Design and expeditious synthesis of organosilanes as potent antivirals targeting multidrug-resistant influenza A viruses

Hu, Yanmei; Wang, Yuanxiang; Li, Fang; Ma, Chunlong; Wang, Jun

doi:10.1016/j.ejmech.2017.04.038

Cited by 29 publications

(30 citation statements)

References 37 publications

(43 reference statements)

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“…The titers of harvested viruses were determined by plaque assay. The drug sensitivity after passages 3, 6, and 10 was determined via plaque assay as described previously 43 . Oseltamivir carboxylate was included as a control and similar fold of drug selection pressure was applied.…”

Section: Discussionmentioning

confidence: 99%

Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

Zhang

Foley

et al. 2018

Sci Rep

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Influenza viruses are respiratory pathogens that are responsible for seasonal influenza and sporadic influenza pandemic. The therapeutic efficacy of current influenza vaccines and small molecule antiviral drugs is limited due to the emergence of multidrug-resistant influenza viruses. In response to the urgent need for the next generation of influenza antivirals, we utilized a fast-track drug discovery platform by exploring multi-component reaction products for antiviral drug candidates. Specifically, molecular docking was applied to screen a small molecule library derived from the Ugi-azide four-component reaction methodology for inhibitors that target the influenza polymerase PAC-PB1N interactions. One hit compound 5 was confirmed to inhibit PAC-PB1N interactions in an ELISA assay and had potent antiviral activity in an antiviral plaque assay. Subsequent structure-activity relationship studies led to the discovery of compound 12a, which had broad-spectrum antiviral activity and a higher in vitro genetic barrier to drug resistance than oseltamivir. Overall, the discovery of compound 12a as a broad-spectrum influenza antiviral with a high in vitro genetic barrier to drug resistance is significant, as it offers a second line of defense to combat the next influenza epidemics and pandemics if vaccines and oseltamivir fail to confine the disease outbreak.

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Section: Discussionmentioning

confidence: 99%

Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

Zhang

Foley

et al. 2018

Sci Rep

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“…Additionally, based on their previous findings in identifying a dual inhibitor of WT and Val27Ala M2 (10), designed and reported the first class of organosilanes that exhibited potent antiviral activity against amantadine-resistant and oseltamivir-resistant viruses. Their most potent organosilane (11) was able to inhibit M2 Ser31Asn currents in TEVC experiments by ~86% at 100 µM and inhibited an A/WSN/33 (H1N1) virus encoding M2 Ser31Asn with an IC 50 of 0.4 µM(Hu et al, 2017b) Barniol-Xicota et al, (2017). also reported a series of dual M2 WT and Val27Ala inhibitors.However, while both compounds 12 and 13 were potent inhibitors of both the WT M2 and M2 Val27Ala, with IC 50 s ranging from 1.9 -16.2 µM by TEVC, only 12 exhibited any antiviral activity (EC 50 = 0.14 µM;Barniol-Xicota et al, 2017), while 13 also exhibited toxicity in MDCK cells (50% cytotoxic concentration (CC 50 ) = 10 µM).…”

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confidence: 97%

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

et al. 2020

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Highlights• The M2 protein of influenza A is a proton-gated proton channel that is required for viral replication • Current influenza strains are resistant to licensed M2 antivirals, so new therapies that target M2 are needed • The structure and function of M2, rise of drug resistance mutations, and current antiviral strategies are discussed AbstractThe ongoing threat of seasonal and pandemic influenza to human health requires antivirals that can effectively supplement existing vaccination strategies. The M2 protein of influenza A virus (IAV) is a proton-gated, proton-selective ion channel that is required for virus replication and is an established antiviral target. While licensed adamantane-based M2 antivirals have been historically used, M2 mutations that confer major adamantane resistance are now so prevalent in circulating virus strains that these drugs are no longer recommended. Here we review the current understanding of IAV M2 structure and function, mechanisms of inhibition, the rise of drug resistance mutations, and ongoing efforts to develop new antivirals that target resistant forms of M2.

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“…Depending on the mutation conferring the resistance, the virus might develop resistance to oseltamivir but remain susceptible to zanamivir 24. Other drugs showing potent antiviral activity are being tested in vitro and considered for potential therapy for multidrug-resistant influenza viruses, for example, the first class of organosilanes that have potent antiviral activity against influenza A viruses that are resistant to amantadine and oseltamivir 25. Another medication, dapivirine, an FDA-approved HIV non-nucleoside reverse transcriptase inhibitor, has broad-spectrum antiviral activity against multiple strains of influenza A and B viruses 26…”

Section: Influenza Pneumoniamentioning

confidence: 99%

Viral Pneumonia: Etiologies and Treatment

Dandachi

Rodriguez‐Barradas

2018

Journal of Investigative Medicine

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Viral pathogens are increasingly recognized as a cause of pneumonia, in immunocompetent patients and more commonly among immunocompromised. Viral pneumonia in adults could present as community-acquired pneumonia (CAP), ranging from mild disease to severe disease requiring hospital admission and mechanical ventilation. Moreover, the role of viruses in hospital-acquired pneumonia and ventilator-associated pneumonia as causative agents or as co-pathogens and the effect of virus detection on clinical outcome are being investigated.More than 20 viruses have been linked to CAP. Clinical presentation, laboratory findings, biomarkers, and radiographic patterns are not characteristic to specific viral etiology. Currently, laboratory confirmation is most commonly done by detection of viral nucleic acid by reverse transcription-PCR of respiratory secretions.Apart from the US Food and Drug Administration-approved medications for treatment of influenza pneumonia, the treatment of non-influenza respiratory viruses is limited. Moreover, the evidence supporting the use of available antivirals to treat immunocompromised patients is modest at best. With the widespread use of molecular diagnostics, an aging population, and advancement in cancer therapy, physicians will face a bigger challenge in managing viral respiratory tract infections. Emphasis on infection control measures to prevent the spread of respiratory viruses especially in healthcare settings is extremely important.

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Design and expeditious synthesis of organosilanes as potent antivirals targeting multidrug-resistant influenza A viruses

Cited by 29 publications

References 37 publications

Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

Viral Pneumonia: Etiologies and Treatment

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