iPSC screening for drug repurposing identifies anti‐RNA virus agents modulating host cell susceptibility

Abstract

Human pathogenic RNA viruses are threats to public health because they are prone to escaping the human immune system through mutations of genomic RNA, thereby causing local outbreaks and global pandemics of emerging or re‐emerging viral diseases. While specific therapeutics and vaccines are being developed, a broad‐spectrum therapeutic agent for RNA viruses would be beneficial for targeting newly emerging and mutated RNA viruses. In this study, we conducted a screen of repurposed drugs using Sendai virus (an RNA virus of the family Paramyxoviridae ), with human‐induced pluripotent stem cells (iPSCs) to explore existing drugs that may present anti‐RNA viral activity. Selected hit compounds were evaluated for their efficacy against two important human pathogens: Ebola virus (EBOV) using Huh7 cells and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) using Vero E6 cells. Selective estrogen receptor modulators (SERMs), including raloxifene, exhibited antiviral activities against EBOV and SARS‐CoV‐2. Pioglitazone, a PPARγ agonist, also exhibited antiviral activities against SARS‐CoV‐2, and both raloxifene and pioglitazone presented a synergistic antiviral effect. Finally, we demonstrated that SERMs blocked entry steps of SARS‐CoV‐2 into host cells. These findings suggest that the identified FDA‐approved drugs can modulate host cell susceptibility against RNA viruses.

Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants

“…Interestingly, raloxifene effect was characterized against Ebola [ 51 , 52 ], Hepatitis C [ 53 , 54 ], Hepatitis B [ 55 ], Zika [ 56 ], Influenza A viruses [ 57 ], and as adjuvant antiviral treatment of chronic Hepatitis C in women [ 58 ]. Raloxifene in vitro activity on SARS-CoV-2 was previously reported [ 59 ], and the drug was observed to reduce infectivity in a dose-dependent manner (IC 50 value of 7.1 μM). Here we report a full characterization of the antiviral activity of raloxifene on SARS-CoV-2 in two cellular contexts, Vero E6 and Calu-3 cell lines, testing the efficacy of the treatment on all the most relevant VOCs, and clearly showing the independence of raloxifene activity from viral variant specificity.…”

“…This study compared the approved pharmacological dosage of raloxifene 60 mg/day, used to treat and prevent osteoporosis in postmenopausal women, with the dosage of 120 mg/day, also extensively evaluated in clinical trials, to confirm the safety and tolerability of the drug in the indication, and to compare the efficacy of the two doses with the aim of gaining further information on possible ER-dependent or independent mechanisms of action. Previous data from screening campaigns reported the antiviral activity of raloxifene [ 59 ]; in this paper we report an in-depth in vitro characterization of the antiviral activity of the drug against the WT and the most common variants of SARS-CoV-2. First of all, we confirmed the anti-CPE of the drug in two relevant experimental systems, Vero E6 monkey kidney cells, commonly used to study coronavirus infection [ 69 – 71 ] and human pulmonary Calu-3 cells, a predictive model of airway epithelial origin [ 72 ].…”

Potential and action mechanism of favipiravir as an antiviral against Junin virus

“…Viral titers were determined at 48 hpi by plaque assay and represented as the percentage inhibition compared to DMSO control for each drug combination. Synergistic inhibition against JUNV growth was determined using SynergyFinder ( https://synergyfinder.fimm.fi/ ) with the Zero Interaction Potency (ZIP) model as previously described [ 72 ]. A synergy score (δ-score) of less than −10 is considered as antagonistic, the score range of −10 to 10 suggests an additive drug interaction, and a score greater than 10 indicates a synergistic effect [ 73 ].…”

Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections

“…Tamoxifen is effective against a broad range of life-threatening infections. As reported in Table 1 , compelling evidence shows that tamoxifen counteracts the proliferation of bacterial species, a wide spectrum of fungal pathogens, human parasites and viruses, including the recently emerged species like Ebola, SARS-CoV, MERS-CoV and SARS-CoV-2 viruses ( Dyall et al, 2014 ; Fan et al, 2017 ; Montoya and Krysan 2018 ; Imamura et al, 2021 ; Zu et al, 2021 ; Allegretti et al, 2022 ).…”