Dapansutrile

Last updated
Dapansutrile
Dapansutrile-line.png
Names
Preferred IUPAC name
3-(Methanesulfonyl)propanenitrile
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.255.888 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 821-352-9
KEGG
PubChem CID
UNII
  • InChI=1S/C4H7NO2S/c1-8(6,7)4-2-3-5/h2,4H2,1H3
    Key: LQFRYKBDZNPJSW-UHFFFAOYSA-N
  • CS(=O)(=O)CCC#N
Properties
C4H7NO2S
Molar mass 133.17 g·mol−1
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H302, H315, H319, H335
P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 (nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3) inflammasome. [1]

Contents

Figure 1. NLRP3 protein domains and multiple NLRP3 form the NLRP3 Inflammasome. The NLRP3 protein is composed of three domains: NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), the apoptosis speck-like protein (ASC), and caspase-1. Image created in biorender.com. NLRP3 protein components and inflammasome (1).png
Figure 1. NLRP3 protein domains and multiple NLRP3 form the NLRP3 Inflammasome. The NLRP3 protein is composed of three domains: NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), the apoptosis speck-like protein (ASC), and caspase-1. Image created in biorender.com.

An inflammasome can be defined as an immune system receptor that induces inflammation through the activation of caspase 1 and caspase 11 when it is triggered by damaged cells, microbial pathogens, and stress. [3] NLRP3 is a canonical inflammasome. [3] The NLRP3 inflammasome comprises NLRP3, the apoptosis spec-like protein (ASC) and the caspase-1 [2] (Figure 1). The NLRP3 inflammasome forms by binding to pattern recognition receptors (PRRs) and damage associated molecular patterns (DAMPS) that activate caspase 1 which then signals for the secretion of pro-inflammatory cytokines IL-1β and IL-18 resulting in pyroptosis [3] [4] [5] Constant activation of the NLRP3 inflammasome is believed to play a direct or indirect role in acute arthritis, atherosclerosis and various neurodegenerative diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD) [6] , [2] ,. [7] This drug was developed by Olactec Therapeutics with the purpose of decreasing IL-1β peripheral inflammation by binding to the NLRP3 protein and inhibiting the formation of the NLRP3 inflammasome. Interestingly, dapansutrile has also been found to reduce levels of pro inflammatory cytokines IL-18 without interfering with TNF-α levels. [1] Stressed cells in the system can ignite the NLRP3 inflammasome which in turn produces the secretion inflammatory cytokines such as IL-1β and IL-18. Dapansutrile has tested in clinical trials and has been proposed as a beneficial compound for the remedy of osteoarthritis, and gouty arthritis. [1] Nevertheless, other preclinical research has proposed dapansutrile to be potentially beneficial for heart failure and multiple sclerosis. [1]

Molecular Structure and Properties

Dapansutrile is a β-sulfonyl nitrile compound with four carbon, seven hydrogen, one nitrogen, two oxygen, and one sulfur atom (Figure 2). [8] [9] The molecular formula of this compound is C4H7NO2S, and it carries a molecular weight of 133.7 g/mol. Compound acknowledged by the names of dapansutrile, OLT1177, and 3-(methylsulfonyl)propanenitrile. [8]

Figure 1. Molecular structure of dapansutrile Chemical Structure of OTL1177.png
Figure 1. Molecular structure of dapansutrile
Figure 2. Molecular Structure of Dapansutrile.
Dapansutrile (OLT1177)
Molecular Formula [8] C4H7NO2S
Molecular Weight [10] 133.7 g/mol
IUPAC Name [8] 3-(methylsulfonyl)propanenitrile
Olatec Therapeutics Name [8] OLT1177
International Non-Proprietary Name [8] Dapansutrile
StorageStore at -20 °C
CAS Number54863-37-5
PubChem ID12714644
SmilesC[S](=O)(=O)CCC#N
Experimental Solubility [11] Soluble to:

