CD147 contributes to SARS-CoV-2-induced pulmonary fibrosis

Wu, Jiao; Chen, Liang; Qin, Chuan; Huo, Fei; Li, Xue; Yang, Xu; Zhang, Kui; Peng, Lin; Liu, Jiangning; Feng, Zhuan; Zhou, Jiansheng; Pei, Zhuo; Wang, Yatao; Sun, Xiuxuan; Wang, Ke; Geng, Jie-Jie; Zheng, Zhaohui; Fu, Xianghui; Liu, Man; Wang, Qingyi; Zhang, Zheng; Bian, Huijie; Zhu, Ping; Chen, Zhi‐Nan

doi:10.1038/s41392-022-01230-5

Cited by 19 publications

(8 citation statements)

References 60 publications

(78 reference statements)

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“…How exactly niclosamide counteracts HuR translocation remains unknown. We did not to detect a strong binding between HuR and niclosamide, therefore, it would be reasonable to assume that niclosamide might indirectly affect the phosphorylation or the dimerization of HuR, which is required for the proper translocation 24 . Since HuR is also involved in brosis and in ammatory cytokine expressions 56 , it would be advantageous to further investigate the effect of HuR/CD147 inhibition combined with niclosamide.…”

Section: Discussionmentioning

confidence: 64%

“…Besides, CD147 receptor mediated signaling has been shown to participate in the disruption of cardiac pericytes by SARS-CoV-2 spike protein 23 . Moreover, CD147 has been shown to contribute to the SARS-CoV-2 induced pulmonary brosis, which is one of the most signi cant post-COVID conditions 24 . Meanwhile, antibody-mediated CD147 blocking could signi cantly reduce viral gene expression in megakaryocytes 21 .…”

Section: Introductionmentioning

confidence: 99%

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Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147

Yang

Zhang

et al. 2023

Preprint

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Background The burst of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the global COVID-19 pandemic. But until today only limited numbers of drugs are discovered to treat COVID-19 patients. Even worse, the rapid mutations of SARS-CoV-2 compromise the effectiveness of existing vaccines and neutralizing antibodies due to the increased viral transmissibility and immune escape. CD147-spike protein, one of the entries of SRAR-CoV-2 into host cells, has been reported as a promising therapeutic target for developing drugs against COVID-19.Methods CRISPR-Cas9 induced gene knockout, western blotting, tet-off protein overexpression, ribonucleoprotein IP and RNA-IP were used to confirm the regulation of HuR on mRNA of CD147. Regulation of niclosamide on HuR nucleo-translocation was assessed by immunofluorescence staining of cell lines, IHC staining of tissue of mouse model and western blotting. Finally, the suppression of niclosamide on SARS-CoV-2 infection induced CD147 was evaluated by ACE2-expressing A549 cells and western blotting.Results We first discovered a novel regulation mechanism of CD147 via the RNA-binding protein HuR. We found that HuR regulates CD147 post-transcription by directly bound to its 3'-UTR. The loss of HuR reduced CD147 in multiple cell lines. Niclosamide inhibited CD147 function by blocking HuR cytoplasmic translocation and diminishing CD147 glycosylation. SARS-CoV-2 infection induced CD147 in ACE2-expressing A549 cells, which could be neutralized by niclosamide in a dose-dependent manner.Conclusion Together, our study reveals a novel regulation mechanism of CD147 and niclosamide can be repurposed as an effective COVID-19 drug by targeting the virus entry, CD147-spike protein.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147

Yang

Zhang

et al. 2023

Preprint

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“…CD147, as a universal receptor of the spike protein, is identified to be able to mediate the cellular entry of SARS-CoV-2 and its VOCs, and meplazumab could effectively block the infection and replication, and alleviate the progression of pulmonary fibrosis. 9 – 11 , 13 To validate these actions of meplazumab in the clinic, we analysed the viral load, negative rate, and viral negative conversation rate in this study. We found that 0.2 mg/kg and 0.3 mg/kg of meplazumab decreased the viral load as early as 3 days post administration, and the effect sustained until the end of observation on day 29, with virus negative rate ranging from 81.0% to 91.7%.…”

Section: Discussionmentioning

confidence: 99%

“…Our latest study revealed that meplazumab alleviates the progression of pulmonary fibrosis of COVID-19 by inhibiting the accumulation of activated fibroblasts and the production of ECM proteins. 13 …”

Section: Introductionmentioning

confidence: 99%

Meplazumab in hospitalized adults with severe COVID-19 (DEFLECT): a multicenter, seamless phase 2/3, randomized, third-party double-blind clinical trial

Bian

Chen

Zheng

et al. 2023

Sig Transduct Target Ther

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Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.

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“…For instance, CD147 is an adhesion molecule that plays a significant role in mediating infection and cytokine storms [66]. It is a signal initiator for cytokine storm, which is closely related to severe COVID-19 infection [67,68] and a mediator of pulmonary fibrosis [69]. Meplazumab, a mAb targeting CD147, has been demonstrated to efficiently block viral entry of SARS-CoV-2 and its variants while alleviating cytokine storm [59,70,71] and progression of pulmonary fibrosis of COVID-19 [69].…”

Section: Block the Other Routes For Viral Entry In Addition To The Rb...mentioning

confidence: 99%

Status and Developing Strategies for Neutralizing Monoclonal Antibody Therapy in the Omicron Era of COVID-19

Ren

Shen

Peng

2023

Viruses

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The monoclonal antibody (mAb)-based treatment is a highly valued therapy against COVID-19, especially for individuals who may not have strong immune responses to the vaccine. However, with the arrival of the Omicron variant and its evolving subvariants, along with the occurrence of remarkable resistance of these SARS-CoV-2 variants to the neutralizing antibodies, mAbs are facing tough challenges. Future strategies for developing mAbs with improved resistance to viral evasion will involve optimizing the targeting epitopes on SARS-CoV-2, enhancing the affinity and potency of mAbs, exploring the use of non-neutralizing antibodies that bind to conserved epitopes on the S protein, as well as optimizing immunization regimens. These approaches can improve the viability of mAb therapy in the fight against the evolving threat of the coronavirus.

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CD147 contributes to SARS-CoV-2-induced pulmonary fibrosis

Cited by 19 publications

References 60 publications

Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147

Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147

Meplazumab in hospitalized adults with severe COVID-19 (DEFLECT): a multicenter, seamless phase 2/3, randomized, third-party double-blind clinical trial

Status and Developing Strategies for Neutralizing Monoclonal Antibody Therapy in the Omicron Era of COVID-19

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