GRP78 targeting: Hitting two birds with a stone

Elfiky, Abdo A.; Baghdady, Ahmed M.; Ali, Shehab A.; Ahmed, Marwan I.

doi:10.1016/j.lfs.2020.118317

Cited by 93 publications

(78 citation statements)

References 121 publications

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“…In this letter, we propose to shed light on the effect of the new variant mutation N501Y of the RBD on the viral recognition by the host cell-surface GRP78. This recognition can be targeted by peptides, antibodies, and phytochemicals ( 10 ).…”

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Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico

Elfiky

Ibrahim

2021

Journal of Infection

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Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico Dear Editor, In this Journal we previously reported the predicted SARS-CoV-2 spike-host cell receptor GRP78 binding site (1). New SARS-CoV-2 variant VUI 202,012/01 started in the UK and currently spreading in Europe and Australia during the last few days. The new variant bears about nine mutations in the spike protein (69-70, 145, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H). The N501Y lies in the receptor-binding domain (RBD) of the spike and interacts with the host-cell receptor ACE2 responsible for viral recognition and entry. We tried to simulate the system of ACE2-SARS-CoV-2 spike RBD in the wildtype and mutated isoform of the RBD (N501Y). Additionally, the GRP78 association with the ACE2-SARS-CoV-2 spike RBD is modeled at the presence of this mutant variant of the viral spike. Based on our previous study, the Heat Shock Protein A5 (HSPA5), also called, Glucose Regulated Protein 78 (GRP78) or Bip, is predicted to bind to the receptor-binding domain (RBD) of the SARS-CoV-2 Spike. 1 The GRP78 is predicted to bind the Spike protein alongside the putative host-cell receptor, the Angiotensin-Converting Enzyme 2 (ACE2). 2 , 3 The binding of GRP78 to the spike/ACE2 complex is predicted using HADDOCK 2.4 webserver 4 (Fig. 1 A). PyMOL V2.2.2 was utilized to do a point mutation (N501Y) to resemble the RBD mutation found in the new variant of COVID-19. 5 We docked GRP78 with both wild type SARS-CoV-2 Spike RBD-ACE2 complex (WT ACE2-RBD), and N501Y mutant SARS-CoV-2 Spike RBD-ACE2 complex (Mut ACE2-RBD). GRP78 and SARS-CoV-2 Spike RBD's active sites were T428, V429, V432, T434, F451, S452, V457 & I489 and C480-C488, respectively, and the rest of HADDOCK options were kept as default. The carbohydrate moieties (NAG) attached to the proteins were held in the structure. The HADDOCK score values for the GRP78 against WT ACE2-RBD and Mut ACE2-RBD are −74.3 ± 0.9 and −95.6 ± 1.0, respectively. This indicates better binding for the GRP78 against Mut ACE2-RBD than the WT ACE2-RBD complexes. There is a 28.7% increase in the HADDOCK score of GRP78 to the Mut ACE2-RBD form compared to the WT ACE2-RBD. The interactions between GRP78 and the two complexes are presented in Table 1. GRP78 is tightly bound to the mutated complex with three H-bonds and five hy

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Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico

Elfiky

Ibrahim

2021

Journal of Infection

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“…The relative transcript levels of Eif2ak3 [encoding the protein PERK ( Hayes et al, 1999 )], Atf4 [encoding the protein ATF4 ( Karpinski et al, 1992 )], Ddit3 [encoding the protein CHOP ( Marola et al, 2019 )], Ppp1r15a [encoding the protein GADD34 ( Clavarino et al, 2012 )], Hspa5 [encoding the protein GRP78 ( Elfiky et al, 2020 )], Hsp90B1 [encoding the protein GRP94 ( Chen et al, 2005 )], and Tnfrsf10B [encoding death receptor 5 (DR5; Dittmann et al, 2020 )] were significantly increased in the GA muscle of the tumor-bearing vehicle-treated group compared to the tumor-free vehicle-treated group ( p < 0.0001 for all comparisons) ( Figure 4 ). Curiously, relative transcript levels of Ern1 [encoding inositol requiring enzyme 1α (IRE1α; Tirasophon et al, 1998 )] were significantly reduced in the tumor-bearing vehicle-treated group compared to the tumor-free vehicle-treated group ( p = 0.001) ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Withaferin A and Ovarian Cancer Antagonistically Regulate Skeletal Muscle Mass

Straughn

Kelm

Kakar

2021

Front. Cell Dev. Biol.

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Cachexia is a complex wasting syndrome that overwhelmingly affects the majority of late-stage cancer patients. Additionally, there are currently no efficacious therapeutic agents to treat the muscle atrophy induced by the cancer. While several preclinical studies have investigated the molecular signals orchestrating cachexia, very little information exists pertaining to ovarian cancer and the associated cachexia. Work from our lab has recently demonstrated that the steroidal lactone Withaferin A (WFA) is capable of attenuating the atrophying effects of ovarian cancer in a preclinical mouse model. However, it remained to be determined whether WFA’s effect was in response to its anti-tumorigenic properties, or if it was capable of targeting skeletal muscle directly. The purpose of this study was to uncover whether WFA was capable of regulating muscle mass under tumor-free and tumor-bearing conditions. Treatment with WFA led to an improvement in functional muscle strength and mass under tumor-bearing and naïve conditions. WFA and ovarian cancer were observed to act antagonistically upon critical skeletal muscle regulatory systems, notably myogenic progenitors and proteolytic degradation pathways. Our results demonstrated for the first time that, while WFA has anti-tumorigenic properties, it also exerts hypertrophying effects on skeletal muscle mass, suggesting that it could be an anti-cachectic agent in the settings of ovarian cancer.

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“…Many reports showed that different natural product derived compounds have promising results against inflammation and viral infections including the newly emerged viral infection (SARS-CoV-2) 15,38–40 . Different natural compounds and their derivatives proved its binding affinity against different SARS-CoV-2 and host-cell targets 38,39,41 .…”

Section: Resultsmentioning

confidence: 99%

In vitro: Natural Compounds (Thymol, Carvacrol, Hesperidine, And Thymoquinone) Against Sars-Cov2 Strain Isolated From Egyptian Patients

Seadawy¹,

Gad²,

Elhoseny³

et al. 2020

Preprint

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The current pandemic of the coronavirus disease-2019 (COVID-19) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Molecular docking combined with cytotoxicity and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp, and Mpro) and host-cell (TMPRSS II, keap 1, and ACE2) targets. The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease (Mpro). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)

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GRP78 targeting: Hitting two birds with a stone

Cited by 93 publications

References 121 publications

Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico

Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico

Withaferin A and Ovarian Cancer Antagonistically Regulate Skeletal Muscle Mass

In vitro: Natural Compounds (Thymol, Carvacrol, Hesperidine, And Thymoquinone) Against Sars-Cov2 Strain Isolated From Egyptian Patients

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