100 mM in DMSO

20 nM in ethanol

Formal Charge [11] 0
Hydrogen Bond Donor Count [11] 0
Hydrogen Bond Acceptor Count [11] 3
Rotatable Bond Count [11] 2
Topological Polar Surface Area [11] 66.3 Å2
Heavy Atom Count [11] 8
Isotope Atom Count [11] 3

Synthesis

OLT1177 is synthesized by alkylation of sodium methanesulfinate with 3-bromopropionitrile. This reaction produces crude methylsulfonylpropionitrile which is then purified through dissolution into acetone, filtration of the sodium bromide bi-product, solvent exchange via distillation, and recrystallization from ethanol. [9]

Dapansutrile's Mechanism of Action

Figure 3. Dapansutrile's Mechanism of Action. A. Depicts the activation and oligomerization of the NLRP3 inflammasome caused by PAMPS and DAMPS. B. When Dapansutrile is administered it binds to the NLRP3 protein and if DAMPS and PAMPS signals are present, Dapansutrile will inhibit NLRP3 inflammasome activation. This leads to an inhibition of the NLRP3 secretion of cytokines (IL-1b and IL-18) and caspase-1 mediated pyroptosis. Image created in biorender.com. Official Dapansutrile Mechanism of Action (2).jpg
Figure 3. Dapansutrile's Mechanism of Action. A. Depicts the activation and oligomerization of the NLRP3 inflammasome caused by PAMPS and DAMPS. B. When Dapansutrile is administered it binds to the NLRP3 protein and if DAMPS and PAMPS signals are present, Dapansutrile will inhibit NLRP3 inflammasome activation. This leads to an inhibition of the NLRP3 secretion of cytokines (IL-1β and IL-18) and caspase-1 mediated pyroptosis. Image created in biorender.com.

Dapansutrile's Reaction Pathways

Dapansutrile denoted as a β-sulfonyl nitrile molecule. Its mechanism of action induces a Pinner reaction which is initiated by reacting with thiols, alcohols and amines. Thus, leading to the formation of thiomidates, imidates and amidines respectively. [12] The nitrile group of OLT1177 is still not denoted as a covalent, noncovalent, irreversible or non-reversible inhibitor as there are currently no studies about its reactivity. [9] [12] Nevertheless, some researchers believe that dapansutrile promotes inhibition of NLRP3 through covalent bonds (Figure 4). [12]

Dapansutrile Mechanism of Action. A. Reaction pathway with sulphur. B. Reaction pathway with oxygen. C. Reaction pathway with nitrogen. Dapansutrile Mechanism of Action.png
Dapansutrile Mechanism of Action. A. Reaction pathway with sulphur. B. Reaction pathway with oxygen. C. Reaction pathway with nitrogen.
Figure 4. Reaction Pathways of Dapansutrile (OLT1177) [12] A. Reaction pathway of Dapansutrile with sulphur.B. Reaction pathway of Dapansutrile with oxygen. C. Reaction Pathway of Dapansutrile with nitrogen.

Summary Biological Effects of Dapansutrile

Reversible or Non-ReversibleNot Known
Primary Mechanism of ActionInhibits:
  • ATPase of NLRP3
  • NLRP3-ASC
  • NLRP3 caspase-1 interactions
  • NLRP3 assembly
SelectivitySelective to NLRP3 inflammasome
IL-1β inhibition % (μM)60% (0.0001–10 μM)
NLRP3 ATPase inhibition % (μM)60% (1 μM)
Pyroptosis Inhibition % (μM)25–40% (0.001–10 μM)
Other TargetsSrc; Fyn; HcK; STAT3; NF-κB
Cytotoxicity Tc50 ± SE (μM)Nontoxic in healthy volunteers (up to 1 gram a day for 8 days in oral form)
References [12] [9]

