Aug 2026· Virulence· Vol 17· 0 citations· 63 references
Medicine
TL;DR
These findings provide the first evidence that NP-targeted PROTAC degrader exhibits therapeutic effects, proposing a novel therapeutic strategy for IAV.
Abstract
ABSTRACT Influenza A virus (IAV) poses a serious threat to public health due to its high mutability and rapid transmissibility. The viral nucleoprotein (NP), a highly conserved and essential component, has emerged as an ideal target for antiviral therapies. However, its biological function has proven challenging to modulate with conventional drugs, and no NP-targeting therapeutics have reached the market so far. Here, we report the development and application of an aptamer-based proteolysis-targeting chimera (PROTAC) for the targeted degradation of IAV NP. Utilizing the Direct-to-Biology (D2B) platform, we efficiently screened and identified NP-PROTAC#4 as a functional candidate. Subsequently, we developed a lipid nanoparticle (LNP) formulation of NP‑PROTAC#4 (LNP@NP‑PROTAC#4) for effective intracellular delivery. Importantly, LNP@NP-PROTAC#4 demonstrated potent antiviral activity both in vitro and in vivo. Mechanistically, NP-PROTAC#4 exerts its antiviral effects by targeting and degrading NP via the ubiquitin-proteasome system. In conclusion, our findings provide the first evidence that NP-targeted PROTAC degrader exhibits therapeutic effects, proposing a novel therapeutic strategy for IAV.
ABSTRACT Influenza viruses continue to pose a significant threat to human and animal health. However, the limited number of licensed antivirals is increasingly compromised by drug resistance driven by high mutation rates. This highlights the urgent need for broad-spectrum therapeutics with novel mechanisms of action. Nanobodies, a new generation of antibody drugs, have great potential in the treatment of influenza virus infections. Neuraminidase (NA) mediates the sialic acid cleavage required for viral release, and its genetic drift is generally slower than that of hemagglutinin (HA) in influenza viruses, making it an attractive target for broad-spectrum antiviral and vaccine development. To construct a phage display nanobody library targeting NA, an alpaca was immunized with the NA protein of the H9N2 influenza virus. A specific nanobody, designated F4, was subsequently screened from the immune library. The nanobody was engineered into an Fc-fused nanobody, F4-Fc, which exhibited inhibitory activity against multiple influenza A and B viruses in vitro and provided robust prophylactic and therapeutic protection against influenza A and influenza B virus infections in vivo. Mechanistically, F4-Fc inhibits NA enzymatic activity and mediates antibody-dependent cellular cytotoxicity. In conclusion, F4-Fc demonstrates prophylactic and therapeutic efficacy against influenza A and B viruses, representing a promising antiviral drug candidate for influenza virus infection. IMPORTANCE Influenza viruses seriously threaten human and animal health, and drugs are crucial for controlling influenza outbreaks. However, the limited variety of existing anti-influenza virus medicines and the high mutation rate of the virus have led to the continuous emergence of drug-resistant strains. Neuraminidase (NA) is a critical surface glycoprotein that exhibits slower antigenic drift than hemagglutinin (HA), making it an attractive target for cross-protective antiviral development. However, broadly active NA-targeting nanobodies, particularly those effective against both influenza A and B viruses, remain limited. Here, we constructed an Fc-fused F4 nanobody (F4-Fc) targeting neuraminidases from multiple influenza A and B viruses and demonstrated its antiviral efficacy in vitro and protective activity in vivo, highlighting its potential as a promising strategy for the prevention and treatment of influenza virus infection. Influenza viruses seriously threaten human and animal health, and drugs are crucial for controlling influenza outbreaks. However, the limited variety of existing anti-influenza virus medicines and the high mutation rate of the virus have led to the continuous emergence of drug-resistant strains. Neuraminidase (NA) is a critical surface glycoprotein that exhibits slower antigenic drift than hemagglutinin (HA), making it an attractive target for cross-protective antiviral development. However, broadly active NA-targeting nanobodies, particularly those effective against both influenza A and B viruses, remain limited. Here, we constructed an Fc-fused F4 nanobody (F4-Fc) targeting neuraminidases from multiple influenza A and B viruses and demonstrated its antiviral efficacy in vitro and protective activity in vivo, highlighting its potential as a promising strategy for the prevention and treatment of influenza virus infection.
Dong-Lan Liu, Yuxuan Zhang, Min Zhang et al.· Journal of Virology· 0 citations
Influenza, an acute respiratory infectious disease caused by influenza viruses, poses a serious public health threat with high infectivity and virulence. Existing antivirals suffer from numerous limitations, such as the frequent emergence of drug resistance and inconvenient administration, highlighting the urgent need for the development of next-generation anti-influenza agents. As a core component of the RNA-dependent RNA polymerase (RdRp) complex, the PB2 subunit mediates cap binding in the cap-snatching process, a prerequisite for viral mRNA transcription. Owing to its indispensable biological roles, high sequence conservation, and distinct structural differences from host proteins, PB2 serves as an attractive therapeutic target for antiviral drug development. Recently, the approval of onradivir, the first-in-class PB2 inhibitor, has not only validated the scientific rationale and feasibility of drug discovery targeting the PB2 subunit but also underscored the considerable clinical potential of this novel class of agents. In this review, we systematically summarize the research advances in PB2 inhibitors and discuss the challenges and prospects for their broader clinical application, with the aim of providing new insights into the development of novel anti-influenza drugs.
