Standalone or combinatorial phenylbutyrate therapy shows excellent antiviral activity and mimics CREB3 silencing

Abstract

Herpesviruses are ubiquitous human pathogens that tightly regulate many cellular pathways including the unfolded protein response to endoplasmic reticulum (ER) stress. Pharmacological modulation of this pathway results in the inhibition of viral replication. In this study, we tested 4-phenylbutyrate (PBA), a chemical chaperone–based potent alleviator of ER stress, for its effects on herpes simplex virus (HSV) type 1 infection. Through in vitro studies, we observed that application of PBA to HSV-infected cells results in the down-regulation of a proviral, ER-localized host protein CREB3 and a resultant inhibition of viral protein synthesis. PBA treatment caused viral inhibition in cultured human corneas and human skin grafts as well as murine models of ocular and genital HSV infection. Thus, we propose that this drug can provide an alternative to current antivirals to treat both ocular HSV-1 and genital HSV-2 infections and may be a strong candidate for human trials.

Salubrinal Exposes Anticancer Properties in Inflammatory Breast Cancer Cells by Manipulating the Endoplasmic Reticulum Stress Pathway

“…Choice of Salubrinal does not undermine the therapeutic potential of Phenylbutyrate, a histone deacetylase inhibitor, approved for the treatment of urea cycle disorders, cancer, hemoglobinopathies, motor neuron diseases, and cystic fibrosis clinical trials (50). It possesses a broad spectrum of molecular functions such as antiviral (51), chromatin regulator and modulator of multiple cell cycle, and apoptosis-related genes (50). Phenylbutyrate has been well studied for its potential in prostate cancer alone (52) or in a combination of Phenylbutyrate and 13-cis retinoic acid (53).…”

Host Molecules That Promote Pathophysiology of Ocular Herpes

“…New drug discoveries that target new viral or host molecules offer hope. These include an HSV-1 gD-targeting aptamer ( Yadavalli et al, 2017 ); innovative use of tranylcypromine to inhibit lysine-specific demethylase 1 (LSD1) which suppresses HSV-1 lytic infection, shedding, and reactivation from latency in animal models ( Hill et al, 2014 ); BX795, which inhibits AKT phosphorylation to block HSV-1 protein synthesis in corneal cells ( Jaishankar et al, 2018 ) and 4-phenylbutyrate (PBA), which reduces ER stress and synergistically increases the efficacy of existing antivirals and by its own, reduces ocular HSV-1 infection ( Yadavalli et al, 2020 ). A couple of above-mentioned drugs such as tranylcypromine and PBA are already approved for other clinical indications, therefore, their approval for treating HSV-1 infection of the eye might be more predictable timewise than the other experimental drugs.…”

Eradication of Candida albicans Biofilm Viability: In Vitro Combination Therapy of Cationic Carbosilane Dendrons Derived from 4-Phenylbutyric Acid with AgNO3 and EDTA

“…PBA is drug used for urea cycle disorders and its effects on microorganisms are poorly studied [42]. However, some assays have shown that it can reduce Shigella infection in vivo using animal models [43], reduce colonization by Salmonella enterica serovar Typhimurium [44], inhibit the growth of Helicobacter pylori and Escherichia coli [45] and reduce herpes simplex virus infection [46]; among others. One of their advantages is also their solubility in water, thus overcome the issues generated by some antifungals that have the disadvantage of poor solubility [47].…”