Second‐Generation Non‐Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis

Migliore, Marco; Pontis, Silvia; Arriba, Ángel L. Fuentes de; Realini, Natalia; Armirotti, Andrea; Romeo, Elisa; Martino, Simona Di; Russo, Debora; Pizzirani, Daniela; Summa, Maria; Lanfranco, Massimiliano; Ottonello, Giuliana; Busquet, Perrine; Jung, Kwang-Mook; García-Guzmán, Miguel; Heim, Roger; Piomelli, Daniele

doi:10.1002/anie.201603746

Cited by 42 publications

(50 citation statements)

References 21 publications

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“…These include b-lactone, b-lactam, and isothiocyanate derivatives, which react covalently with the catalytic cysteine of NAAA (Alhouayek et al, 2015;Armirotti et al, 2012;Solorzano et al, 2009Solorzano et al, , 2010, and benzothiazole piperazine derivatives, which inhibit NAAA through a reversible noncovalent mechanism (Migliore et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The N-Acylethanolamine Acid Amidase Inhibitor ARN077 Suppresses Inflammation and Pruritus in a Mouse Model of Allergic Dermatitis

Sasso

Summa

Armirotti

et al. 2018

Journal of Investigative Dermatology

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N-acylethanolamine acid amidase (NAAA), a cysteine hydrolase highly expressed in macrophages and B lymphocytes, catalyzes the degradation of palmitoylethanolamide. Palmitoylethanolamide is an agonist of PPAR-α and an important regulator of pain and innate immunity. In this study, we investigated the properties of the NAAA inhibitor, ARN077, in a mouse model of allergic contact dermatitis. Acute topical applications of ARN077 attenuated key signs of DNFB-induced dermatitis in a dose-dependent manner. Moreover, ARN077 increased tissue palmitoylethanolamide content and normalized circulating levels of cytokines and immunoglobulin E. No such effect was seen in PPAR-α-deficient mice. Moreover, mice lacking NAAA failed to develop edema or scratching behavior after challenge with DNFB, confirming that this enzyme plays an important role in dermatitis. Consistent with this conclusion, subchronic applications of ARN077 suppressed DNFB-induced inflammation when administered either before or after the DNFB challenge. The effects of subchronic ARN077 were dose dependent and comparable in size to those produced by the steroids clobetasol and dexamethasone. Unlike the latter, however, ARN077 did not cause skin atrophy. The results identify NAAA as a promising target for the development of effective and safe treatments for atopic dermatitis and other inflammatory disorders of the skin.

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Section: Discussionmentioning

confidence: 99%

The N-Acylethanolamine Acid Amidase Inhibitor ARN077 Suppresses Inflammation and Pruritus in a Mouse Model of Allergic Dermatitis

Sasso

Summa

Armirotti

et al. 2018

Journal of Investigative Dermatology

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“…FAAH is widely distributed (11) although it is most abundant in the brain and liver (12), whereas NAAA is almost exclusively expressed in immune cells (13,14) such as monocytes and tissue macrophages (15,16) but is also found in prostate epithelium (13,17). In light of the analgesic and antiinflammatory actions of PEA, multiple NAAA inhibitors have been developed over the last decade (18,19) and shown to exhibit beneficial effects in a range of rodent models of human disease, including inflammation (20)(21)(22)(23)(24)(25), allergic contact dermatitis (26), spinal cord trauma (27), neuropathic pain (28,29), chronic pain (30), inflammatory bowel disease (31), lung inflammation (25,32), arthritis (14), and multiple sclerosis (33).…”

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confidence: 99%

“…These properties are mediated by the activity of the FAAH substrate anandamide on cannabinoid receptors (18). Whereas FAAH hydrolyzes long-chain polyunsaturated NAEs, including anandamide, more efficiently than short unsaturated ones such as PEA (34), NAAA demonstrates an opposite substrate preference in vivo (27,28,31,33) and in vitro (35,36), with PEA being its optimal substrate (15,37). Another major difference between the two enzymes, besides tissue distribution, is their intracellular localization: FAAH is found in the cytosol tethered to the outer face of mitochondria and the endoplasmic reticulum (38), whereas NAAA is localized to acidic organelles such as the lysosome (16,37,39).…”

