Nirmatrelvir exerts distinct antiviral potency against different human coronaviruses

Li, Jiajing; Solanki, Kundan; Atre, Rajat; Lavrijsen, Marla; Pan, Qiaoling; Baig, Mirza S.; Li, Pengfei

doi:10.1016/j.antiviral.2023.105555

Cited by 14 publications

(11 citation statements)

References 23 publications

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“…A famous example is nirmatrelvir, the prodrug of the main protease (M pro ) inhibitor developed against SARS-CoV-2. Recently, it was shown to effectively inhibit the replication of seasonal coronaviruses, including 229E, in various in vitro assays [27]. Azelastine-HCl was predicted in silico to inhibit the coronavirus protease M pro and was later confirmed in vitro as well [28][29][30]; therefore, this direct antiviral mechanism could contribute to its activity against SARS-CoV-2 variants and HCoV-229E.…”

Section: Discussionmentioning

confidence: 94%

Antiviral Potential of Azelastine against Major Respiratory Viruses

Fischhuber,

Bánki,

Kimpel

et al. 2023

Viruses

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The Coronavirus Disease 2019 (COVID-19) pandemic and the subsequent increase in respiratory viral infections highlight the need for broad-spectrum antivirals to enable a quick and efficient reaction to current and emerging viral outbreaks. We previously demonstrated that the antihistamine azelastine hydrochloride (azelastine-HCl) exhibited in vitro antiviral activity against SARS-CoV-2. Furthermore, in a phase 2 clinical study, a commercial azelastine-containing nasal spray significantly reduced the viral load in SARS-CoV-2-infected individuals. Here, we evaluate the efficacy of azelastine-HCl against additional human coronaviruses, including the SARS-CoV-2 omicron variant and a seasonal human coronavirus, 229E, through in vitro infection assays, with azelastine showing a comparable potency against both. Furthermore, we determined that azelastine-HCl also inhibits the replication of Respiratory syncytial virus A (RSV A) in both prophylactic and therapeutic settings. In a human 3D nasal tissue model (MucilAirTM-Pool, Epithelix), azelastine-HCl protected tissue integrity and function from the effects of infection with influenza A H1N1 and resulted in a reduced viral load soon after infection. Our results suggest that azelastine-HCl has a broad antiviral effect and can be considered a safe option against the most common respiratory viruses to prevent or treat such infections locally in the form of a nasal spray that is commonly available globally.

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Section: Discussionmentioning

confidence: 94%

Antiviral Potential of Azelastine against Major Respiratory Viruses

Fischhuber,

Bánki,

Kimpel

et al. 2023

Viruses

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“…Overall, our findings demonstrate that B6C11S can effectively reduce viral titer and alleviate illness severity in hamsters infected with SARS-CoV-2 Alpha. In comparison to the main protease inhibitor nirmatrelvir, which exclusively inhibits human coronaviruses, 44 B6C11S possesses the extra advantage of suppressing multiple respiratory viruses, including SARS-CoV-2, H1N1, and RSV.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Benzene with Alkyl Chains Is a Universal Scaffold for Multivalent Virucidal Antivirals

Zhu,

Gasbarri,

Zebret

et al. 2024

ACS Cent. Sci.

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Most viruses start their invasion by binding to glycoproteins' moieties on the cell surface (heparan sulfate proteoglycans [HSPG] or sialic acid [SA]). Antivirals mimicking these moieties multivalently are known as broad-spectrum multivalent entry inhibitors (MEI). Due to their reversible mechanism, efficacy is lost when concentrations fall below an inhibitory threshold. To overcome this limitation, we modify MEIs with hydrophobic arms rendering the inhibitory mechanism irreversible, i.e., preventing the efficacy loss upon dilution. However, all our HSPGmimicking MEIs only showed reversible inhibition against HSPG-binding SARS-CoV-2. Here, we present a systematic investigation of a series of small molecules, all containing a core and multiple hydrophobic arms terminated with HSPG-mimicking moieties. We identify the ones that have irreversible inhibition against all viruses including SARS-CoV-2 and discuss their design principles. We show efficacy in vivo against SARS-CoV-2 in a Syrian hamster model through both intranasal instillation and aerosol inhalation in a therapeutic setting (12 h postinfection). We also show the utility of the presented design rules in producing SA-mimicking MEIs with irreversible inhibition against SA-binding influenza viruses.

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“…90,123,139,140 It has been reported that Nirmatrelvir demonstrated distinct antiviral potency against prevalent variants of SARS-CoV-2, such as Alpha, Beta, Delta, Gamma, Omicron 141 and different human coronaviruses. 142 Nirmatrelvir has become a promising scaffold for computer-guided design of its better-acting analogs. 143 Using a hybrid approach combining machine learning and free energy simulations, six new derivatives were designed by modifying parent nirmatrelvir, so that they bind strongly to SARS-CoV-2 Mpro and might be less toxic to the human body than the original inhibitor.…”

Section: Promising Targets For Pharmacological Action On Sars-cov-2mentioning

confidence: 99%

Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

Yevsieieva,

Lohachova,

Kyrychenko

et al. 2023

RSC Adv.

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Nirmatrelvir exerts distinct antiviral potency against different human coronaviruses

Cited by 14 publications

References 23 publications

Antiviral Potential of Azelastine against Major Respiratory Viruses

Antiviral Potential of Azelastine against Major Respiratory Viruses

Benzene with Alkyl Chains Is a Universal Scaffold for Multivalent Virucidal Antivirals

Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

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