Enhancing the protein fitness of interferon-lambda through computational design and glyco-engineering for prophylactic nasal drugs against respiratory viruses

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Abstract Interferon-λ (IFN-λ), a type III interferon that selectively targets epithelial cells, holds strong potential as an intranasal antiviral due to its ability suppress respiratory virus replication without inducing systemic inflammation. However, clinical translation of human IFN-λ3 (hIFN-λ3) is hindered by limited thermostability, protease susceptibility, and rapid mucosal clearance. In this study, instability-prone elements in hIFN-λ3 are eliminated through artificial intelligence (AI)-based backbone remodeling targeted surface hydrophobic patch engineering. A protease-sensitive loop replaced with de novo α-helix, which shields neighboring patches forms new core, yielding engineered variant (hIFN-λ3-DE1) enhanced thermostability (Tm >90 °C), resistance, preserved activity structural integrity even after extended heat stress (two weeks at 50°C). Further glyco-engineering introduces N-linked glycan site distant from receptor-binding interfaces, improving solubility, production yield, diffusion synthetic nasal mucus. Intranasal administration the resulting (G-hIFN-λ3-DE1) enables effective penetration provides robust prophylactic protection against influenza infection vivo mouse model. These findings highlight versatile strategy combines AI-driven design develop scalable, bioavailable, functionally biologics for prophylaxis.

Language: Английский

---

Cell-intrinsic regulation of phagocyte function by interferon lambda during pulmonary viral, bacterial super-infection

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(8), P. e1012498 - e1012498

Published: Aug. 23, 2024

Influenza infections result in a significant number of severe illnesses annually, many which are complicated by secondary bacterial super-infection. Primary influenza infection has been shown to increase susceptibility methicillin-resistant Staphylococcus aureus (MRSA) altering the host immune response, leading immunopathology. Type III interferons (IFNs), or IFNλs, have gained traction as potential antiviral therapeutics due their restriction viral replication without damaging inflammation. The role IFNλ regulating epithelial biology super-infection recently established; however, impact on cells is less defined. In this study, we infected wild-type and IFNLR1 -/- mice with A/PR/8/34 followed S . USA300. We demonstrated that global enhanced clearance through increased uptake phagocytes, was be cell-intrinsic specifically myeloid mixed bone marrow chimeras. also showed depletion CX 3 CR1 expressing cells, but not neutrophils, sufficient significantly reduce burden compared intact IFNLR1. These findings provide insight into how an influenza-infected lung impedes during show direct cell intrinsic for signaling cells.

Language: Английский

---

Nanomedicines for Pulmonary Drug Delivery: Overcoming Barriers in the Treatment of Respiratory Infections and Lung Cancer

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(12), P. 1584 - 1584

Published: Dec. 11, 2024

The pulmonary route for drug administration has garnered a great deal of attention in therapeutics treating respiratory disorders. It allows the delivery drugs directly to lungs and, consequently, maintenance high concentrations at action site and reduction systemic adverse effects compared other routes, such as oral or intravenous. Nevertheless, is challenging, system tries eliminate inhaled particles, being main responsible mucociliary escalator. Nanomedicines represent primary strategy overcome limitations this they can be engineered prolong retention avoid their clearance while reducing distribution effects. This review analyses use pulmonary-administered nanomedicines treat infectious diseases affecting lung carcinoma, two pathologies that major health threats.

Language: Английский

---

Size-tailored and acid-degradable polyvinyl alcohol microgels for inhalation therapy of bacterial pneumonia

Journal of Materials Chemistry B, Journal Year: 2024, Volume and Issue: 12(37), P. 9325 - 9334

Published: Jan. 1, 2024

The schematic illustrates the pulmonary distribution of various sizes G@PIP upon inhalation, and degradation within microacidic lung environment to facilitate release PIP antibiotic for treating infections.

Language: Английский

---