomotropic agents and derivatives of amaryllis derived alkaloids against lytic HSV-1 infections (McClain et al, 2015; McNulty et al, 2016). The former include 16F19, and 4F17; the latter include alkaloids R430, MP4B6, and MP4G10 referred to as C7, C5, and C3, respectively.…”

“…Therefore, we estimated the toxicity of compounds that were more effective in both NPCs and neurons than in Vero cells, i.e., quinazolinones CB-3-176, CB-3-155, the nostodione KK-6-131, 4F17-derivatives CH-1-80 and CH-1-91, the epigenetic inhibitors AT9283, and WP1066. Cytotoxicity was assayed in all three cell types by flow cytometry using fixable viability dye (McClain et al, 2015), following exposure for 48 h at different concentrations (Fig. 2).…”