Inhibiting the transcription and replication of Ebola viruses by disrupting the nucleoprotein and VP30 protein interaction with small molecules

Ma, Yanhong; Xu, Hong; Wu, Fang; Xu, Xinfeng; Li, Rui; Zhong, Jin; Zhou, Yaoqi; Liu, Shuwen; Zhan, Jian; Xü, Wei

doi:10.1038/s41401-023-01055-0

Cited by 6 publications

(4 citation statements)

References 56 publications

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“…Identification of antivirals against filoviruses typically included high-throughput screenings using relatively large libraries and complex molecules. ,− Due to their size, these compounds are potentially highly potent but are often unspecific binders and tend to have high off-target effects. In addition, they usually offer only reduced chemical diversity, making modification more challenging.…”

Section: Discussionmentioning

confidence: 99%

Development of a Crystallographic Screening to Identify Sudan Virus VP40 Ligands

Werner,

Krapoth,

Norris

et al. 2024

ACS Omega

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The matrix protein VP40 of the highly pathogenic Sudan virus (genus Orthoebolavirus) is a multifunctional protein responsible for the recruitment of viral nucleocapsids to the plasma membrane and the budding of infectious virions. In addition to its role in assembly, VP40 also downregulates viral genome replication and transcription. VP40's existence in various homooligomeric states is presumed to underpin its diverse functional capabilities during the viral life cycle. Given the absence of licensed therapeutics targeting the Sudan virus, our study focused on inhibiting VP40 dimers, the structural precursors to critical higher-order oligomers, as a novel antiviral strategy. We have established a crystallographic screening pipeline for the identification of smallmolecule fragments capable of binding to VP40. Dimeric VP40 of the Sudan virus was recombinantly expressed in bacteria, purified, crystallized, and soaked in a solution of 96 different preselected fragments. Salicylic acid was identified as a crystallographic hit with clear electron density in the pocket between the N-and the C-termini of the VP40 dimer. The binding interaction is predominantly coordinated by amino acid residues leucine 158 (L158) and arginine 214 (R214), which are key in stabilizing salicylic acid within the binding pocket. While salicylic acid displayed minimal impact on the functional aspects of VP40, we delved deeper into characterizing the druggability of the identified binding pocket. We analyzed the influence of residues L158 and R214 on the formation of virus-like particles and viral RNA synthesis. Site-directed mutagenesis of these residues to alanine markedly affected both VP40's budding activity and its effect on viral RNA synthesis, underscoring the potential of the salicylic acid binding pocket as a drug target. In summary, our findings lay the foundation for structure-guided drug design to provide lead compounds against Sudan virus VP40.

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Section: Discussionmentioning

confidence: 99%

Development of a Crystallographic Screening to Identify Sudan Virus VP40 Ligands

Werner,

Krapoth,

Norris

et al. 2024

ACS Omega

View full text Add to dashboard Cite

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“…Transcription is also dependent on the transcriptional initiation factor VP30 [ 29 , 35 ]. The transcription-activating function of VP30 depends on an RNA hairpin structure that is formed at the transcription start signal of the NP gene [ 23 , 27 , 64 , 65 ].…”

Section: Ebola Virus: From a Virology Point Of Viewmentioning

confidence: 99%

“…In addition, VP30 is speculated to promote L transcription reinitiation during the sequential transcription of all the EBOV genes and to regulate cotranscriptional GP gene editing since VP30 acts as a trans -acting factor to cis -acting sequences that regulate the cotranscriptional editing of the GP gene [ 23 , 65 ].…”

Section: Ebola Virus: From a Virology Point Of Viewmentioning

confidence: 99%

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Navigating the Complex Landscape of Ebola Infection Treatment: A Review of Emerging Pharmacological Approaches

Almeida-Pinto,

Pinto,

Rocha

2024

Infect Dis Ther

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In 1976 Ebola revealed itself to the world, marking the beginning of a series of localized outbreaks. However, it was the Ebola outbreak that began in 2013 that incited fear and anxiety around the globe. Since then, our comprehension of the virus has been steadily expanding. Ebola virus (EBOV), belonging to the Orthoebolavirus genus of the Filoviridae family, possesses a non-segmented, negative single-stranded RNA genome comprising seven genes that encode multiple proteins. These proteins collectively orchestrate the intricate process of infecting host cells. It is not possible to view each protein as monofunctional. Instead, they synergistically contribute to the pathogenicity of the virus. Understanding this multifaceted replication cycle is crucial for the development of effective antiviral strategies. Currently, two antibody-based therapeutics have received approval for treating Ebola virus disease (EVD). In 2022, the first evidence-based clinical practice guideline dedicated to specific therapies for EVD was published. Although notable progress has been made in recent years, deaths still occur. Consequently, there is an urgent need to enhance the therapeutic options available to improve the outcomes of the disease. Emerging therapeutics can target viral proteins as direct-acting antivirals or host factors as host-directed antivirals. They both have advantages and disadvantages. One way to bypass some disadvantages is to repurpose already approved drugs for non-EVD indications to treat EVD. This review offers detailed insight into the role of each viral protein in the replication cycle of the virus, as understanding how the virus interacts with host cells is critical to understanding how emerging therapeutics exert their activity. Using this knowledge, this review delves into the intricate mechanisms of action of current and emerging therapeutics.

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Structure‐based design of antibodies targeting the EBNA1 DNA‐binding domain to block Epstein–Barr virus latent infection and tumor growth

Han,

Wu,

Zhang

et al. 2024

MedComm

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The Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) is critically involved in maintaining episomes during latent infection and promoting tumorigenesis. The development of an epitope‐specific monoclonal antibody (mAb) for EBNA1 holds great promise due to its high affinity and specificity, offering a new and innovative approach for the treatment of EBV‐related diseases. In this proof‐of‐concept study, we employed a structure‐based design strategy to create three unique immunogens specifically targeting the DNA binding state of the EBNA1 DBD. By immunizing mice, we successfully generated a mAb, named 5E2‐12, which selectively targets the DNA binding interface of EBNA1. The 5E2‐12 mAb effectively disrupts the interaction between EBNA1 and DNA binding, resulting in reduced proliferation of EBV‐positive cells and inhibition of xenograft tumor growth in both cellular assays and mouse tumor models. These findings open up new avenues for the development of innovative biological macromolecular drugs that specifically target EBNA1 and provide potential for clinical therapy options for early‐stage EBV‐positive tumors. The epitope‐specific mAb approach demonstrates novelty and innovation in tackling EBV‐related diseases and may have broad implications for precision medicine strategies in the field of viral‐associated cancers.

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Inhibiting the transcription and replication of Ebola viruses by disrupting the nucleoprotein and VP30 protein interaction with small molecules

Cited by 6 publications

References 56 publications

Development of a Crystallographic Screening to Identify Sudan Virus VP40 Ligands

Development of a Crystallographic Screening to Identify Sudan Virus VP40 Ligands

Navigating the Complex Landscape of Ebola Infection Treatment: A Review of Emerging Pharmacological Approaches

Structure‐based design of antibodies targeting the EBNA1 DNA‐binding domain to block Epstein–Barr virus latent infection and tumor growth

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