EBOV VP35

EBOV VP35 Full Name

Ebola Virus VP35 protein

EBOV VP35 Introduction

The Ebola virus VP35 protein is a multifunctional virulence factor that serves as the essential polymerase cofactor for the viral L protein and acts as one of the most potent interferon antagonists known among viral proteins. VP35 is a 340-amino-acid protein encoded by the VP35 gene of Ebola virus and is a critical component of the viral ribonucleoprotein (RNP) complex. Structurally, VP35 comprises an N-terminal oligomerization domain and a C-terminal interferon inhibitory domain (IID), also referred to as the dsRNA-binding domain. The N-terminal region mediates VP35 self-oligomerization, which is essential for its polymerase cofactor function, and also facilitates interactions with the viral L protein and nucleoprotein (NP). The C-terminal IID adopts a unique fold that contains a basic patch (first basic patch) responsible for binding double-stranded RNA (dsRNA) and a second basic patch involved in protein-protein interactions. VP35 is classified as a type I interferon (IFN) antagonist because of its ability to potently suppress IFN-α/β production, which is a cornerstone of the host innate antiviral response. The protein exists in both monomeric and oligomeric states within infected cells, with oligomerization being essential for its role in viral RNA synthesis. VP35 is highly conserved across Ebola virus species and across the broader Filoviridae family, underscoring its indispensable role in the viral life cycle and its importance as a potential therapeutic target.

Figure 1. Ebola virus VP35 perturbs type I interferon signaling to facilitate viral replication.

VP35 employs multiple complementary mechanisms to suppress the host innate immune response, making it a master regulator of immune evasion during Ebola virus infection. The primary mechanism involves sequestration of dsRNA, which is a critical pathogen-associated molecular pattern (PAMP) generated during viral replication. By binding dsRNA through its IID basic patch, VP35 prevents the activation of cytoplasmic RNA sensors such as RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated protein 5), which would otherwise initiate a signaling cascade leading to interferon regulatory factor 3 (IRF-3) and IRF-7 activation and subsequent type I IFN production. Additionally, VP35 directly interacts with and inhibits the activation of RIG-I by blocking its interaction with the adaptor protein MAVS (mitochondrial antiviral-signaling protein). Beyond RIG-I pathway suppression, VP35 has been shown to inhibit the activation of the IKKε and TBK-1 kinases, which phosphorylate IRF-3 and IRF-7, thereby blocking a critical downstream step in IFN induction. VP35 also functions as a dsRNA-binding protein that masks viral replication intermediates from recognition by protein kinase R (PKR) and 2'-5'-oligoadenylate synthetase (OAS), both of which are IFN-stimulated genes that restrict viral replication. In its polymerase cofactor role, VP35 directly interacts with the L protein to stimulate processive RNA synthesis and bridges the polymerase complex with NP-coated viral RNA templates. Structural studies have revealed that VP35 oligomerization creates a central channel that accommodates RNA, facilitating efficient polymerase-template engagement. The dual functionality of VP35 in both replication and immune evasion makes it arguably the most critical virulence determinant of Ebola virus.

The dual functions of VP35 in viral replication and immune suppression make it an exceptionally attractive target for therapeutic intervention against Ebola virus disease. Inhibiting VP35 could simultaneously block viral RNA synthesis and restore the host innate immune response, providing a synergistic antiviral effect. Several strategies for targeting VP35 have been explored, including small molecules designed to disrupt the VP35-IID dsRNA binding interaction, peptides that interfere with VP35 oligomerization, and compounds that block the VP35-L protein interaction interface. High-throughput screening and structure-based drug design campaigns have identified lead compounds that can inhibit VP35 dsRNA binding activity with micromolar potency, though optimization toward clinical candidates remains ongoing. The high-resolution crystal structures of the VP35 IID in complex with dsRNA have provided detailed mechanistic insights that guide rational inhibitor design. From a clinical perspective, VP35 mutants that have lost their interferon antagonist function are dramatically attenuated In Vivo, demonstrating that VP35-mediated immune evasion is essential for viral pathogenesis. This genetic evidence strongly supports the therapeutic potential of VP35 inhibitors. In animal models, viruses with VP35 mutations exhibit reduced replication kinetics and are cleared more efficiently, confirming that VP35 is required for virulence. Combination therapies pairing VP35 inhibitors with existing antiviral agents such as remdesivir or monoclonal antibodies could provide multi-modal suppression of EBOV and reduce the risk of resistance development. As the threat of Ebola outbreaks persists and given the limited therapeutic arsenal currently available, VP35-directed antiviral strategies represent a promising frontier in filovirus drug discovery.

Alternate Names for EBOV VP35

EBOV VP35; Ebola Virus VP35 protein; Ebola virus; EBOV; VP35

• 1. Leung DW et al. Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35. Nat Struct Mol Biol. 2010;17(2):165-172.
  2. Edwards MR et al. The Ebola virus VP35 protein inhibits activation of interferon beta by targeting multiple components of the RIG-I signaling pathway. J Virol. 2015;89(11):6007-6019.
  3. Brown CS et al. In silico designed small molecule inhibitors of Ebola virus VP35 interfere with dsRNA binding. Antiviral Res. 2020;182:104896.
  4. Luthra P et al. A high-throughput screen identifies small molecule inhibitors of the Ebola virus VP35 interferon antagonist. PLoS Pathog. 2018;14(9):e1007269.
  5. Cao et al. Ebola virus VP35 perturbs type I interferon signaling to facilitate viral replication. Virologica Sinica. 2023. doi: 10.1016/j.virs.2023.10.004