<i>In silico</i>and<i>in vitro</i>evaluation of imatinib as an inhibitor for SARS-CoV-2

Mulgaonkar, Nirmitee; Wang, Haoqi; Mallawarachchi, Samavath; Růžek, Daniel; Martina, Benedict; Fernando, Sandun

doi:10.1080/07391102.2022.2045221

Cited by 7 publications

(7 citation statements)

References 33 publications

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“…E64d inhibits cathepsin-L, an essential enzyme in regulating the endosomal fusion [ 20 , 28 ]; whereas, camostat inhibits TMPRSS2 serine protease, an essential enzyme in regulating the membrane route [ 20 ]. Imatinib inhibits both pathways by directly binding to Spike [ 27 , 29 ]. In TMPRSS2-negative cells, infection of both lenti-Delta and lenti-Omicron Spike was inhibited by E64d and imatinib, but not by camostat ( Figure 2 a), verifying their endosomal route.…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Omicron Specific Mutations Affecting Infectivity, Fusogenicity, and Partial TMPRSS2-Independency

Strobelt

Broennimann

Adler

et al. 2023

Viruses

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The COVID-19 pandemic resulted from the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since its first appearance in 2019, new SARS-CoV-2 variants of concern (VOCs) have emerged frequently, changing the infection’s dynamic. SARS-CoV-2 infects cells via two distinct entry routes; receptor-mediated endocytosis or membrane fusion, depending on the absence or presence of transmembrane serine protease 2 (TMPRSS2), respectively. In laboratory conditions, the Omicron SARS-CoV-2 strain inefficiently infects cells predominantly via endocytosis and is phenotypically characterized by decreased syncytia formation compared to the earlier Delta variant. Thus, it is important to characterize Omicron’s unique mutations and their phenotypic manifestations. Here, by utilizing SARS-CoV-2 pseudovirions, we report that the specific Omicron Spike F375 residue decreases infectivity, and its conversion to the Delta S375 sequence significantly increases Omicron infectivity. Further, we identified that residue Y655 decreases Omicron’s TMPRSS2 dependency and entry via membrane fusion. The Y655H, K764N, K856N and K969N Omicron revertant mutations, bearing the Delta variant sequence, increased the cytopathic effect of cell–cell fusion, suggesting these Omicron-specific residues reduced the severity of SARS-CoV-2. This study of the correlation of the mutational profile with the phenotypic outcome should sensitize our alertness towards emerging VOCs.

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Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Omicron Specific Mutations Affecting Infectivity, Fusogenicity, and Partial TMPRSS2-Independency

Strobelt

Broennimann

Adler

et al. 2023

Viruses

View full text Add to dashboard Cite

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“…It is well known that if this protein is interrupted with the targeted therapy, mitotic progression gets interrupted, which leads to the death of malignant cells [10][11][12]. During the outbreak of COVID-19 in late 2019, there was widespread interest in the repurposing of most anticancer drugs as potential inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike and host angiotensin-converting enzyme 2 (ACE2) interactions as a strategy to prevent viral transmission [13,14]. SARS-CoV-2 is the causative agent of the pandemic viral disease COVID-19 [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…Although the speed with which COVID-19 vaccines have been developed is remarkable, their long-term protection effect and effectiveness against emerging variants and potential future variants of SARS-CoV-2 and other coronaviruses remains to be determined [17][18][19][20]. Considering that ACE2 also serves as the receptor for the SARS-CoV and SARS-CoV-2 viruses [13,14], the binding of the S1 domain of the SARS Coronavirus spike protein to ACE2 initiates viral entry into the host cell [21][22][23]. This area of interaction between SARS-CoV-2 and ACE2 has become of therapeutic interest to develop possible treatments against COVID-19 [24,25].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological and computational evaluation of novel oxindole derivatives as inhibitors of Aurora A Kinase and SARS-CoV-2 Spike/Host ACE2 Interaction

