Organocatalytic enantioselective construction of chiral spiro N , N -acetal carbon stereocenters and axially chiral 3-arylindoles has been achieved in one pot.

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA’s ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.

Activation of the NLRP3 inflammasome requires the expression of NLRP3, which is strictly regulated by its capacity to directly recognize microbial-derived substances. Even though the involvement of caspase-1 activation in macrophages via NLRP3 and NLRC4 has been discovered, the accurate mechanisms by which Shigella infection triggers NLRP3 activation remain inadequately understood. Here, we demonstrate that IpaH4.5, a Shigella T3SS effector, triggers inflammasome activation by regulating NLRP3 expression through the E3 ubiquitin ligase activity of IpaH4.5. First, we found that IpaH4.5 interacted with NLRP3. As a result, IpaH4.5 modulated NLRP3 protein stability and inflammasome activation. Bacteria lacking IpaH4.5 had dramatically reduced ability to induce pyroptosis. Our results identify a previously unrecognized target of IpaH4.5 in the regulation of inflammasome signaling and clarify the molecular basis for the cytosolic response to the T3SS effector.