ASP5286 is an analog of the natural product cyclosporin A that maintains the anti-HCV activity of cyclosporin A by binding to cyclophilin, but was optimized to be less immunosuppresive than cyclosporin A. The macrocycle was identified through semisynthetic derivitization of a related natural product, FR901459. The Astellas team was able to [...]

AL-611 is a prodrug to a nucleoside inhibitor of HCV NS5B polymerase. While there have been very successful nucleoside drugs (e.g. sofosbuvir), several nucleoside inhibitors of HCV previously failed in the clinic due to severe toxicities, in some cases due to incorporation of the nucleosides into host RNA. The Janssen Biopharma (formerly [...]

Despite the remarkable emergence of HAART in the 1990s, the fight against HIV infection is by no means finished. At the ACS Fall 2024 meeting in Denver, CO, Gilead Sciences presented the structure and discovery story of elunonavir (GS-1156), a novel HIV protease inhibitor with remarkable metabolic stability and a human half-life exceeding two weeks. Based on BMS’ atazanavir, the compound incorporates structural elements inspired by Gilead’s HCV NS5A inhibitor program which led to ledipasvir, as “stabilizer” motifs to avoid the extensive CYP metabolism seen in current inhibitors.

CDI (Clostridioides difficile) infection is a leading cause of healthcare-associated diarrhea with significant morbidity and mortality, and with the rise of hypervirulent and resistant strains, novel and selective antibiotics to treat these infections are needed. Cadazolid, a hybrid antibiotic that combines pharmacophores of two classes of antibacterials, demonstrated potent activity in vitro against relevant C. difficile strains, while avoiding native gut flora. Additionally, the compound was designed to be gut-restricted, with minimal systemic circulation following PO dosing.

ETX0282 is an oral prodrug of a class A, C, and D serine β-lactamase inhibitor in clinical development for drug-resistant enterobacterial infections in combination with the beta-lactam drug cefpodoxime proxetil. Impressively ETX0282 had no observed adverse effect levels (NOAELs) of 500 mg/kg/day and 400 mg/kg/day in rat and dog, respectively, [...]