GS-441524

Remdesivir is a phosphoramide prodrug that works by releasing the monophosphate form of the nucleoside analog GS-441524 into lung cells. This monophosphate is then converted to the biologically active triphosphate metabolite 2-NTP. As a structural analog of ATP, 2-NTP effectively blocks viral RNA replication and transcription by inhibiting the RNA-dependent RNA polymerase activity of SARS-CoV-2.

Fig. 1 Metabolic pathways of remdesivir to the active 2-NTP metabolite in lungs. (Mackman RL, et al. 2023)

Infection with feline coronavirus (FCoV) can cause feline infectious peritonitis virus (FIPV), which is almost 100% fatal without treatment. GS-441524, an antiviral agent for the treatment of FIPV, is given orally twice daily or via daily subcutaneous injection for about 12 weeks. Although short treatment duration rules out problems with adherence, the high frequency of administration could induce handling stress in cats. Thus, a long-acting formulation with a single administration would be of clinical value. Polylactide-co-glycolide (PLGA) was used as a carrier, which was used to efficiently encapsulate GS-441524 with sustained-release capability and GS-441524-loaded PLGA nanoparticles (GS-PLGA NP) were prepared. Particle size of GS-PLGA NP was 216 nm, encapsulation efficiency was 78%, and 7-day release was 92%. When GS-PLGA NP was administered at 22 mg/kg in cats, higher systemic exposure can be expected than that by injecting GS-441524 at 4 mg/kg once a week (relative bioavailability, 152%). In addition to lower toxicity, GS-PLGA NP also showed improved cellular uptake and antiviral efficacy against FCoV compared to GS-441524 alone.

Fig. 2 The synthesis and the sustained-release of the GS-PLGA NP. (Jin M, et al. 2025)