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The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease., The NLR family protein NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors (1). Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a CARD [...]

A peptide contained in the venom of the predatory marine snail Conus tulipa, ρ-TIA, has previously been shown to possess α[sub 1]-adrenoreceptor antagonist activity. Here, we further characterize its pharmacological activity as well as its structure-activity relationships. In the isolated rat vas deferens, ρ-TIA inhibited α[sub 1]-adrenoreceptor-mediated increases in cytosolic Ca[sup 2+] concentration that were triggered by norepinephrine, but did not affect presynaptic α[sub 2]-adrenoreceptor-mediated responses. In radio-ligand binding assays using [[sup 125]I]HEAT, ρ-TIA displayed slightly greater potency at the α[sub 1B] than at the α[sub 1A] or α[sub 1D] subtypes. Moreover, although it did not affect the rate of association for [³H]prazosin binding to the α[sub 1B]adrenoreceptor, the dissociation rate was increased, indicating non-competitive antagonism by ρ-TIA. N-terminally truncated analogs of ρ-TIA were less active than the full-length peptide, with a large decline in activity observed upon removal of the fourth residue of ρ-TIA (Arg[sup 4]). An alanine walk of ρ-TIA confirmed the importance of Arg[sup 4] for activity and revealed a number of other residues clustered around Arg[sup 4] that contribute to the potency of ρ-TIA. The unique allosteric antagonism of ρ-TIA resulting from its interaction with receptor residues that constitute a binding site that is distinct from that of the classical competitive α[sub 1]-adrenoreceptor antagonists may allow the development of inhibitors that are highly subtype selective. [ABSTRACT FROM AUTHOR]