Pharmacokinetics

Selectivity

Dapansutrile targets the inhibition of the NLRP3 ATPase and thus blocks the activation of the inflammasome's ASC, and caspase-1 interaction; thereby preventing the assembly of the inflammasome and inflammatory signals such as IL-1β and IL-18. This drug also inhibits pyroptosis. Nevertheless, the drug does not impact the mRNA levels of the NLRP3, ASC, caspase-1, IL-1β, and IL-18 genes. [9]

Research of dapansutrile presents that the compound solely inhibits the NLRP3 inflammasome. Murine macrophages were used and stimulated with lipopolysaccharides and either flagellin or the dsDNA analog Poly(dA:dT) to activate inflammasomes such as NLRC4 and AIM 2 respectively. When Dapansutrile was added they found no difference in the release of TNF-α and IL-1β cytokines to when these inflammasomes were activated. [9]

Other Drug Targets

Other known targets of dapansutrile include several phosphorylated kinases such as Src; Fyn; HcK; STAT3. [12] Human monocyte derived macrophages (HMDM) cells were stimulated with lipopolysaccharide, and nigericin. Dapansutrile was then added and they found a 26%, 35%, 43% and 33% reduction of these phosphorylated kinases respectively. [9]

Dosages

In vitro: Human derived macrophages were cultured to study the effect of dapansutrile cytokine production. It was found that dapansutrile at a 1 μM dose inhibited secretion of IL-1β by 60%, and IL-18 levels by 70%. The drug was also found to selectively inhibit pyroptosis at 10 μM. [9]

In vivo: A phase one clinical trial of 35 subjects was conducted to establish the safety of dapansutrile. The daily mean plasma concentration maximum (Cmax) for a single oral dose of dapansutrile was 2,700 ng/mL for the 100-mg dose, 9,800 ng/mL for the 300 mg dose and 32,00 ng/mL for the 1,000 mg dose (Figure 5). [9] Dapansutrile was also studied if given repeatedly once per day for 8 days with a dose of either 100 mg, and 300 mg, or 1,000 mg. The subjects mean plasma concentration on day 8 were 4,800 ng/mL for the 100 mg dose, 15,800 ng/mL for the 300 mg dose and 41,400 ng/mL for the 1,000 mg dose. [9]

Figure 5. Plasma Concentration after a Single Oral Dose of OLT1177 versus Time. Plasma concentration for a single dose of OLT1177: 100 mg of OLT1177 (red), 300 mg (blue), 1,000 mg (green). Reposted with permission. Plasma Concentration after a Single Dose of OTL1177.png
Figure 5. Plasma Concentration after a Single Oral Dose of OLT1177 versus Time. Plasma concentration for a single dose of OLT1177: 100 mg of OLT1177 (red), 300 mg (blue), 1,000 mg (green). Reposted with permission.
Dapansutrile (OLT1177) Pharmacokinetics (PK) after Single Oral Dose [9]
Mean PK Characteristic (units)100 mg

N=5

300 mg

N=5

1000 mg

N=5

AUC0-t (h*ng/ml)76457.07324650.71918963.5
AUC0-24 (h*ng/ml)40121.19157378.19461809.56
Residual Area %0.710.741.12
Cmax (ng/ml)2,7009,80032,000
T1/2 el(h)23.0122.824.15
Kel (h)0.03090.03170.0307
Cl/F (L/h) i.e. oral clearance1.320.971.11
Vd/F (L)43.9531.8637.63
Dapansutrile (OLT1177) Pharmacokinetics (PK) after Multiple Oral Dose (8 days) [9]
Mean PK Characteristic (units)N100 mg

N=5

N300 mgN1000 mg
AUC0-τ (h*ng/ml)570288.753260409.2457231127.44
Cmax (ng/ml)54,800415,800541,400
Cmin(ng/ml)51,71046,820518,700
Cave(ng/ml)52,930310,900530,100
T1/2 el(h)516.01321.34524.72
Clss/F(L/h)51.4731.1751.49
Vd/F (L)535.22336.19548.56

