Ceftazidime is a potential drug to inhibit SARS-CoV-2 infection in vitro by blocking spike protein–ACE2 interaction

Lin, Changdong; Li, Yue; Zhang, Yuebin; Liu, Zhaoyuan; Mu, Xiaoli; Gu, Cheng; Liu, Jing; Li, Yutang; Li, Guohui; Chen, Jianfeng

doi:10.1038/s41392-021-00619-y

Cited by 36 publications

(39 citation statements)

References 5 publications

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“…We first established the antiviral efficacy of the predicted targets - individual knockdown of the 26 predicted SL targets resulted in an overall reduction in viral replication (P=6.57E-07; Figure 3b ) and reduced cell viability (P=0.047; Figure 3c ) compared to scrambled siRNAs. Of note, the knockdown of ACE2 and TMPRSS2 also markedly reduced viral replication, consistent with their previously recognized potential as effective drug targets (Lin et al 2021; Hoffman et al 2020). Second, we tested if the predicted targets indeed selectively reduce the viability of the infected cells but not the non-infected cells.…”

Section: Resultssupporting

confidence: 86%

“…Numerous recent studies have contributed to the understanding of the biology of SARS-CoV-2 infection (for example, Paules & Fauci, 2021; V’kovski et al 2020; Bojkova et al 2020; Forster et al 2020). A lot of interest has been focused on targeting ACE2 and TMPRSS2 , the virus entry receptors (Muralidhar et al 2021; Ragia & Manolopoulos, 2020) and the search for drugs targeting these genes is underway (Lin et al 2021; Hoffman et al 2020). However, the direct targeting of the viral life cycle to inhibit its proliferation remains challenging.…”

Section: Introductionmentioning

confidence: 99%

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Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

Pal

Cheng

Nair

et al. 2021

Preprint

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Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal (SL) partners of such altered host genes. Pursuing this antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL with altered host genes. The predicted SL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. Integrating our predictions with the results of these screens, we further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming non-infected cells. Our results are made publicly available, to facilitate their in vivo testing and further validation.

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Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

Pal

Cheng

Nair

et al. 2021

Preprint

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“…The third and fourth-generation cephalosporins have been successfully used as empirical antibiotics with hospital-acquired infections. Some of them, such as ceftazidime and cefepime, have shown outstanding outcomes with bacterial pneumonia [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Ceftazidime and Cefepime in the Management of COVID-19 Patients: Single Center Report from Egypt

et al. 2021

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The purpose of this study was to explore the value of using cefepime and ceftazidime in treating patients with COVID-19. A total of 370 (162 males) patients, with RT-PCR-confirmed cases of COVID-19, were included in the study. Out of them, 260 patients were treated with cefepime or ceftazidime, with the addition of steroids to the treatment. Patients were divided into three groups: Group 1: patients treated with cefepime (124 patients); Group 2: patients treated with ceftazidime (136 patients); Group 3 (control group): patients treated according to the WHO guidelines and the Egyptian COVID-19 management protocol (110 patients)/ Each group was classified into three age groups: 18–30, 31–60, and >60 years. The dose of either cefepime or ceftazidime was 1000 mg twice daily for five days. Eight milligrams of dexamethasone were used as the steroidal drug. Careful follow-ups for the patients were carried out. In vitro and in silico Mpro enzyme assays were performed to investigate the antiviral potential of both antibiotics. The mean recovery time for Group 1 was 12 days, for Group 2 was 13 days, and for Group 3 (control) was 19 days. No deaths were recorded, and all patients were recovered without any complications. For Group 1, the recovery time was 10, 12, and 16 days for the age groups 18–30, 30–60, and >60 years, respectively. For Group 2, the recovery time was 11, 13, and 15 days for the age groups 18–30, 30–60, and >60 years, respectively. For Group 3 (control), the recovery time was 15, 16, and 17 days for the age groups 18–30, 30–60, and >60 years, respectively. Both ceftazidime and cefepime showed very good inhibitory activity towards SARS CoV-2′s Mpro, with IC50 values of 1.81 µM and 8.53 µM, respectively. In conclusion, ceftazidime and cefepime are efficient for the management of moderate and severe cases of COVID-19 due to their potential anti-SARS CoV-2 activity and low side effects, and, hence, the currently used complex multidrug treatment protocol can be replaced by the simpler one proposed in this study.

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“…Due to the lack of known COVID-19 active ligands, it is important to ensure that the used program can replicate the binding mode of a known experimental inhibitor for the studied enzyme. Although no effective antiviral drug against COVID-19 infection is currently available, several reports have indicated that RdRp inhibitor (Remdesivir) [ 23 ], spike protein inhibitor (Ceftazidime) [ 24 ], protease inhibitor (N3) [ 25 ], in addition to methyltransferase inhibitor (Sinefungin) [ 18 ] have the potential for designing active SARS-CoV-2 inhibitors. In the attempt to have reference values (positive control) the anti-viral drug Remdesivir, antibacterial drug Ceftazidime, Michael acceptor inhibitor N3 and Sinefungin were considered as comparative standards for the molecular docking.…”

Section: Methodsmentioning

confidence: 99%

Anti-COVID-19 activity of some benzofused 1,2,3-triazolesulfonamide hybrids using in silico and in vitro analyses

Shaaban

Elwakil

Hamed

et al. 2021

Chemometrics and Intelligent Laboratory Systems

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic fatal infection with no known treatment. The severity of the disease and the fast viral mutations forced the scientific community to search for potential solution. Here in the present manuscript, some benzofused1,2,3triazolesulfonamide hybrids were synthesized and evaluated for their anti- SARS-CoV-2 activity using in silico prediction then the most potent compounds were assessed using in-Vitro analysis. The in-Silico study was assessed against RNA dependent RNA polymerase, Spike protein S1, Main protease (3CLpro) and 2'-O-methyltransferase (nsp16). It was found that 4b and 4c showed high binding scores against RNA dependent RNA polymerase reached -8.40 and -8.75 Kcal/mol, respectively compared to the approved antiviral (remdesivir -6.77 Kcal/mol). Upon testing the binding score with SARS-CoV-2 Spike protein it was revealed that 4c exhibited the highest score (-7.22 Kcal/mol) compared to the reference antibacterial drug Ceftazidime (-6.36 Kcal/mol). Surprisingly, the two compounds 4b and 4c showed the highest binding scores against SARS-CoV-2 3CLpro (-8.75, -8.48 Kcal/mol, respectively) and nsp16 (- 8.84 and – 8.89 Kcal/mol, respectively) displaying many types of interaction with all the enzymes binding sites. The derivatives 4b and 4c were examined in vitro for their potential anti-SARS-CoV-2 and it was revealed that 4c was the most promising compound with IC50 reached 758.8108 mM and complete (100%) inhibition of the binding of SARS-CoV-2 virus to human ACE2 can be accomplished by using 0.01 mg.

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Ceftazidime is a potential drug to inhibit SARS-CoV-2 infection in vitro by blocking spike protein–ACE2 interaction

Cited by 36 publications

References 5 publications

Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

Efficacy of Ceftazidime and Cefepime in the Management of COVID-19 Patients: Single Center Report from Egypt

Anti-COVID-19 activity of some benzofused 1,2,3-triazolesulfonamide hybrids using in silico and in vitro analyses

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