Cerracchio, Claudia (2024) Coronaviruses and herpesviruses infections: potential antiviral activity of natural and synthetic compounds. [Tesi di dottorato]

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Abstract

Coronaviruses (CoVs) emerge or remerge and can mutate into new and more dangerous strains, such as SARS CoV-2, causing coronavirus disease 2019 (COVID-19) pandemic and CCoV-HuPn-2018, a novel canine-feline recombinant alphacoronavirus isolated from human patients. Herpesviruses are another challenge both for humans and animals. Clinical symptoms caused by lesions in the peripheral and central nervous system and upper respiratory tract are provoked by primary infection by herpes simplex virus type 1 (HSV-1). Recurrent ocular shedding leads to corneal scarring which can progress to vision loss. Similar properties to HSV-1 are provoked by Bovine herpesvirus 1 (BoHV-1), which causes health and economic losses to the cattle industry. Both these viruses established latency in sensory neurons of trigeminal ganglia, but immunosuppression leads to a periodic reactivation of the infection, provoking a spread of virus and recurrent disease. And several case of drug resistance have been detected from monotherapy or combination therapy of DNA polymerase inhibitors against HSV-1. In this context, the pharmaceutical industry is constantly looking for new active drugs involving original mechanisms of action. Based on this evidence, this PhD research project focused on the study of both coronaviruses and herpesviruses infections. Thus, to explore the mechanism of action of two alphacoronaviruses, CCoV and Feline Coronavirus (FCoV), the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor involving in several functions, like chemical and microbial defence was investigated. It has been observed that AhR was considerably activated by CCoV and FCoV infections, and that the selective AhR antagonist CH223191 reduces in vitro replication of these CoVs, responsible for both enteric and respiratory diseases in dogs and cats, respectively. Interestingly, 3-O-methylfunicone (OMF), penisimplicissin (PS) and vermistatin (VER), which are funicone-like compounds produced by the fungus Talaromyces pinophilus, as well as 6-Pentyl-α-Pyrone (6PP), isolated from Trichoderma atroviride, have shown antiviral activity against CCoV, potentially inhibiting AhR. In addition, it has been observed the alkalinization of lysosomes in the presence of VER or PS, which may be involved in the observed antiviral activities. The AhR activation also modulates viral replication of BoHV-1. Hence, during BoHV-1 in vitro infection, the potential antiviral activity of some natural compounds, like OMF, and Taurisolo®, a grape pomace polyphenolic extract obtained from the Aglianico cultivar grape, was investigated. Both these natural substances have shown an excellent defence reaction during BoHV-1 infection involving AhR. Furthermore, experiments of combination therapy of DNA polymerase inhibitors, like acyclovir (ACV) and foscarnet (PFA), and helicase-primase complex inhibitor, such as amenamevir (AMV), have been carried out against HSV-1 to know if these combination therapies may represent a valid alternative to well-known monotherapy of ACV or PFA, that have shown cases of HSV-1 drug resistance. Overall, these findings provide evidence on structural knowledge as well as on functional mechanism of new potential antivirals. They may be considered useful starting points for the development of drugs against coronaviruses as well as herpesviruses infections.

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