Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

Zhao, Miaomiao; Yang, Weili; Yang, Fengying; Zhang, Li; Huang, Weijin; Hou, Wei; Fan, Chen; Jin, Ronghua; Feng, Yingmei; Wang, Youchun; Yang, Jin-Kui

doi:10.1038/s41392-021-00558-8

Cited by 423 publications

(436 citation statements)

References 57 publications

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“…The development of small molecule entry inhibitors of SARS-CoV-2 fall behind. Besides the aforementioned chloroquine and arbidol, several small molecule inhibitors targeting host proteases have been explored to inhibit SARS-CoV-2 entry, including TMPRSS2 inhibitors camostat mesylate 16 , nafamostat mesylate 106 , and bromhexine hydrochloride 107 , cathepsin L inhibitors E-64d 16 , 108 , K11777 109 , and SID26681509 110 , and furin inhibitor naphthofluorescein 111 . In general, targeting cellular factors may result in substantial advantages such as a broader range of therapies and reduced chances of developing drug resistance, however, the translational potential of these host protease inhibitors might be limited.…”

Section: Antiviral Therapies Against Sars-cov-2 Cell Entrymentioning

confidence: 99%

SARS-CoV-2 cell entry and targeted antiviral development

Chen

Achi

et al. 2021

Acta Pharmaceutica Sinica B

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19), which threatens human health and public safety. In the urgent campaign to develop anti-SARS-CoV-2 therapies, the initial entry step is one of the most appealing targets. In this review, we summarize the current understanding of SARS-CoV-2 cell entry, and the development of targeted antiviral strategies. Moreover, we speculate upon future directions toward next-generation of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.

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Section: Antiviral Therapies Against Sars-cov-2 Cell Entrymentioning

confidence: 99%

SARS-CoV-2 cell entry and targeted antiviral development

Chen

Achi

et al. 2021

Acta Pharmaceutica Sinica B

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“…Furin, TMPRSS2 and Cathepsin L are important proteolytic enzyme, which are key regulators of SARS-CoV-2 infection 22,23 . Overexpression of these enzymes facilitates cellular infection.…”

Section: Discussionmentioning

confidence: 99%

“…The activity of Furin/TMPRSS2/Cathepsin L the ten SARS-CoV-2 variants Because Furin, TMPRSS2, and Cathepsin L play important roles in SARS-CoV-2 infection [21][22][23] , mutationrelated structural changes in the virus may in uence the functions of these enzymes. We found that the ability of the D614G reference strain to infect 293T-ACE2 cells was signi cantly increased when Furin, TMPRSS2, or Cathepsin L was overexpressed (Fig 2E).…”

Section: Infectivities Of 10 Sars-cov-2 Variantsmentioning

confidence: 99%

Comparison of 10 emerging SARS-CoV-2 Variants: infectivity, animal tropism, and antibody neutralization

Zhang

Cui

et al. 2021

Preprint

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Ten emerging SARS-CoV-2 variants—B.1.1.298, B.1.1.7, B.1.351, P.1, P.2, B.1.429, B.1.525, B.1.526-1, B.1.526-2, B.1.1.318—and seven corresponding single amino acid mutations in the receptor-binding domain were examined using SARS-CoV-2 pseudovirus. The results indicate that the current SARS-CoV-2 variants do not increase infectivity among humans. The K417N/T, N501Y, or E484K-carrying variants exhibited increased abilities to infect to mouse ACE2-overexpressing cells. The activities of Furin, TMPRSS2, and cathepsin L were increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y caused significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines was mainly caused by the E484K mutation, while the neutralization of E484K-carrying variants was decreased by 1.1–6.2-fold. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants.

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“…Circulating levels of CTSL are increased after SARS-CoV-2 infection where they are positively correlated with disease course and severity [ 18 ] and, importantly, SARS-CoV-2 pseudovirus infection results in increased CTSL expression in human cells in vitro and in human ACE2-transgenic mice in vivo, while CTSL overexpression leads to enhancement of pseudovirus infection in human cells. Moreover, CTSL functionally cleaves the SARS-CoV-2 spike protein leading to enhanced viral entry and amantadine significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection both in vitro and in vivo.…”

Section: Adamantanes Against Sars-cov-2: In Vitro and Preclinical Investigationsmentioning

confidence: 99%

Potential for the Repurposing of Adamantane Antivirals for COVID-19

Butterworth

2021

Drugs R D

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Several adamantanes have established actions against coronaviruses. Amantadine, rimantadine, bananins and the structurally related memantine are effective against human respiratory coronavirus HCoV-OC43, bovine coronavirus and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and a spiroadamantane amine is effective against the coronavirus strain 229E. Molecular docking studies suggest that amantadine may block the viral E protein channel, leading to impaired viral propagation. Additionally, amantadine analogues may inhibit entry of the virus into the host cell by increasing the pH of the endosomes and thus inhibiting the action of host cell proteases such as Cathepsin L. High-throughput drug screen gene expression analysis identified compounds able to down-regulate Cathepsin L expression where the fifth most potent agent of 466 candidates was amantadine. Amantadine inhibits severe acute respiratory syndrome coronavirus 2 replication in vitro but does not inhibit the binding of the spike protein to ACE2. Adamantanes also may act against coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via antagonism of glutamate (NMDA) and the α-7 subtype of the nicotinic acetylcholine receptor located on bronchial and alveolar epithelial cells. As an NMDA receptor antagonist, memantine has the potential to inhibit entry of SARS-CoV-2 into these cell populations. Amantadine and memantine are widely employed for the treatment of neurodegenerative diseases and a pathophysiologic link between the antiviral and anti-Parkinson actions of amantadine has been entertained. Case reports involving 23 patients with reverse transcription polymerase chain reaction-confirmed coronavirus disease 2019 (COVID-19) and a range of co-morbidities including type 2 diabetes mellitus, Parkinson’s disease, multiple sclerosis and severe cognitive impairment reveal significant potential benefits of amantadine and memantine for the prevention and/or treatment of coronavirus disease 2019 and its neurological complications.

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Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

Cited by 423 publications

References 57 publications

SARS-CoV-2 cell entry and targeted antiviral development

SARS-CoV-2 cell entry and targeted antiviral development

Comparison of 10 emerging SARS-CoV-2 Variants: infectivity, animal tropism, and antibody neutralization

Potential for the Repurposing of Adamantane Antivirals for COVID-19

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