Pharmacodynamics

Safety and Efficacy of Dapansutrile

In the Marchetti et al. study, seven of the 35 subjects reported adverse events. Five of the cases were in the single dose study while two cases were in the multi-regimen group. However, the adverse effects were considered unrelated to dapansutrile. [9] Subjects presented no changes in blood pressure (systolic and diastolic), urinalysis, heart rate, liver function enzymes or acute phase proteins in the cohort after an 8-day trial with up to daily 1,000 mg dosing of dapansutrile. [9]

Adverse Events [9]
Single Dose Administration of OLT1177Multidose Administration of OLT1177
DoseAdverse EventDoseAdverse Event
PlaceboHeadache100 mgDiarrhea
100 mgEczema100 mgHeadache
1000 mgMigraine
1000 mgBack pain

Potential Therapeutic Applications

Neurodegenerative diseases

Multiple Sclerosis:

Multiple sclerosis (MS) is a neurodegenerative disease characterized by the immune system deteriorating myelin. Myelin damage leads to the disruption of neuronal signaling, and dysregulrated inflammatory levels. [13] Dapansutrile was used in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model to understand its possible underlying effects for MS. It was found that mice fed with the dapansutrile diet protected the mice from demyelination in the spinal cord as well as decreased their levels of interleukins IL-1β and IL-18. [14] Currently, it is unclear whether the drug could inhibit microglial reactivity, but currently it has no known benefits to aid in the prevention of dementia and cognitive function. [1]

Inflammation

Gouty Arthritis:

Gouty arthritis is an inflammatory joint disorder, partly induced to the activation of the NLRP3 inflammasome and excess IL-1β activation which leads to gout attacks. [15] This is due to excess uric acid in the blood which promotes the formation of uric acid crystals in the joints. Uric acid is a known danger signal and induce the cleavage signal of the caspase-1 NLRP3 inflammasome. [16]

Animal Model Experiments: In 2018, two murine models were used to validate Dapansutrile as a drug beneficial for acute joint inflammation. They injected zymosan or monosodium urate crystals in order to induce gouty arthritis in mice. OLT1177 was then either injected intraperitoneally or through their diet. In essence, the drug reduced joint inflammation, as well as interleukin levels [6] demonstrating its therapeutic benefit for this disease.

Clinical Trials: As for clinical trials, Olatec Therapeutics also conducted a phase 2.a trials where Dapansutrile was given to 29 subjects with gouty arthritis. [1]

Cardiovascular Diseases

Acute Myocardial Infarction/ Heart Attack:

One of the major downstream effects of having coronary artery disease is possibility of having an acute myocardial infarction or heart attack. [2] In mouse models, Dapansutrile was found to decrease infarct size a dose-dependent manner. [2]

Heart Failure:

Olatec Therapeutics conducted a phase 1 clinical trial for Dapansutrile as a potential therapeutic for systolic heart failure. [17] They have carried out a Phase 1 double blinded study with a total of 30 subjects to assess the drug's safety and pharmacodynamics. The drug was given in capsule form and the subjects were divided into 3 cohorts. Each cohort had 8 subjects taking an oral capsule with 100 mg Dapansutrile while 2 subjects were given the placebo capsule. Although the completion date of this clinical trial was on November 21, 2019, the results of the study have not yet been published. [17]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) / COVID-19:

Dapansutrile has been proposed by a number of scientists as a measure to reduce cardiovascular outcomes that seem to be brought on by COVID-19. [18] The rationale behind using Dapansutrile is to inhibit the NLRP3 inflammasome and reduce the chances of a cytokine storm which seems to cause multi-organ failure in COVID-19 patients. [18] Subjects with COVID-19 have shown to have an increased concentration of pro-inflammatory cytokines resulting in the cytokine storm, and thus producing an exhaustion of lymphocytes. [19] NLRP3 not only activates cytokines but other key players that can inflict myocardial damages, and Acute Respiratory Distress Syndrome (ARDS), and its inhibition has been found to deter these outcomes. [18] [20] Thus, dapansutrile is proposed as a possible mediator to relief and prevent COVID-19 symptoms and effects.

