12 Posts

Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases
ABSTRACT: Pharmacologically inhibiting nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome activation results in potent therapeutic effects in a wide variety of preclinical inflammatory disease models. NLRP3 deubiquitination is essential for efficient NLRP3 inflammasome activity, but it remains unclear whether this process can be harnessed for therapeutic benefit. Here, we show that thiolutin (THL), an inhibitor of the JAB1/MPN/Mov34 (JAMM) domain–containing metalloprotease, blocks NLRP3 inflammasome activation by canonical, noncanonical, alternative, and transcription-independent pathways at nanomolar concentrations. In addition, THL potently inhibited the activation of multiple NLRP3 mutants linked with cryopyrin-associated periodic syndromes (CAPS). Treatment with THL alleviated NLRP3-related diseases in mouse models of lipopolysaccharide-induced sepsis, monosodium urate–induced peritonitis, experimental autoimmune encephalomyelitis, CAPS, and methionine-choline–deficient diet-induced nonalcoholic fatty liver disease. Mechanistic studies revealed that THL inhibits the BRCC3-containing isopeptidase complex (BRISC)–mediated NLRP3 deubiquitination and activation. In addition, we show that holomycin, a natural methyl derivative of THL, displays an even higher inhibitory activity against NLRP3 inflammasome than THL. Our study validates that posttranslational modification of NLRP3 can be pharmacologically targeted to…
Cooperative N-heterocyclic Carbene and Iridium Catalysis Enables Stereoselective and Regiodivergent [3 + 2] and [3 + 3] Annulation Reactions
ABSTRACT: A cooperative N-heterocyclic carbene (NHC)/iridium catalysis has been developed to achieve highly stereoselective and regiodivergent [3 + 2] and [3 + 3] annulation reactions of 2-indolyl allyl carbonates with enals. The use of the NHC catalyst has introduced switchable homoenolate and enolate intermediates from the common enal precursor via a simple adjustment of reaction conditions in a predictable manner. This protocol furnishes two types of biologically important products, pyrrolo[1,2-a]indoles and pyridine[1,2-a]indoles, with high diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). Notably, all four stereoisomers of these products with two vicinal stereocenters could be afforded through permutations of the enantiomers of the two chiral catalysts. Mechanistic investigations and further computational density functional theory calculations give an explanation of the origin of the regioselectivity. In addition, the NHC-enolate intermediate generated from formylcyclopropanes was also compatible in this cooperative catalytic system and thus the arsenal of optically pure pyrrolo[1,2-a]indole products was enriched. For detail:https://pubs.acs.org/doi/abs/10.1021/acscatal.1c00081