Lipids play a crucial role in the entry and egress of viruses, regardless of whether they are naked or enveloped. Recent evidence shows that lipid involvement in viral infection goes much further. During replication, many viruses rearrange internal lipid membranes to create niches where they replicate and assemble. Because of the close connection between lipids and inflammation, the derangement of lipid metabolism also results in the production of inflammatory stimuli. Due to its pivotal function in the viral life cycle, lipid metabolism has become an area of intense research to understand how viruses seize lipids and to design antiviral drugs targeting lipid pathways. Palmitoylethanolamide (PEA) is a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that also counteracts SARS-CoV-2 entry and its replication. Our work highlights for the first time the antiviral potency of PEA against SARS-CoV-2, exerting its activity by two different mechanisms. First, its binding to the SARS-CoV-2 S protein causes a drop in viral infection of ~70%. We show that this activity is specific for SARS-CoV-2, as it does not prevent infection by VSV or HSV-2, other enveloped viruses that use different glycoproteins and entry receptors to mediate their entry. Second, we show that in infected Huh-7 cells, treatment with PEA dismantles lipid droplets, preventing the usage of these vesicular bodies by SARS-CoV-2 as a source of energy and protection against innate cellular defenses. This is not surprising since PEA activates PPAR-α, a transcription factor that, once activated, generates a cascade of events that leads to the disruption of fatty acid droplets, thereby bringing about lipid droplet degradation through β-oxidation. In conclusion, the present work demonstrates a novel mechanism of action for PEA as a direct and indirect antiviral agent against SARS-CoV-2. This evidence reinforces the notion that treatment with this compound might significantly impact the course of COVID-19. Indeed, considering that the protective effects of PEA in COVID-19 are the current objectives of two clinical trials (NCT04619706 and NCT04568876) and given the relative lack of toxicity of PEA in humans, further preclinical and clinical tests will be needed to fully consider PEA as a promising adjuvant therapy in the current COVID-19 pandemic or against emerging RNA viruses that share the same route of replication as coronaviruses.

Fibroblast growth factors (FGFs) are a family of proteins that play a crucial role in the development and maintenance of various tissues in the body. There are three function‐al groups of FGFs: canonical FGFs (cFGFs), intracellularly retained FGFs, and metabolic (also called endocrine) FGFs. cFGFs are secreted and act in an autocrine/paracrine fashion to regulate differentiation during foetal development, as well as tissue repair in adults. Recent studies have also begun to unravel the role of cFGFs during viral infections, suggesting that FGF‐2 and other canonical FGFs may have an important virus‐specific role, also by the regulation of the immune response. Because dysregulation in the FGF pathways is pivotal in cancer development, FGFs are the target of many anticancer drugs. These drugs may be repurposed to treat viral infection, since dysregulation of FGF signalling has been implicated in the pathogenesis of viral infections, such as hepatitis C. Overall, the role of cFGFs during viral infection is an underrepresented area of current research. This review focuses on overviewing the effects of canonical FGFs during infection by different viruses. Many studies highlight that the effects of FGFs during viral infection may be complex and context‐dependent. While there is evidence to suggest that FGFs may have a beneficial impact on the immune response and tissue repair during viral infection, further studies are needed to fully understand the mechanisms underlying these effects and to determine in what cases FGFs could be targeted as a therapeutic approach for viral infection.

In the wake of the COVID‐19 pandemic, awareness of emerging pathogens has significantly increased, prompting greater investment in research and preparedness. In this context, arboviral diseases are recognized as unmet medical challenges due to their rapid spread. Notably, the geographical range of several flaviviral diseases is expanding: Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to outbreaks associated with a rise in microcephaly cases in tropical regions. To contribute to the development of novel antiviral therapies, evaluation of a set of compounds with an antiviral activity against ZIKV was carried out. These compounds were originally identified as inhibitors of bovine viral diarrhea virus, another member of the Flaviviridae family. Two related compounds turned out to be active against ZIKV. One emerged as a particularly strong antiviral candidate, demonstrating high efficacy in inhibiting ZIKV replication, and became the focus of this study. Its activity was tested against a number of viruses of human health relevance and the compound was found to be effective against a number of viruses that use the endoplasmic reticulum as a replication hub. Indeed, we found that the Reticulon 3 protein is potently downregulated in the presence of the compound, whereas other endoplasmic reticulum‐resident proteins are not affected. Because Reticulon 3 has a role in the replication of positive‐sense single‐stranded RNA viruses, an indirect antiviral effect of the compound studied was hypothesized. This compound may be considered as a promising lead for further studies aimed at the development of broad‐spectrum antiviral drugs.

A small library of 23 pyrrole-based tricyclic derivatives bearing bulky amine moieties was synthesized, and all were evaluated for their antiviral activities against ZIKV and SARS-CoV. Three compounds, derivatives 2g, 2h and 2j, elicited interesting activity against ZIKV: compound 2g, containing a bornylamine residue, showed the best activity against Huh-7 cells with EC₅₀ and CC₅₀ values of 0.4 μM and 230.5 μM, respectively, and a Selectivity Index (SI) of 501. All three compounds reduce ZIKV yield primarily by impairing viral protein.

In this work, we synthesized a small library of tricyclic compounds to assess whether they might have both anticancer and antiviral activity against three viruses that have recently caused epidemics. Concerning their anti-tumour activity, derivative 1 was found to be the compound with the highest GI₅₀ values on some cancer cell line panels. Particularly, in melanoma cell lines, its GI₅₀ values ranged between 1.54 μM (MALME-3M) and 2.03 μM (M14). Several derivatives with considerable anti-tumour activity showed antiviral activity as well, against influenza A virus (e.g., derivative 19, selectivity index of 21.36 in MDCK cells) or against Zika virus (compound 13, selectivity index of 20.20 in Huh-7 cells). Moreover, compounds 13 and 12 showed anti-SARS-CoV-2 activity, with selectivity indices of 150.00 and 63.63, respectively. Compound 1, for its anticancer activity, and 13, for its anti-SARS-CoV-2 activity, together with the compounds active against Zika virus and influenza A virus, are promising candidates for further studies.

Endoplasmic reticulum (ER) oxidoreductases are promising targets for host-targeted antiviral agents (HTAs) because of their essential role in protein folding, including the maturation of viral proteins. Human protein disulfide isomerase family member A3 (PDIA3) is involved in the folding of N-glycosylated client proteins, including viral envelope proteins, making it an attractive but underexplored antiviral target. Here, we describe the discovery of a novel N-hydroxyindole-2-carboxamide class of PDIA3 inhibitors, exemplified by compound AV22 (1o), which effectively inhibits PDIA3 activity and exerts broad-spectrum antiviral activity against major human respiratory viruses. Mechanistic studies indicated that AV22 (1o) increased the release of non-infectious coronavirus particles and reduced disulfide bond formation in the coronavirus spike protein, indicating that its antiviral effect stems from interference with PDIA3 activity. This new class of HTAs provides promising leads for drug discovery targeting viral envelope protein maturation vulnerabilities and is suitable for developing new BSAs.