Identification and characterization of two conserved G-quadruplex forming motifs in the Nipah virus genome and their interaction with G-quadruplex specific ligands

Majee, Prativa; Mishra, Subodh Kumar; Pandya, Nirali; Shankar, Uma; Pasadi, Sanjeev; Muniyappa, K.; Nayak, Debasis; Kumar, Amit

doi:10.1038/s41598-020-58406-8

Cited by 46 publications

(33 citation statements)

References 59 publications

(68 reference statements)

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“…The translation of some SARS-CoV-2 proteins requires the involvement of human ribosomes; thus, it is possible to repress the translation of SARS-CoV-2 proteins via stabilizing the G-quadruplex structures. In fact, this inhibition effect has been reported in some other viral studies [67,71]. The negative-sense strand serves as templates for the synthesis of the positive-sense strand and the sub-genomic RNAs.…”

Section: Discussionsupporting

confidence: 52%

“…However, it is well-acknowledged that the RNA Gquadruplexes is more stable than their DNA counterparts [65,66] and SARS-CoV-2 is a single-strand RNA virus, which may be conducive to its structure formation. Several emerging studies have demonstrated the formation of two-quartet G-quadruplexes in viral sequences, which could serve as antiviral elements under the presence of G-quadruplex ligands [53,67,68]. Moreover, the K + (potassium ion), one of the primary positive ions inside human cells, can strongly support the formation of G-quadruplexes.…”

Section: Discussionmentioning

confidence: 99%

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Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

Zhang

Xiao

et al. 2020

Preprint

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The Coronavirus Disease 2019 pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) quickly become a global public health emergency. Gquadruplex, one of the non-canonical secondary structures, has shown potential antiviral values. However, little is known about G-quadruplexes on the emerging SARS-CoV-2. Herein, we characterized the potential G-quadruplexes both in the positive and negative-sense viral stands. The identified potential G-quadruplexes exhibits similar features to the G-quadruplexes detected in the human transcriptome. Within some bat and pangolin related beta coronaviruses, the G-quartets rather than the loops are under heightened selective constraints. We also found that the SUD-like sequence is retained in the SARS-CoV-2 genome, while some other coronaviruses that can infect humans are depleted. Further analysis revealed that the SARS-CoV-2 SUD-like sequence is almost conserved among 16,466 SARS-CoV-2 samples. And the SARS-CoV-2 SUDcore-like dimer displayed similar electrostatic potential pattern to the SUD dimer. Considering the potential value of G-quadruplexes to serve as targets in antiviral strategy, we hope our fundamental research could provide new insights for the SARS-CoV-2 drug discovery. Respiratory Syndrome (MERS) in 2012 [2,5], and COVID-19. Scientists identified and sequenced the virus early in this outbreak, and named it SARS-CoV-2[6]. The symptoms of the patients infected with the novel coronavirus vary from person to person, and fever, cough, and fatigue are the most common ones[7-10]. The clinical chest CT (Computed tomography) and nucleic acid testing are the most typical methods of diagnosing 10]. It is worth noting that the recent achievements in AI (Artificial Intelligence) aid diagnosis technology[11] and CRISPR-Cas12-based detection methods [12] are expected to expand the diagnosis of COVID-19. Despite the great efforts of the researchers, so far, no specific clinical drugs or vaccines have been developed to cope with COVID-19. SARS-CoV-2 is a Betacoronavirus within the Coronaviridae family that is the culprit responsible for the COVID-19 pandemic [13,14] (Fig. 1A). Studies have confirmed that SARS-CoV-2 is a positive-sense single-stranded RNA ((+)ssRNA) virus with a total length of approximately 30k. The positive-sense RNA strand of SARS-CoV-2 can serve as a template to produce viral proteins related to replication, structure composition, and other functions or events [15,16]. One of the hotspots is how the SARS-CoV-2 entry the host cells. SARS-CoV-2 has shown a great affinity to the angiotensin-converting enzyme 2 (ACE2), which has been proved to be the binding receptor for SARS-CoV-2 [17,18]. After entering the host cells, the viral genomic RNA will be released to the cytoplasm, and the ORF1a/ORF1ab are subsequently translated into replicase polyproteins of pp1a/pp1ab, which will be cleaved into some non-structural proteins (nsps). These non-structure proteins ultimately form the replicase-transcriptase complex for replication and transcription....

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

Zhang

Xiao

et al. 2020

Preprint

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“…The G4 binders TMPyP4, ex-NDI 2, and BRACO-19 are reported to inhibit bacterial growth and virulence via a G4-mediated mechanism ( Perrone et al, 2017 ; Mishra et al, 2019a , b ). Conserved G-rich regions in the Zika virus ( Fleming et al, 2016 ), Herpes Simplex virus ( Artusi et al, 2015 ), Nipah ( Majee et al, 2020a ), Adenovirus ( Majee et al, 2020b ), and other viruses have also been shown to form G4 conformations and are proposed as anti-viral drug targets ( Ruggiero and Richter, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Conserved G-Quadruplex Motifs in Gene Promoter Region Reveals a Novel Therapeutic Approach to Target Multi-Drug Resistance Klebsiella pneumoniae