Xinru Zhang, Heng Jia, Xianglong Wang et al.· ACS Infectious Diseases· 0 citations
Abstract The persistent threat of influenza pandemics and seasonal outbreaks, coupled with rising resistance to existing antiviral drugs targeting influenza viruses, necessitates the development of new therapeutics. This study investigated the antiviral potential of cell-penetrating peptide–conjugated host nucleolin (NCL)-binding peptide drugs, AGM-380d (dimeric) and AGM-380t (tetrameric), as innovative, broad-spectrum host-directed anti-influenza therapies. Infection with both influenza A and B viruses (IAVs and IBVs) significantly increased NCL expression and colocalization with viral nucleoprotein (NP), a core component of viral ribonucleoprotein complexes, in both in vitro and in vivo settings. The peptide drugs rapidly localized to the nucleolus and specifically bound to NCL. This targeted binding successfully disrupted the interaction between NCL and the NP of IAV and IBV, effectively blocking nuclear NP trafficking and inhibiting the replication of both pandemic and seasonal strains. Importantly, AGM-380d and AGM-380t protected mice from lethal IAV challenge by markedly reducing lung viral replication and pathology. The combination of AGM-380t with oseltamivir resulted in 100% protection from mortality following the deadly IAV challenge. In conclusion, AGM-380d and AGM-380t are highly promising as novel, broad-spectrum host-directed antivirals for the management of seasonal and pandemic influenza.
Thu Ha Nguyen, Muhammad Sharif, Jae-hyun Kim et al.· PNAS Nexus· 0 citations
Influenza pandemics have had devastating impacts in the 20th and 21st centuries, resulting in millions of deaths. It is challenging to control the influenza virus through antiviral drugs due to its rapid evolution to evade the host immune system. The 3D8 single chain variable fragment (scFv) protein, known for its nuclease activity against DNA and RNA viruses, has demonstrated broad antiviral properties in various models. In this study, we investigated the impact of administration routes and dosages on the distribution of exogenously administered 3D8 scFv. Our results suggested that repeated intranasal (IN) injection primarily targets lung tissue, while intravenous (IV) administration ensures systemic distribution, including lung tissues via the bloodstream. Furthermore, we explored the efficacy of exogenous and endogenous 3D8 scFv in inhibiting influenza A virus (H1N1/PR8) replication in mouse models. Our findings revealed that while both approaches exhibited antiviral activity, with constitutive pre-infection expression of 3D8 scFv showed 100% survival, whereas mice receiving exogenous 3D8 scFv post-infection exhibited 33.3% survival. These findings highlight the potential of 3D8 scFv as a promising antiviral strategy against influenza and suggest its possible applications in transgenic livestock for future disease control.
Quynh Xuan Thi Luong, Yongjun Lee, Cheng-Min Lin et al.· International Journal of Mol...· 0 citations
It is demonstrated that nanobodies targeting the PLpro/ISG15 interface can achieve synergistic antiviral and immunomodulatory effects, providing a proof-of-concept for a novel therapeutic approach to combat SARS-CoV-2 and potentially other emerging coronaviruses.
Guo-Long Liu, Jian-Tao Chen, Fang Wu et al.· Journal of Virology· 0 citations
Dengue virus (DENV), a mosquito-borne pathogen belonging to the Flaviviridae family, continues to be a major global public health concern, causing millions of infections annually across tropical and subtropical regions. The virus encodes both structural and non-structural proteins that play critical roles in its replication, assembly, and immune evasion. Despite substantial research progress, there is still no specific antiviral drug available, and current treatment remains primarily supportive. This review highlights the significance of DENV structural proteins (C, prM/M, and E) and non-structural proteins (NS1–NS5) as potential molecular targets for antiviral interventions. Green-synthesized silver, gold, and iron oxide nanoparticles have demonstrated strong inhibitory activity against DENV by targeting key viral proteins such as the envelope (E), NS3 protease/helicase, and NS5 RNA-dependent RNA polymerase. These nanoparticles interfere with viral entry, replication, and protein synthesis while exhibiting high biocompatibility and minimal cytotoxicity. Collectively, the findings discussed in this review underscore the promise of eco-friendly nanotechnology as a sustainable and effective platform for developing next-generation antiviral therapies against dengue virus.
D. M. Kumar, R. Bharath, P. Venkataraman et al.· Viruses· 0 citations
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