Eni,

Cassel,

Namba-Nzanguim

et al. 2024

Preprint

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Isatin (indol-2,3-dione), a secondary metabolite of tryptophan has been used as the core structure in the designation of several compounds that have been tested and identified as potent inhibitors of apoptosis, potential antitumor agents, anticonvulsants, and antiviral agents. In this work, several analogues of isatin hybrids have been synthesized and characterized, and their inhibitory activities established as inhibitors of both Aurora A kinase and SARS-CoV-2 spike/host ACE2 interactions. Amongst the synthesized isatin hybrids, compounds 6a – 6d, and 6m exhibited interesting Aurora A kinase inhibitory activity while compounds 6h and 6l showed interesting activity in blocking SARS-CoV-2 spike with the ACE2 protein. Compounds 6f, 6g, and 6i possessed both inhibitory activities. Pharmacophore profiling indicated that compound 6g, tightly fits Aurora A kinase and SARS-CoV-2 pharmacophore while 6d fits SARS-CoV-2 and 6l Aurora A kinase. This work is a proof of concept that most existing cancer drugs possess antiviral properties. Molecular modeling showed that the active compound for each protein adopted different binding modes, hence interacting with a different set of amino acid residues in the binding site. For the Aurora A kinase inhibitors, it was shown that the important residues for binding were Leu139, Ala213, Lys162 and Glu211. The weaker activities against spike/ACE2 could be explained by the small sizes of the ligands that fail to address the important interactions for binding to the angiotensin II receptor site.

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“…It is well known that if this protein is interrupted with the targeted therapy, mitotic progression gets interrupted, which leads to the death of malignant cells [ 10 – 12 ]. During the outbreak of COVID-19 in late 2019, there was widespread interest in the repurposing of most anticancer drugs as potential inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike and host angiotensin-converting enzyme 2 (ACE2) interactions as a strategy to prevent viral transmission [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Although the speed with which COVID-19 vaccines have been developed is remarkable, their long-term protection effect and effectiveness against emerging variants and potential future variants of SARS-CoV-2 and other coronaviruses remains to be determined [ 17 – 20 ]. Considering that ACE2 also serves as the receptor for the SARS-CoV and SARS-CoV-2 viruses [ 13 , 14 ], the binding of the S1 domain of the SARS Coronavirus spike protein to ACE2 initiates viral entry into the host cell [ 21 – 23 ]. This area of interaction between SARS-CoV-2 and ACE2 has become of therapeutic interest to develop possible treatments against COVID-19 [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Eni,

Cassel,

Namba-Nzanguim

et al. 2024

Med Chem Res

View full text Add to dashboard Cite

Isatin (indol-2,3-dione), a secondary metabolite of tryptophan, has been used as the core structure to design several compounds that have been tested and identified as potent inhibitors of apoptosis, potential antitumor agents, anticonvulsants, and antiviral agents. In this work, several analogs of isatin hybrids have been synthesized and characterized, and their activities were established as inhibitors of both Aurora A kinase and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike/host angiotensin-converting enzyme II (ACE2) interactions. Amongst the synthesized isatin hybrids, compounds 6a, 6f, 6g, and 6m exhibited Aurora A kinase inhibitory activities (with IC50 values < 5 $$\mu$$ μ M), with GScore values of −7.9, −7.6, −8.2 and −7.7 kcal/mol, respectively. Compounds 6g and 6i showed activities in blocking SARS-CoV-2 spike/ACE2 binding (with IC50 values in the range < 30 $$\mu$$ μ M), with GScore values of −6.4 and −6.6 kcal/mol, respectively. Compounds 6f, 6g, and 6i were both capable of inhibiting spike/ACE2 binding and blocking Aurora A kinase. Pharmacophore profiling indicated that compound 6g tightly fits Aurora A kinase and SARS-CoV-2 pharmacophores, while 6d fits SARS-CoV-2 and 6l fits Aurora A kinase pharmacophore. This work is a proof of concept that some existing cancer drugs may possess antiviral properties. Molecular modeling showed that the active compound for each protein adopted different binding modes, hence interacting with a different set of amino acid residues in the binding site. The weaker activities against spike/ACE2 could be explained by the small sizes of the ligands that fail to address the important interactions for binding to the ACE2 receptor site.

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In silicoandin vitroevaluation of imatinib as an inhibitor for SARS-CoV-2

Cited by 7 publications

References 33 publications

SARS-CoV-2 Omicron Specific Mutations Affecting Infectivity, Fusogenicity, and Partial TMPRSS2-Independency

SARS-CoV-2 Omicron Specific Mutations Affecting Infectivity, Fusogenicity, and Partial TMPRSS2-Independency

Design, synthesis, and biological and computational evaluation of novel oxindole derivatives as inhibitors of Aurora A Kinase and SARS-CoV-2 Spike/Host ACE2 Interaction

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

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