Advances in structure-assisted antiviral discovery for animal viral diseases

Tomar, Shailly; Mahajan, Supreeti; Kumar, Ravi

doi:10.1016/b978-0-12-816352-8.00019-9

Cited by 9 publications

(6 citation statements)

References 99 publications

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“…In India, the CHIKV outbreak of 2006 has infected ~1.38 million people [70]. Different approaches such as FRET-based protease assays and in vitro antiviral assays have been developed to find efficacious antivirals against alphaviruses [12,[71][72][73][74][75]. Nano-biomaterials are being investigated as potential antivirals against CHIKV [76,77] and can also be beneficial for the development of new antivirals against alphavirus infections.…”

Section: Discussionmentioning

confidence: 99%

Alphavirus antivirals targeting RNA‐dependent RNA polymerase domain of nsP4 divulged using surface plasmon resonance

et al. 2022

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Alphaviruses are continuously re-emerging and pose a global threat to human health and currently no antiviral drug is commercially available for alphaviral infections. Alphavirus non-structural protein nsP4, which possesses RNA-dependent RNA polymerase (RdRp) activity, is a potential antiviral target. To date, no antiviral drug is commercially available against alphaviruses. Since RdRp is the key virus-specific enzyme involved in viral genome replication, this study identifies and validates the antiviral efficacy of small molecules targeting alphavirus RdRp. Purified nsP4 was characterized using the surface plasmon resonance (SPR) assay, and the binding affinities of divalent metal ions, ribonucleotides, and in vitro transcribed viral RNA oligonucleotides were obtained in the micromolar (lM) range. Further, four potential inhibitors, piperine (PIP), 2-thiouridine (2TU), pyrazinamide (PZA), and chlorogenic acid (CGA), were identified against nsP4 RdRp using a molecular docking approach. The SPR assay validated the binding of PIP, 2TU, PZA, and CGA to purified nsP4 RdRp with K D of 0.08, 0.13, 0.66, and 9.87 µM, respectively. Initial testing of these molecules as alphavirus replication inhibitors was done using SINV-IRES-Luc virus. Detailed assessment of antiviral efficacy of molecules against CHIKV was performed by plaque reduction assay, qRT-PCR, and immunofluorescence assay. PIP, 2TU, PZA, and CGA showed antiviral potency against CHIKV with EC 50 values of 6.68, 27.88, 36.26, and 53.62 µM, respectively. This study paves the way towards the development of novel broadspectrum alphavirus antivirals targeting nsP4 RdRp.

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Section: Discussionmentioning

confidence: 99%

Alphavirus antivirals targeting RNA‐dependent RNA polymerase domain of nsP4 divulged using surface plasmon resonance

et al. 2022

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“…The crystal structure of the NTF2-like domain of G3BP1 in complex with a 25-mer peptide from SFV nsP3 was retrieved from RCSB-PDB (ID: 5FW5) for structure-based in silico virtual screening and molecular docking studies. PyRx 0.8 [54] and AutoDock 4.2 [55] were used to perform virtual screening and molecular docking studies. The LOPAC 1280 (library of pharmacologically active compounds) library was used to screen the top hit compounds.…”

Section: Virtual Screening and Molecular Docking Of G3bp1 Proteinmentioning

confidence: 99%

“…Moreover, in the other viral mechanism, G3BP1 is cleaved by the viral proteases, which leads to the manipulation of stress activiated SG pathway and innate antiviral response in viral infected cells. For instance, the lead protease (L pro ) of and the 3C protease (3C pro ) of FMDV cleave G3BP1 [25] [29] [30], Human enterovirus D68 (EV-D68) cleaves G3BP1, which leads to the disassembly of SGs [31]. In a few viruses, G3BP1 inhibits viral replication through positively regulating retinoic acid-inducible gene 1 (RIG-1) mediated antiviral response in the infected cells [32] such as in Enterovirus 71 (EV71), Sendai virus (SeV), etc [31].…”

Section: Introductionmentioning

confidence: 99%

Targeting the host protein G3BP1 for the discovery of novel antiviral inhibitors against Chikungunya virus

Mahajan

Kumar

Singh

et al. 2022

Preprint

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Molecular interactions of Chikungunya virus (CHIKV) non-structural protein 3 (nsP3) with GTPase Activating Protein SH3 Domain Binding Protein 1 (G3BP1) host protein is important for efficient replication of CHIKV. CHIKV nsP3 protein binds to the nuclear transport factor 2 (NTF2)-like domain of G3BP1 via two tandem FGDF motifs and disrupts the stress granules (SGs) formation. Interestingly, this makes the G3BP1 host protein an additional drug target for antiviral research. In this study, seven potential small molecules targeting FGDF motif binding pocket of G3BP1 have been identified using structure-based virtual screening approach. Binding energies and binding modes of the molecules were further analyzed in detail through molecular docking, dynamics and simulations. Surface Plasmon Resonance (SPR) and Isothermal Titration Calorimetry (ITC) experiments confirmed the binding of identified molecules to purified G3BP1 with binding affinities in micromolar (μM) range. The antiviral efficacy of molecules targeting G3BP1 was evaluated by in vitro cell culture-based antiviral studies. All seven molecules L-7, WIN, SB2, NAL, DHD, GSK and FLU effectively diminished the CHIKV replication with EC50 values of 1.996, 0.403, 5.387, 1.528, 7.394, 3.664, and 0.618 μM, respectively. Moreover, the CHIKV infected cells treated with these molecules seemed to have fewer virus-induced SGs than virus infected control cells. Interestingly, the inhibitors showed no adverse effect on SG formation in oxidative stress condition. It further substantiated that these inhibitors effectively bind to the NTF2-like domain of G3BP1, obstruct the nsP3-G3BP1 interactions, and halts virus replication. This is the first report of small molecules targeting G3BP1, the host protein playing a crucial role in CHIKV viral replication and in the formation of SGs for host antiviral response.

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“…Like other cells, the ACE2 receptor is present on the surface of respiratory epithelial cells which makes these cells more susceptible to SARS-CoV-2 infection rather than cells with low levels of ACE2 receptor [ 12 ]. This coronavirus harbors a nucleocapsid with 30 kb + ssRNA [ 13 , 14 ]. The whole-genome sequence of SARS-CoV-2 is greatly identical and unique [ 15 , 16 ].…”

Section: Covid-19 Pathophysiology and Mechanism Of Actionmentioning

confidence: 99%

Does the Global Outbreak of COVID-19 or Other Viral Diseases Threaten the Stem Cell Reservoir Inside the Body?

Bagheri

Karimipour

Heidarzadeh

et al. 2021

Stem Cell Rev and Rep

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Advances in structure-assisted antiviral discovery for animal viral diseases

Cited by 9 publications

References 99 publications

Alphavirus antivirals targeting RNA‐dependent RNA polymerase domain of nsP4 divulged using surface plasmon resonance

Alphavirus antivirals targeting RNA‐dependent RNA polymerase domain of nsP4 divulged using surface plasmon resonance

Targeting the host protein G3BP1 for the discovery of novel antiviral inhibitors against Chikungunya virus

Does the Global Outbreak of COVID-19 or Other Viral Diseases Threaten the Stem Cell Reservoir Inside the Body?

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