The Small-Compound Inhibitor K22 Displays Broad Antiviral Activity against Different Members of the Family Flaviviridae and Offers Potential as a Panviral Inhibitor

García-Nicolás, Obdulio; V’kovski, Philip; Vielle, Nathalie J.; Ebert, Nadine; Züst, Roland; Portmann, Jasmine; Stalder, Hanspeter; Gaschen, Véronique; Vièyres, Gabrielle; Stoffel, Michael Hubert; Schweizer, Matthias; Summerfield, Artur; Engler, Olivier; Pietschmann, Thomas; Todt, Daniel; Alves, Marco P.; Thiel, Volker; Pfaender, Stephanie

doi:10.1128/aac.01206-18

Cited by 10 publications

(12 citation statements)

References 42 publications

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“…This is consistent with reports that show reduction in success rate of infections due to host cell perturbation [11] or for viral mutants [6], where CM formation is hindered. This effect is also associated with the antiviral activity of membrane re-organization inhibitors like K22 [9,8] that likely influences τ F . Φ also increases from HCV to PV to JEV based on our estimates of the life cycle parameters above (Fig 4c).…”

Section: Compartmentalization Of Replication Defines the Fate Of Virumentioning

confidence: 99%

“…The vesicular membranous structures (also known as replication compartments, CMs) formed, provide a conducive micro-environment for efficient viral replication, protect viral RNA and proteins from cytosolic degradation and host defense systems. Impeding membrane re-organizations have been shown to decelerate cellular infection dynamics [5,6], lower viral yield [7,8,9,10] and reduce the propensity of the virus to establish productive cellular infection in the host cell [6,11,12]. In general, failure to establish viral infection has been associated with cellular heterogeneity and is attributed to the random loss of genome segments by RNA degradation in the early stages of infection [13,14,15]).…”

Section: Introductionmentioning

confidence: 99%

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Life cycle process dependencies of positive-sense RNA viruses suggest strategies for inhibiting productive cellular infection

Chhajer¹,

Rizvi

Roy

2020

Preprint

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Positive strand (+)RNA viruses are the most common and clinically important human pathogens. Their life cycle processes are broadly conserved across many virus families but they employ different life cycle strategies for their growth in the cell. Upon RNA genome release into the cytoplasm post cellular entry, viral translation generates structural and non-structural proteins that induce intracellular remodelling, forming membrane compartments that foster viral replication leading to virus particle formation. We present a generalized dynamical model for intracellular (+)ssRNA virus growth that accounts for these critical steps. Our model can capture experimental growth dynamics for several RNA viruses as well as parse the effect of viral mutations and host cell permissivity. We show that Poliovirus (PV) employs rapid replication and virus assembly whereas Japanese Encephalitis virus leverages its higher rate of translation and efficient host membrane reorganization for enhanced viral dynamics compared to Hepatitis C virus. Since the slow membrane reorganization represents a crucial bottleneck for replication, stochastic simulations demonstrate that an infection event, even with multiple viral genomes, can go to extinction if all seeding viral RNA degrade before establishing robust viral replication. We estimate this probability of productive cellular infection, termed ‘Cellular Infectivity (Φ)’ using stochastic simulations. Φ varies for a virus-host pair with initial virus seeding and life cycle perturbations like increase in cytoplasmic RNA degradation and delay in compartment formation can reduce infectivity. Extent of synergy among these parameters while seemingly diverse for viruses is defined by Φ. Therefore, our model suggests new avenues for inhibition of viral infections by targeting early life cycle bottlenecks.

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Section: Compartmentalization Of Replication Defines the Fate Of Virumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Life cycle process dependencies of positive-sense RNA viruses suggest strategies for inhibiting productive cellular infection

Chhajer¹,

Rizvi

Roy

2020

Preprint

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“…For ATGL detection, we used the following reagents: ATGL S 5´-CTCATCCAggCCAATgTCTg-3´, ATGL A 5´-A CCATCCACgTAgCgCAC-3´, ATGL-FAM 5´-6FAM-TCCCCgTgTACTgTgggCTCA-BBQ-3´. We quantified HCV RNA with the primers and probes previously described [83]. Intracellular HCV RNA was quantified in duplex with GAPDH, as before [83].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…We quantified HCV RNA with the primers and probes previously described [83]. Intracellular HCV RNA was quantified in duplex with GAPDH, as before [83]. The extracellular HCV RNA however was quantified alone.…”

Section: Plos Pathogensmentioning

confidence: 99%

The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly

et al. 2020

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Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/β hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis.

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“…However, up to date, there are no approved antiviral therapies for flaviviruses. Several preclinical and investigational drugs have been assessed for anti-flavivirus activity [11][12][13][14]. However, flaviviruses often escape antivirals that target specific viral proteins because of the high mutation rates [15].…”

Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Benzavir-2 against Emerging Flaviviruses

Gwon

Strand

Lindqvist

et al. 2020

Viruses

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Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA-and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC 50 value of 0.8 ± 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.

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The Small-Compound Inhibitor K22 Displays Broad Antiviral Activity against Different Members of the Family Flaviviridae and Offers Potential as a Panviral Inhibitor

Cited by 10 publications

References 42 publications

Life cycle process dependencies of positive-sense RNA viruses suggest strategies for inhibiting productive cellular infection

Life cycle process dependencies of positive-sense RNA viruses suggest strategies for inhibiting productive cellular infection

The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly

Antiviral Activity of Benzavir-2 against Emerging Flaviviruses

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