Aug 2026· International Journal of Biological Macromolecules· Vol 380, pp.
154111
· 0 citations
Medicine
TL;DR
Overall, iLYTAC converts non-neutralizing antibodies into functional degraders of viral proteins, enabling effective suppression of infection and providing a potential platform for broad-spectrum antiviral therapeutics.
Abstract
Targeted protein degradation (TPD) enables selective elimination of disease-related proteins, including viral proteins. Here, we evaluated the antiviral potential of an IGF2-fused lysosomal targeting chimera (iLYTAC) in ZIKV- and IAV-infected models. We first confirmed that iLYTAC efficiently mediates uptake of extracellular proteins via the IGF2-IGF2R pathway and traffics to lysosomes. In combination with anti-E-cadherin antibody, iLYTAC reduced E-cadherin levels by 2-fold, indicating functional lysosomal targeting. For antiviral application, iLYTAC combined with non-neutralizing anti-ZIKV E IgG significantly reduced viral titers (106.25 to 105.05 PFU/mL), decreased viral RNA and protein levels, and promoted lysosomal colocalization of E protein, which was abolished by lysosome inhibition. In ZIKV-infected mice, iLYTAC combined with anti-E IgG reduced viral loads across tissues and blood, alleviated organ pathology and inflammation. Similarly, in H1N1-infected A549 cells, iLYTAC with non-neutralizing anti-HA IgG reduced cytopathic effects and viral titers, while selectively degrading HA via lysosomes without affecting NP. Overall, iLYTAC converts non-neutralizing antibodies into functional degraders of viral proteins, enabling effective suppression of infection and providing a potential platform for broad-spectrum antiviral therapeutics.
The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated complement overactivation challenge current antiviral strategies that mainly target viral entry. This study aimed to develop dual targeting engineered binding proteins capable of simultaneously blocking viral infection and complement activation. Two proteins, SBP10 and SBP16, were engineered by integrating an ACE2-mimicking peptide with a mannose-binding lectin (MBL) domain. Binding affinity and antiviral activity were evaluated using biochemical and functional assays, including inhibition of S protein-ACE2 interaction, neutralization of multiple SARS-CoV-2 variants, and assessment of lectin pathway-mediated complement activation. Both SBP10 and SBP16 bound the spike protein with low-nanomolar affinity and effectively blocked its interaction with ACE2. The proteins exhibited broad-spectrum neutralizing activity against several variants, including Alpha, Beta, Delta, and Omicron. Moreover, they significantly suppressed spike-induced activation of the lectin complement pathway. In vivo experiments further demonstrated that treatment with SBP10 or SBP16 markedly reduced spike protein-induced lung injury. In conclusion, SBP10 and SBP16 function as dual targeting engineered binding proteins that inhibit viral entry while attenuating complement-mediated inflammation, highlighting a promising therapeutic strategy for controlling SARS-CoV-2 infection and its associated immune dysregulation.
Fan Pu, Yiwan Guo, Xinni Pan et al.· Antiviral Research· 0 citations
The findings demonstrate that the pSFV-driven Trim-Away system is a powerful tool for viral protein degradation and provides a significant advantage against rapidly mutating viruses.
These findings establish TROP2 as a robust LTR and provide a versatile eTPD platform with profound translational potential for tumor treatment, as well as design TRTAC-drug conjugates, enabling targeted protein degradation together with enhanced drug delivery.
This work pioneers the development of CA-targeted degraders, providing a framework for next-generation anti-HIV therapies with high potency and resistance barriers, via a proteasome-driven pathway.
Mei Wang, Ze-Yu Peng, Yang Zhou et al.· Journal of Medicinal Chemist...· 0 citations
These findings establish ALOX15 as an essential component of mitochondrial antiviral immunity and a promising host-directed target for antiviral therapy, identifying ALOX15 as a host-directed target for anti-influenza therapy.
Jing-yu Weng, Xin-xing Chen, Hui-er Ye et al.· Nature Immunology· 0 citations
Targeting the intrinsically disordered oncoprotein c-Myc remains challenging due to its lack of druggable pockets, hindering small-molecule inhibitor development for decades. Antibody-based strategies utilizing TRIM21-mediated targeted protein degradation (TPD), such as TRIM-Away, offer a promising alternative for endogenous c-Myc degradation but are limited by ineffective intracellular antibody delivery and uneven endogenous TRIM21 levels in various cancer cells. To overcome these, herein we disclose an acid-responsive nanoplatform using amorphous carbonated calcium phosphate nanoparticles (ACCP NPs) for effective intracellular co-delivery of TRIM21 and antibodies. Under mild biomimetic conditions, TRIM21-antibody complexes were effectively mineralized and encapsulated in the formed nanoparticles. Following endocytic uptake, these acid-sensitive ACCP NPs disassembled in endo/lysosomes, facilitating subsequent endo/lysosomal escape and cytosolic cargo release, leading to eventual intracellular TPD. In vitro, mineralized TRIM21-antibody complexes from ACCP NPs effectively degraded various intracellular targets, particularly c-Myc, across diverse cell types, including those that are TRIM21-deficient. Specifically, m-T21-c-Myc Ab nanoparticle degraded c-Myc via the ubiquitin-proteasome system and concurrently reduced MAX levels, synergistically inhibiting c-Myc transcriptional activity. In vivo, m-T21-c-Myc Ab significantly suppressed tumor growth without major organ toxicity. This work establishes ACCP NP-based TPD as a versatile and efficient platform for TRIM21/antibody-mediated degradation and a promising strategy for targeting other "undruggable" proteins.
L. Peng, Jiaoyu Chen, Xia Liu et al.· Angewandte Chemie· 0 citations
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