et al. 2020

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An opportunistic pathogen, Klebsiella pneumoniae is known to cause life-threating nosocomial infection with a high rate of morbidity and mortality. Evolutions of multi-drug-resistant and hyper-virulent strains of K. pneumoniae make the situation worse. Currently, there is no incisive drug molecule available for drug-resistant hyper-virulent K. pneumoniae infection that emphasizes the need for identification of novel and more promising drug targets in K. pneumoniae . Recently, various non-canonical structures of nucleic acids especially G-quadruplex (G4) motifs have been identified as potential therapeutic targets against several human pathogenic bacteria and viruses including Mycobacterium tuberculosis , Streptococcus pneumoniae , human immunodeficiency virus (HIV), Ebola, and Nipah. Therefore, in present study we screened the K. pneumoniae genomes for identification of evolutionary conserved G4 structure-forming motifs as promising anti-bacterial drug targets. Bioinformatics analysis revealed the presence of six highly conserved G4 motifs in the promoter region of five essential genes that play a critical role in nutrient transport and metabolism. Biophysical studies showed the formation of G4 structure by these conserved motifs. Circular Dichroism melting analysis showed the stabilization of these G4 motifs by a well-known G4-stabilizing agent, BRACO-19. The stabilization of these motifs by BRACO-19 was also able to stop the primer extension process, which is an essential phenomenon for expression of the G4-harboring gene. The addition of G4-specific ligand at low micromolar range was observed to be lethal for the growth of this bacteria and negatively controlled the expression of the G4-harboring genes via G4 structure stabilization. These observations strengthen the formation of G4 structures by the predicted G4 motif in vivo , which can be stabilized by G4 ligands like BRACO-19. This stabilization of G4 structures can attenuate the expression of G4-harboring essential genes and thus play a critical role in the regulation of gene expression. Thus, taking all given result in consideration, for the first time, this study showed the new therapeutic avenue for combating K. pneumoniae infection by characterizing the conserved G4 motifs as promising therapeutic targets.

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“…A recent analysis revealed the presence of GQ motifs in various genes of Klebsiella pneumoniae that influenced the gene expression (Shankar et al, 2020). Likewise, several human infecting viruses including Zika (Fleming et al, 2016), Nipah (Majee et al, 2020a), Herpes Simplex virus (Biswas et al, 2016), Human Papillomavirus (Tlučková et al, 2013), and Human Adenovirus (Majee et al, 2020b) are reported to possess potential GQ forming sequences. G-quadruplex sequences in the L gene of Ebola virus and the FIGURE 1 | G-quadruplex topologies and GQ in Vibrio cholerae reference genome.…”

Section: Introductionmentioning

confidence: 99%

Exploring Computational and Biophysical Tools to Study the Presence of G-Quadruplex Structures: A Promising Therapeutic Solution for Drug-Resistant Vibrio cholerae

et al. 2020

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Vibrio cholerae, a gram-negative bacterium that causes cholera, has already caused seven major pandemics across the world and infects roughly 1.3-4 million people every year. Cholera treatment primarily involves oral rehydration therapy supplemented with antibiotics. But recently, multidrug-resistant strains of V. cholerae have emerged. High genomic plasticity further enhances the pathogenesis of this human pathogen. Guanines in DNA or RNA assemble to form G-quadruplex (GQ) structures which have begun to be seen as potential drug targeting sites for different pathogenic bacteria and viruses. In this perspective, we carried out a genome-wide hunt in V. cholerae using a bio-informatics approach and observed ∼85 G-quadruplex forming motifs (VC-PGQs) in chromosome I and ∼45 putative G-quadruplexs (PGQs) in chromosome II. Ten putative G-quadruplex forming motifs (VC-PGQs) were selected on the basis of conservation throughout the genus and functional analysis displayed their location in the essential genes encoding bacterial proteins, for example, methyl-accepting chemotaxis protein, orotate phosphoribosyl transferase protein, amidase proteins, etc. The predicted VC-PGQs were validated using different bio-physical techniques, including Nuclear Magnetic Resonance spectroscopy, Circular Dichroism spectroscopy, and electrophoretic mobility shift assay, which demonstrated the formation of highly stable GQ structures in the bacteria. The interaction of these VC-PGQs with the known specific GQ ligand, TMPyP4, was analyzed using ITC and molecular dynamics studies that displayed the stabilization of the VC-PGQs by the GQ ligands and thus represents a potential therapeutic strategy against this enteric pathogen by inhibiting the PGQ harboring gene expression, thereby inhibiting the bacterial growth and virulence. In summary, this study reveals the presence of conserved GQ forming motifs in the V. cholerae genome that has the potential to be used to treat the multi-drug resistance problem of the notorious enteric pathogen.

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Identification and characterization of two conserved G-quadruplex forming motifs in the Nipah virus genome and their interaction with G-quadruplex specific ligands

Cited by 46 publications

References 59 publications

Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

Conserved G-Quadruplex Motifs in Gene Promoter Region Reveals a Novel Therapeutic Approach to Target Multi-Drug Resistance Klebsiella pneumoniae

Exploring Computational and Biophysical Tools to Study the Presence of G-Quadruplex Structures: A Promising Therapeutic Solution for Drug-Resistant Vibrio cholerae

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