The Alphavirus Exit Pathway: What We Know and What We Wish We Knew

Brown, Rebecca S.; Wan, Judy J.; Kielian, Margaret

doi:10.3390/v10020089

Cited by 76 publications

(46 citation statements)

References 169 publications

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“…This finding indicated that prodrug entry into cells is requisite for anti-viral efficacy. The cell lysate also showed a drug concentration-dependent decline in Gag accumulation in samples treated with the prodrug (lanes 2-4) but not in the samples treated with the pre-activated mixture (lanes [6][7][8]. The diminished intracellular Gag accumulation in cells exposed to the prodrug was reported previously and found to reflect Gag mis-sorting to degradative compartments 3 .…”

Section: Resultssupporting

confidence: 73%

Selective Targeting of Virus Replication by Proton Pump Inhibitors

Watanabe

Ehrlich

Strickland

et al. 2020

Sci Rep

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Two proton pump inhibitors, tenatoprazole and esomeprazole, were previously shown to inhibit HIV-1 egress by blocking the interaction between Tsg101, a member of the ESCRT-I complex, and ubiquitin.Here, we deepen our understanding of prazole budding inhibition by studying a range of viruses in the presence of tenatoprazole. furthermore, we investigate the relationship between the chemistry of prodrug activation and HIV-1 inhibition for diverse prazoles currently on the market. We report that tenatoprazole is capable of inhibiting the replication of members of the enveloped filo, alpha, and herpes virus families but not the flavivirus group and not the non-enveloped poliovirus. Another key finding is that prazole prodrugs must be activated inside the cell, while their rate of activation in vitro correlated to their efficacy in cells. Our study lays the groundwork for future efforts to repurpose prazole-based compounds as antivirals that are both broad-spectrum and selective in nature.

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Section: Resultssupporting

confidence: 73%

Selective Targeting of Virus Replication by Proton Pump Inhibitors

Watanabe

Ehrlich

Strickland

et al. 2020

Sci Rep

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“…NiV (31), IAV (32), and EBOV (33) are thought to derive their envelopes from lipid rafts of the plasma membrane, which could specify their lipid content and thus surfactin sensitivity. Alphaviruses such as CHIKV, Mayaro, and Una also bud from the plasma membrane, although neither the lipid content nor the involvement of lipid rafts has been explored (34). Together, these observations suggest that the lipid content of enveloped viruses may explain their differential sensitivity to surfactin.…”

Section: Discussionmentioning

confidence: 97%

Peptidoglycan-Associated Cyclic Lipopeptide Disrupts Viral Infectivity

Johnson

Hage

Kalveram

et al. 2019

J Virol

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Enteric viruses exploit bacterial components, including lipopolysaccharides (LPS) and peptidoglycan (PG), to facilitate infection in humans. Because of their origin in the bat enteric system, we wondered if severe acute respiratory syndrome coronavirus (SARS-CoV) or Middle East respiratory syndrome CoV (MERS-CoV) also use bacterial components to modulate infectivity. To test this question, we incubated CoVs with LPS and PG and evaluated infectivity, finding no change following LPS treatment. However, PG from Bacillus subtilis reduced infection Ͼ10,000-fold, while PG from other bacterial species failed to recapitulate this. Treatment with an alcohol solvent transferred inhibitory activity to the wash, and mass spectrometry revealed surfactin, a cyclic lipopeptide antibiotic, as the inhibitory compound. This antibiotic had robust dose-and temperature-dependent inhibition of CoV infectivity. Mechanistic studies indicated that surfactin disrupts CoV virion integrity, and surfactin treatment of the virus inoculum ablated infection in vivo. Finally, similar cyclic lipopeptides had no effect on CoV infectivity, and the inhibitory effect of surfactin extended broadly to enveloped viruses, including influenza, Ebola, Zika, Nipah, chikungunya, Una, Mayaro, Dugbe, and Crimean-Congo hemorrhagic fever viruses. Overall, our results indicate that peptidoglycan-associated surfactin has broad viricidal activity and suggest that bacteria by-products may negatively modulate virus infection. IMPORTANCE In this article, we consider a role for bacteria in shaping coronavirus infection. Taking cues from studies of enteric viruses, we initially investigated how bacterial surface components might improve CoV infection. Instead, we found that peptidoglycan-associated surfactin is a potent viricidal compound that disrupts virion integrity with broad activity against enveloped viruses. Our results indicate that interactions with commensal bacterial may improve or disrupt viral infections, highlighting the importance of understanding these microbial interactions and their implications for viral pathogenesis and treatment.

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“…CHIKV capsid contains two functional domains: the highly positively charged N-terminal RNA binding domain and the C-terminal serine protease domain (44). Following self-cleavage from the nascent structural polyprotein, the capsid protein specifically interacts with the replicated genomic RNA (49S RNA) to form NCs in the cytoplasm (45). The NCs are then transported to the plasma membrane, where they interact with envelope proteins to drive the budding of virus particles from the plasma membrane (46).…”

Section: Resultsmentioning

confidence: 99%

Infectious Chikungunya Virus (CHIKV) with a Complete Capsid Deletion: a New Approach for a CHIKV Vaccine

Zhang

Deng

et al. 2019

J Virol

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Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes epidemics of debilitating disease worldwide. Currently, there are no licensed vaccines or antivirals available against CHIKV infection. In this study, we generated a novel live attenuated vaccine (LAV) candidate for CHIKV with a complete deficiency of capsid (ΔC-CHIKV). It could propagate in BHK-21 cells, and had antigenic properties similar to those of native CHIKV. Vaccination of either immunocompromised IFNAR Ϫ/Ϫ mice or immunocompetent C57BL/6 mice with a single dose of ΔC-CHIKV conferred complete protection upon challenge with wild-type (WT) CHIKV. Taken together, this vaccine candidate appeared to be safe and efficacious, representing a novel strategy for CHIKV vaccine design. IMPORTANCE Currently, there is no licensed vaccine against CHIKV infection. An ideal CHIKV vaccine should generate an optimal balance between efficacy and safety. Live attenuated vaccines that can elicit strong immune responses often involve a trade-off of reduced safety. Here, a novel live attenuated vaccine candidate for CHIKV lacking the entire capsid gene, ΔC-CHIKV, was developed. It was demonstrated to be genetically stable, highly attenuated, immunogenic, and able to confer complete protection against lethal CHIKV challenge after a single dose of immunization. Such an infectious vaccine candidate devoid of capsid provides a novel strategy for the development of a live attenuated CHIKV vaccine.

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The Alphavirus Exit Pathway: What We Know and What We Wish We Knew

Cited by 76 publications

References 169 publications

Selective Targeting of Virus Replication by Proton Pump Inhibitors

Selective Targeting of Virus Replication by Proton Pump Inhibitors

Peptidoglycan-Associated Cyclic Lipopeptide Disrupts Viral Infectivity

Infectious Chikungunya Virus (CHIKV) with a Complete Capsid Deletion: a New Approach for a CHIKV Vaccine

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