Host Cell Targets for Unconventional Antivirals against RNA Viruses

Abstract

The recent COVID-19 crisis has highlighted the importance of RNA-based viruses. The most prominent members of this group are SARS-CoV-2 (coronavirus), HIV (human immunodeficiency virus), EBOV (Ebola virus), DENV (dengue virus), HCV (hepatitis C virus), ZIKV (Zika virus), CHIKV (chikungunya virus), and influenza A virus. With the exception of retroviruses which produce reverse transcriptase, the majority of RNA viruses encode RNA-dependent RNA polymerases which do not include molecular proofreading tools, underlying the high mutation capacity of these viruses as they multiply in the host cells. Together with their ability to manipulate the immune system of the host in different ways, their high mutation frequency poses a challenge to develop effective and durable vaccination and/or treatments. Consequently, the use of antiviral targeting agents, while an important part of the therapeutic strategy against infection, may lead to the selection of drug-resistant variants. The crucial role of the host cell replicative and processing machinery is essential for the replicative cycle of the viruses and has driven attention to the potential use of drugs directed to the host machinery as therapeutic alternatives to treat viral infections. In this review, we discuss small molecules with antiviral effects that target cellular factors in different steps of the infectious cycle of many RNA viruses. We emphasize the repurposing of FDA-approved drugs with broad-spectrum antiviral activity. Finally, we postulate that the ferruginol analog (18-(phthalimide-2-yl) ferruginol) is a potential host-targeted antiviral.

Polydopamine-based nanomedicines for efficient antiviral and secondary injury protection therapy

“…IAV is a severe acute respiratory virus that infects approximately 1 billion people and causes 300,000 to 500,000 deaths annually ( 34 ). Current attempts to design clinical therapies for viral infection usually inhibit viral replication using small-molecule drugs; nevertheless, their efficacy is limited by poor bioavailability, nontargeted release, and adverse side effects ( 35 , 36 ). Many kinds of delivery systems such as micelles, nanoliposomes, nanoemulsions, and biopolymer NPs can be designed to enhance the efficacy of antiviral drugs by overcoming the above obstacles ( 37 – 39 ).…”

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

“…In the experimental design of this study, double serial dilutions were used from 0.4 to 25.6 µM for phthFGL, resulting in IC 99 values of 25.6 µM for the three tested viruses ZIKV, CHIKV, and HHV-2. Unpublished studies strongly suggest that implicated in the antiviral mechanism of action of phthFGL is the disruption of the viral polyprotein translation, via alteration in actin remodeling, as well as other related cellular and viral processes involved in the replicative complex formation [18,22].…”

“…In that work, it was found that phthFGL has a good affinity for key viral targets, including chikungunya nonstructural protein 2 (nsP2), Zika and dengue virus NS5 methyltransferase, and herpesvirus thymidine kinase (TK) with a higher binding energy value than that of acyclovir itself [20]. Additionally, like IVM, phthFGL showed features suggesting potential inhibition towards cellular therapeutic targets, as demonstrated by its high free energy value with G-Actin and tubulin [20,22]. However, experimental evidence to confirm those predictions needs to be obtained, though some evidence gathered by collaborators points to this molecule as a host-targeted antiviral [22].…”

“…Additionally, like IVM, phthFGL showed features suggesting potential inhibition towards cellular therapeutic targets, as demonstrated by its high free energy value with G-Actin and tubulin [20,22]. However, experimental evidence to confirm those predictions needs to be obtained, though some evidence gathered by collaborators points to this molecule as a host-targeted antiviral [22]. PhthFGL is structurally an analog of ferruginol (1), a well-known bioactive molecule, which possesses a phthalimide moiety attached at the C18 position.…”

“…Additionally, combining drugs with different mechanisms of action can help prevent the development of resistance by attacking the infectious agent through multiple pathways [26]. Concurrent agents that target virus entry and virus replication, called directly acting antivirals, and cellular proteins involved in and necessary for viral replication, called host-targeting antivirals, offer opportunities to discover synergistic drug combinations [22,28,29].…”