Discovery of GS-7682, a Novel 4'-Cyano-Modified -Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine -nucleoside GS-646089 () with broad antiviral activity against RSV (EC = 3-46 nM), human metapneumovirus (EC = 210 nM), human rhinovirus (EC = 54-61 nM), and enterovirus (EC = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [()-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation and .

An adaptable soft-mold embossing process for fabricating optically-accessible, microfeature-based culture systems and application toward liver stage antimalarial compound testing.

Advanced cell culture methods for modeling organ-level structure have been demonstrated to replicate in vivo conditions more accurately than traditional in vitro cell culture. Given that the liver is particularly important to human health, several advanced culture methods have been developed to experiment with liver disease states, including infection with Plasmodium parasites, the causative agent of malaria. These models have demonstrated that intrahepatic parasites require functionally stable hepatocytes to thrive and robust characterization of the parasite populations' response to investigational therapies is dependent on high-content and high-resolution imaging (HC/RI).