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confidence: 99%

Molecular mechanism of activation of the immunoregulatory amidase NAAA

Gorelik

Gebai

Illés

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Palmitoylethanolamide is a bioactive lipid that strongly alleviates pain and inflammation in animal models and in humans. Its signaling activity is terminated through degradation by N-acylethanolamine acid amidase (NAAA), a cysteine hydrolase expressed at high levels in immune cells. Pharmacological inhibitors of NAAA activity exert profound analgesic and antiinflammatory effects in rodent models, pointing to this protein as a potential target for therapeutic drug discovery. To facilitate these efforts and to better understand the molecular mechanism of action of NAAA, we determined crystal structures of this enzyme in various activation states and in complex with several ligands, including both a covalent and a reversible inhibitor. Self-proteolysis exposes the otherwise buried active site of NAAA to allow catalysis. Formation of a stable substrate- or inhibitor-binding site appears to be conformationally coupled to the interaction of a pair of hydrophobic helices in the enzyme with lipid membranes, resulting in the creation of a linear hydrophobic cavity near the active site that accommodates the ligand’s acyl chain.

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“…Based on the structure of pyrrolidine derivatives, our research group identified a class of novel inhibitors with oxazolidone moiety, represented by F96 and F215, with nanomolar potency against NAAA (Yang et al, 2015;Li et al, 2017;Ren et al, 2017;Wu et al, 2019;Zhou et al, 2019). Migliore et al reported third-generation NAAA inhibitors based on a benzothiazole-piperazine scaffold that is stable in mouse plasma and liver microsomes (Migliore et al, 2016). Despite great efforts in the development of NAAA inhibitors, medicinal chemistry diversity has remained low.…”

Section: Discussionmentioning

confidence: 99%

Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation

Yang

et al. 2020

Front. Pharmacol.

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N-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that inhibits the degradation of palmitoylethanolamide (PEA), an endogenous lipid that induces analgesic, anti-inflammation, and anti-multiple sclerosis through PPARa activation. Only a few potent NAAA inhibitors have been reported to date, which is mainly due to the restricted substrate-binding site of NAAA. Here, we established a high-throughput fluorescence-based assay for NAAA inhibitor screening. Several new classes of NAAA inhibitors were discovered from a small library of natural products. One of these is atractylodin, a polyethylene alkyne compound from the root of Atractylodes lancea (Thunb) DC., which significantly inhibits NAAA activity and has an IC 50 of 2.81 µM. Kinetic analyses and dialysis assays suggested that atractylodin engages in competitive inhibition via reversible reaction to the enzyme. Docking assays revealed that atractylodin occupies the catalytic cavity of NAAA, where the atractylodin furan head group has a hydrophobic-related interaction with the backbone of the Trp181 and Leu152 residues of human NAAA. Further investigation indicated that atractylodin significantly increases PEA and OEA levels and dose-dependently inhibits LPS-induced nitrate, TNF-a, IL-1b, and IL-6 pro-inflammatory cytokine release in BV-2 microglia. Our results show that atractylodin elevates cellular PEA levels and inhibits microglial activation by inhibiting NAAA activity, which in turn could contribute to NAAA functional research.

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Second‐Generation Non‐Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis

Cited by 42 publications

References 21 publications

The N-Acylethanolamine Acid Amidase Inhibitor ARN077 Suppresses Inflammation and Pruritus in a Mouse Model of Allergic Dermatitis

The N-Acylethanolamine Acid Amidase Inhibitor ARN077 Suppresses Inflammation and Pruritus in a Mouse Model of Allergic Dermatitis

Molecular mechanism of activation of the immunoregulatory amidase NAAA

Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation

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