Herpes simplex virus-specified DNA polymerase is the target for the antiviral action of 9-(2-phosphonylmethoxyethyl)adenine.

Foster, Susan D.; Černý, Jaroslav; Cheng, Yung‐Chi

doi:10.1016/s0021-9258(18)52426-1

Cited by 36 publications

(5 citation statements)

References 30 publications

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“…Diversity between these viral families, which include both DNA and RNA viruses, and viruses that are both enveloped and not, is extremely broad (5). The drugs which are available to treat some of these viruses target the varying proteins encoded by the different viral genomes (6)(7)(8). Oseltamivir (Tamiflu) and zanamivir (Relenza) work on influenza by inhibiting neuraminidase, a viral enzyme that propagates infection by facilitating the spread of viral particles throughout the host (8).…”

Section: Introductionmentioning

confidence: 99%

“…Oseltamivir (Tamiflu) and zanamivir (Relenza) work on influenza by inhibiting neuraminidase, a viral enzyme that propagates infection by facilitating the spread of viral particles throughout the host (8). Acyclovir, a treatment for herpes simplex virus, inhibits viral DNA polymerase (6). Paxlovid, the new drug for SARS-CoV-2, is a protease inhibitor that blocks viral enzymes responsible for catalyzing critical maturation steps within the virus's lifecycle (7).…”

Section: Introductionmentioning

confidence: 99%

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A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex

Selvarajah¹,

Lingappa²,

Michon³

et al. 2021

Preprint

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Antiviral compounds displaying remarkable features have been identified by an unconventional drug screen and advanced through animal validation. Efficacy is observed against the six viral families causing most human respiratory viral disease, irrespective of strain, including both influenza (FLUV) and SARS-CoV-2, with cell culture EC50 at or below 100 nM. Survival benefit is demonstrated in pigs against another member of family Coronaviridae, porcine epidemic diarrhea virus (PEDV), and shown equally effective in mild and severe disease. Respiratory syncytial virus (RSV) titer is reduced by drug treatment in cotton rats. A substantial barrier to viral resistance is demonstrated for FLUV. Drug resin affinity chromatography (DRAC) reveals a novel drug target: a multi-protein complex (MPC) formed transiently, in an energy-dependent fashion, and composed of host proteins implicated in both viral lifecycles and manipulation of innate immunity. The protein composition of this host MPC is modified upon viral infection, with increase or decrease of some proteins and appearance or complete loss of others. Valosin-containing protein, also known as Transitional endoplasmatic reticulum ATPase (VCP/p97), is present in the target MPC of uninfected cells and significantly increased in both FLUV and CoV infection. SQSTM1/p62, a key regulator of the autophagy pathway of innate immunity whose dysfunction is implicated in cytokine storm, is i) found in the target MPC from uninfected cells, ii) diminished in DRAC eluates by infection, and iii) restored by drug treatment of infected cells. 14-3-3 is one of likely several proteins that comprise the drug-binding site. Advanced compounds with improved pharmacokinetic (PK) properties and lung exposure are approaching criteria for a Target Product Profile. We propose these novel drug targets to comprise a previously unappreciated molecular basis for homeostasis that is modified by viruses to allow exploitation for viral propagation and is restored by treatment with the therapeutic compounds presented. This discovery has transformative implications for treatment of respiratory viral-related disease, applicable to everything from seasonal FLUV to COVID-19 and future novel respiratory viruses, due to the pan-family nature of drug activity and barrier to resistance development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex

Selvarajah¹,

Lingappa²,

Michon³

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…An analog of deoxyadenosine monophosphate ( Figure 2 D), adefovir ( Figure 2 E), is a drug already licensed as an anti-hepatitis B virus agent [ 52 ]. Adefovir also inhibits HSV replication [ 53 , 54 ]. Because of its similarity to CDV and tenofovir ( Figure 2 G), adefovir does not require activation by TK.…”

Section: Nucleotide Analogs: Cidofovir Adefovir and Brincidofovirmentioning

confidence: 99%

Current Drugs to Treat Infections with Herpes Simplex Viruses-1 and -2

Sadowski

Upadhyay

Greeley

et al. 2021

Viruses

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Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the absence of visible signs and symptoms, yet still result in lifelong infection, it is imperative that we provide interventions to keep them at bay, especially in immunocompromised patients. While numerous experimental vaccines are under consideration, current intervention consists solely of antiviral chemotherapeutic agents. This review explores all of the clinically approved drugs used to prevent the worst sequelae of recurrent outbreaks by these viruses.

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“…The diversity between these viral families, which include both DNA and RNA viruses, and viruses that are both enveloped and not, is extremely broad [5]. The drugs that are available to treat some of these viruses target the varying proteins encoded by the different viral genomes [6][7][8]. Oseltamivir (Tamiflu) and zanamivir (Relenza) work on influenza by inhibiting neuraminidase, a viral enzyme that propagates infection by facilitating the spread of viral particles throughout the host [8].…”

Section: Introductionmentioning

confidence: 99%

“…Oseltamivir (Tamiflu) and zanamivir (Relenza) work on influenza by inhibiting neuraminidase, a viral enzyme that propagates infection by facilitating the spread of viral particles throughout the host [ 8 ]. Acyclovir, a treatment for herpes simplex virus, inhibits viral DNA polymerase [ 6 ]. Nirmatrelvir, the major component of Paxlovid, the new drug for SARS-CoV-2, is a protease inhibitor that blocks viral enzymes responsible for catalysing critical maturation steps within the virus's life cycle [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex

Michon,

Müller-Schiffmann,

Lingappa

et al. 2024

Open Biol.

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We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host–virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.

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Herpes simplex virus-specified DNA polymerase is the target for the antiviral action of 9-(2-phosphonylmethoxyethyl)adenine.

Cited by 36 publications

References 30 publications

A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex

A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex

Current Drugs to Treat Infections with Herpes Simplex Viruses-1 and -2

A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex

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