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 .

15-Lipoxygenase-Mediated Lipid Peroxidation Regulates LRRK2 Kinase Activity.

Mutations in that increase its kinase activity are strongly linked to genetic forms of Parkinson's disease (PD). However, the regulation of endogenous wild-type (WT) LRRK2 kinase activity remains poorly understood, despite its frequent elevation in idiopathic PD (iPD) patients. Various stressors such as mitochondrial dysfunction, lysosomal dyshomeostasis, or vesicle trafficking deficits can activate WT LRRK2 kinase, but the specific molecular mechanisms are not fully understood.