Telaprevir Treatment Reduces Paralysis in a Mouse Model of Enterovirus D68 Acute Flaccid Myelitis

Frost, Joshua; Rudy, Michael J.; Leser, J. Smith; Tan, Haozhou; Hu, Yanmei; Wang, Junyang; Clarke, Penny; Tyler, Kenneth L.

doi:10.1128/jvi.00156-23

Cited by 9 publications

(3 citation statements)

References 30 publications

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“… 27 , 28 EV‐D68 has been identified as a key linked agent of these biannual AFM epidemics based on accumulating clinical, immunological, and epidemiological data. 29 For instance, EV‐B forms have also been detected through HFMD, despite EV‐A types being more frequently linked to HFMD. 30 , 31 A prospective epidemiological survey in Rochester, New York, revealed a noteworthy incidence rate of EV infections, which are common in the newborn period.…”

Section: Disease Pathogenesis Of Npevs Infectionmentioning

confidence: 99%

“…Severe instances of specific EV infections may manifest with various symptoms such as acute flaccid paralysis (AFP), herpangina, hepatitis, pleurodynia, diarrhea, fever, upper and lower respiratory infections, pericarditis, conjunctivitis, meningitis, encephalitis, pancreatitis, and potentially, diabetes 27,28 . EV‐D68 has been identified as a key linked agent of these biannual AFM epidemics based on accumulating clinical, immunological, and epidemiological data 29 . For instance, EV‐B forms have also been detected through HFMD, despite EV‐A types being more frequently linked to HFMD 30,31 .…”

Section: Disease Pathogenesis Of Npevs Infectionmentioning

confidence: 99%

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Beyond polio: Exploring non‐polio enteroviruses, global health preparedness, and the “Disease X” paradigm

Anjum,

Haque,

Akter

et al. 2024

Health Science Reports

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Background and AimsDisease X represents the possibility that an unidentified infection may spread globally and start a pandemic. This study explored various aspects of emerging non‐polio enteroviruses (NPEVs) as a possible source of “Disease X,” an enigmatic agent declared by the World Health Organization, and discussed the potential impact of NPEVs on global public health.MethodsIn this perspective article, we collected information from publicly available sources such as Google Scholar, PubMed, and Scopus. We used NPEVs, viral diseases, pandemics, and zoonotic diseases as keywords. We extracted information from the most relevant articles.ResultsNotable outbreaks caused by NPEVs include enterovirus D68 (EV‐D68) and enterovirus A71 (EV‐A71), among many others. With a focus on therapeutic and preventative components, alternate modes of therapy, and the development of broad‐spectrum antivirals, this analysis looks at the origin, epidemiology, genetic alterations, transmission dynamics, and disease pathophysiology of NPEVs. The information presented in the review indicates the current risk assessment of NPEVs, taking into account the following factors: the need for research and therapeutic interventions, the diversity of clinical manifestations, the impact of genetic variability on virulence, the persistence of emergence despite vaccination efforts, recurrent outbreaks, and the global impact of these viruses.ConclusionThere is a possibility that NPEVs could trigger global pandemics based on their zoonotic origins and urges for complete readiness, continuous research, cooperation, and a comprehensive strategy to combat emerging infectious diseases in a constantly changing global environment. It is peak time to acknowledge how important it is to abide by safety and health laws to prevent these illnesses.

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Section: Disease Pathogenesis Of Npevs Infectionmentioning

confidence: 99%

Section: Disease Pathogenesis Of Npevs Infectionmentioning

confidence: 99%

Beyond polio: Exploring non‐polio enteroviruses, global health preparedness, and the “Disease X” paradigm

Anjum,

Haque,

Akter

et al. 2024

Health Science Reports

View full text Add to dashboard Cite

show abstract

“…Our previous study validated the 2A pro as a viable antiviral drug target and discovered telaprevir as the first 2A pro inhibitor. 9,27 In this follow-up study, we solved the X-ray crystal structures of 2A pro wild-type and the C107A mutant. Unfortunately, our efforts in cocrystallizing telaprevir with 2A pro have not been successful, mainly due to compound precipitation at high drug concentrations (mM).…”

Section: ■ Conclusionmentioning

confidence: 99%

Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors

Tan,

Liu,

et al. 2023

J. Med. Chem.

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Enterovirus D68 (EV-D68) virus is a nonpolio enterovirus that typically causes respiratory illness and, in severe cases, can lead to paralysis and death in children. There is currently no vaccine or antiviral for EV-D68. We previously discovered the viral 2A protease (2Apro) as a viable antiviral drug target and identified telaprevir as a 2Apro inhibitor. 2Apro is a viral cysteine protease that cleaves the viral VP1-2A polyprotein junction. In this study, we report the X-ray crystal structures of EV-D68 2Apro, wild-type, and the C107A mutant and the structure-based lead optimization of telaprevir. Guided by the X-ray crystal structure, we predicted the binding pose of telaprevir in 2Apro using molecular dynamics simulations. We then utilized this model to inform structure-based optimization of the telaprevir’s reactive warhead and P1–P4 substitutions. These efforts led to the discovery of 2Apro inhibitors with improved antiviral activity than telaprevir. These compounds represent promising lead compounds for further development as EV-D68 antivirals.

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Doxycycline inhibits neurotropic enterovirus proliferation in vitro

Chi,

Liu,

et al. 2024

Virus Research

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Telaprevir Treatment Reduces Paralysis in a Mouse Model of Enterovirus D68 Acute Flaccid Myelitis

Abstract: Recent outbreaks of EV-D68 in 2014, 2016, and 2018 have resulted in over 600 cases of a paralytic illness that is known as AFM. AFM is a predominantly pediatric disease with no FDA-approved treatment, and many patients show minimal recovery from limb weakness.

Cited by 9 publications

References 30 publications

Beyond polio: Exploring non‐polio enteroviruses, global health preparedness, and the “Disease X” paradigm

Beyond polio: Exploring non‐polio enteroviruses, global health preparedness, and the “Disease X” paradigm

Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors

Doxycycline inhibits neurotropic enterovirus proliferation in vitro

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