Environmentally Triggerable Retinoic Acid-Inducible Gene I Agonists Using Synthetic Polymer Overhangs
Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern recognition receptor (PRR) that potently activates antiviral innate immunity upon recognition of 5′ triphosphorylated double-stranded RNA (pppRNA). Accordingly, RNA ligands of the RIG-I pathway have recently emerged as promising antiviral agents, vaccine adjuvants, and cancer immunotherapeutics. However, RIG-I is expressed constitutively in virtually all cell types, and therefore administration of RIG-I agonists causes risk for systemic inflammation and possible dose-limiting toxicities. Here, we establish proof-of-concept and initial design criteria for pppRNA prodrugs capable of activating the RIG-I pathway in response to specific environmental stimuli. We show that covalent conjugation of poly(ethylene glycol) (PEG) to the 3′ end of the complementary strand, i.e., on the same side but opposite strand as the 5′ triphosphate group, can generate a synthetic overhang that prevents RIG-I activation. Additionally, conjugation of PEG through a clea...
Christian R. Palmer; Max E. Jacobson; Olga Fedorova; Anna M. Pyle; John T. Wilson
We recently generalized the formerly alignment-dependent multivariate image analysis applied to quantitative structure–activity relationships (MIA-QSAR) method through the application of the discrete Fourier transform (DFT), allowing for its application to noncongruent and structurally dive ... mehr
Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is ... mehr
This review focuses on the type A cytochrome c oxidases (CcO), which are found in all mitochondria and also in several aerobic bacteria. CcO catalyzes the respiratory reduction of dioxygen (O2) to water by an intriguing mechanism, the details of which are fairly well understood today as a r ... mehr