A thiazepino[4,5-a]benzimidazole derivative hampers the RNA replication of Eurasian serotypes of foot-and-mouth disease virus

Fan

et al. 2015

Viruses

Foot-and-mouth disease (FMD) is a highly contagious disease of domestic and wild ruminants that is caused by FMD virus (FMDV). FMD outbreaks have occurred in livestock-containing regions worldwide. Apigenin, which is a flavonoid naturally existing in plant, possesses various pharmacological effects, including anti-inflammatory, anticancer, antioxidant and antiviral activities. Results show that apigenin can inhibit FMDV-mediated cytopathogenic effect and FMDV replication in vitro. Further studies demonstrate the following: (i) apigenin inhibits FMDV infection at the viral post-entry stage; (ii) apigenin does not exhibit direct extracellular virucidal activity; and (iii) apigenin interferes with the translational activity of FMDV driven by internal ribosome entry site. Studies on applying apigein in vivo are required for drug development and further identification of potential drug targets against FDMV infection.

Section: Introductionmentioning

confidence: 99%

Apigenin Restricts FMDV Infection and Inhibits Viral IRES Driven Translational Activity

Fan

et al. 2015

Viruses

“…The many and varied roles of FMDV 3Cpro make it an attractive target for pharmacological inhibition, and a relatively recent study developed an improved cell-based assay to test candidate compounds and then used it to identify AG7088 (rupintrivir) as a potent 3C inhibitor (van der Linden et al, 2014). This is particularly interesting as rupintrivir was originally developed by Pfizer as an aerosolized treatment for the common cold in humans and therefore may prove amenable to adaptation as an intranasal biotherapeutic to impede the early stages of FMDV infection in outbreak situations.…”

Section: Antiviral Interventionsmentioning

confidence: 99%

“…While data have yet to be generated in natural hosts of FMDV, in vitro , 1,2,4,5‐tetrahydro‐[1,4]thiazepino[4,5‐a]benzimidazole inhibited replication of FMDV serotypes O, A, C and Asia‐1, likely through interaction with the 2C protein (Lefebvre et al., ). In another study, the nucleoside analogue 2′‐C‐methylcytidine (2′CMC) prevented the establishment of FMDV infection in severe combined immunodeficient mice (Lefebvre et al., ).…”

Section: Biotherapeuticsmentioning

confidence: 99%

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 5 - Biotherapeutics and Disinfectants

Robinson

Knight-Jones

Charleston

et al. 2016

Transbound Emerg Dis

SummaryWe assessed knowledge gaps in foot-and-mouth disease (FMD) research. Findings are reported in a series of papers, and in this article, we consider biotherapeutics and disinfectants. The study took the form of a literature review (2011)(2012)(2013)(2014)(2015) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. While vaccines will remain the key immunological intervention used against FMD virus (FMDV) for the foreseeable future, it takes a few days for the immune system to respond to vaccination. In an outbreak situation, protection could potentially be provided during this period by the application of rapid, short-acting biotherapeutics, aiming either to stimulate a non-specific antiviral state in the animal or to specifically inhibit a part of the viral life cycle. Certain antiviral cytokines have been shown to promote rapid protection against FMD; however, the effects of different immune-modulators appear to vary across species in ways and for reasons that are not yet understood. Major barriers to the effective incorporation of biotherapeutics into control strategies are cost, limited understanding of their effect on subsequent immune responses to vaccines and uncertainty about their potential impact if used for disease containment. Recent research has highlighted the importance of environmental contamination in FMDV transmission. Effective disinfectants for FMDV have long been available, but research is being conducted to further develop methods for quantitatively evaluating their performance under field, or near-field, conditions. During outbreaks in South Korea in 2010 there was public concern about potential environmental contamination after the mass use of disinfectant and mass burial of culled stock; this should be considered during outbreak contingency planning.

“…Successful efforts to target viral 5’-UTR structures have often leveraged the synthetic tuning of a known RNA binding scaffold. 25, 27, 30 We recently employed this approach to develop RNA-targeted antivirals based on dimethylamiloride (DMA) that target the internal ribosomal entry site (IRES) region in the 5’-UTR of EV71. The DMA scaffold had been previously reported to be poised for tuning for specific RNA constructs via a facile three-step synthesis.…”

Section: Introductionmentioning

confidence: 99%

Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Zafferani

Haddad

Luo

et al. 2020

Preprint

The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, has rendered our understanding of coronavirus biology more essential than ever. Small molecule chemical probes offer to both reveal novel aspects of virus replication and to serve as leads for antiviral therapeutic development. The RNA-biased amiloride scaffold was recently tuned to target a viral RNA structure critical for translation in enterovirus 71, ultimately uncovering a novel mechanism to modulate positive-sense RNA viral translation and replication. Analysis of CoV RNA genomes reveal many conserved RNA structures in the 5’-UTR and proximal region critical for viral translation and replication, including several containing bulge-like secondary structures suitable for small molecule targeting. Following phylogenetic conservation analysis of this region, we screened an amiloride-based small molecule library against a less virulent human coronavirus, OC43, to identify lead ligands. Amilorides inhibited OC43 replication as seen in viral plaque assays. Select amilorides also potently inhibited replication competent SARS-CoV-2 as evident in the decreased levels of cell free virions in cell culture supernatants of treated cells. Reporter screens confirmed the importance of RNA structures in the 5’-end of the viral genome for small molecule activity. Finally, NMR chemical shift perturbation studies of the first six stem loops of the 5’-end revealed specific amiloride interactions with stem loops 4, 5a, and 6, all of which contain bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Taken together, the use of multiple orthogonal approaches allowed us to identify the first small molecules aimed at targeting RNA structures within the 5’-UTR and proximal region of the CoV genome. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA-targeted antivirals.