Cutillas, V. | bioRxiv Science

bioRxiv2025

Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 M). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated [~]24 hours post-infection significantly reduced log10 viral RNA copies/mLxday area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

microbiology↗

bioRxiv2023

Discovery and engineering of hypercompact epigenetic modulators for durable gene activation

Programmable epigenetic modulators provide a powerful toolkit for controlling gene expression in novel therapeutic applications, but recent discovery efforts have primarily selected for potency of effect rather than contextual robustness or durability thereof. Current CRISPR-based tools are further limited by large cargo sizes that impede clinical delivery and, in gene activation contexts, by brief activity windows that preclude transient, single-dose strategies such as lipid nanoparticle (LNP) delivery. To address these limitations, we perform high-throughput screening to discover novel classes of transcriptional modulators derived from thousands of human, viral, and archaeal proteomes. We identify high-potency activators capable of mitotically stable gene activation in a multitude of cellular contexts and leverage machine learning models to rationally engineer variants with improved activities. In liver and T-cells, novel hypercompact activators (64 to 98 amino acids) derived from vIRF2 core domain (vCD) achieve superior potency and durable activation lasting weeks beyond the current large activators ([~]five-fold larger). In a humanized mouse model, we target a human hypercholesterolemia susceptibility gene and achieve activation persisting five weeks after a single dose by LNP delivery. Our discovery pipeline provides a predictive rubric for the development of contextually robust, potent, and persistent activators of compact size, broadly advancing the therapeutic potential of epigenetic gene activation.

synthetic biology↗