Related Research Articles

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Itaconic acid</span> Chemical compound

Itaconic acid (also termed methylidenesuccinic acid and 2-methylidenebutanedioic acid) is a fatty acid containing five carbons (carbon notated as C), two of which are in carboxyl groups (notated as -CO2H) and two others which are double bonded together (i.e., C=C). (itaconic acid's chemical formula is C5H6O4, see adjacent figure and dicarboxylic acids). At the strongly acidic pH levels below 2, itaconic acid is electrically neutral because both of its carboxy residues are bound to hydrogen (notated as H); at the basic pH levels above 7, it is double negatively charged because both of its carboxy residues are not bound to H, i.e., CO2 (its chemical formula is C5H4O42-); and at acidic pH's between 2 and 7, it exists as a mixture with none, one, or both of its carboxy residues bound to hydrogen. In the cells and most fluids of living animals, which generally have pH levels above 7, itaconic acid exists almost exclusively in its double negatively charged form; this form of itaconic acid is termed itaconate. Itaconic acid and itaconate exist as cis and trans isomers (see cis–trans isomerism). Cis-itaconic acid and cis-itaconate isomers have two H's bound to one carbon and two residues (noted as R) bound to the other carbon in the double bound (i.e., H2C=CR2) whereas trans-itaconic acid and trans-itaconate have one H and one R residue bound to each carbon of the double bound. The adjacent figure shows the cis form of itaconic acid. Cis-aconitic acid spontaneously converts to its thermodynamically more stable (see chemical stability) isomer, trans-aconitic acid, at pH levels below 7. The medical literature commonly uses the terms itaconic acid and itaconate without identifying them as their cis isomers. This practice is used here, i.e., itaconic acid and itaconate refer to their cis isomers while the trans isomer of itaconate (which has been detected in fungi but not animals) is here termed trans-itaconate (trans-itaconic acid is not further mentioned here).

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

<span class="mw-page-title-main">NLRP3</span> Human protein and coding gene

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">NLRP12</span> Protein-coding gene in the species Homo sapiens

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.

<span class="mw-page-title-main">NOD-like receptor</span> Class of proteins

The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">Cryopyrin-associated periodic syndrome</span> Medical condition

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and keratoendotheliitis fugax hereditaria in which the autoinflammatory symptoms affect only the anterior segment of the eye.

<span class="mw-page-title-main">Pyrin domain</span>

A pyrin domain is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes.

<span class="mw-page-title-main">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

<span class="mw-page-title-main">GSDMD</span> Protein found in humans

Gasdermin D is a protein that in humans is encoded by the GSDMD gene on chromosome 8. It belongs to the gasdermin family which is conserved among vertebrates and comprises six members in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and DFNB59 (Pejvakin). Members of the gasdermin family are expressed in a variety of cell types including epithelial cells and immune cells. GSDMA, GSDMB, GSDMC, GSDMD and GSDME have been suggested to act as tumour suppressors.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

<span class="mw-page-title-main">Thirumala-Devi Kanneganti</span> Indian immunologist

Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

PANoptosis is a unique, innate immune, inflammatory, and lytic cell death pathway driven by caspases and RIPKs and regulated by multiprotein PANoptosome complexes. The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer. Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes, have been characterized so far.

References

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  7. ↑ Guan, Yadi; Han, Fang (2020). "Key Mechanisms and Potential Targets of the NLRP3 Inflammasome in Neurodegenerative Diseases". Frontiers in Integrative Neuroscience. 14: 37. doi: 10.3389/fnint.2020.00037 . ISSN   1662-5145. PMC   7393579 . PMID   32792920.
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  14. ↑ Sánchez-Fernández, Alba; Skouras, Damaris B.; Dinarello, Charles A.; López-Vales, Rubèn (2019). "OLT1177 (Dapansutrile), a Selective NLRP3 Inflammasome Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis Pathogenesis". Frontiers in Immunology. 10: 2578. doi: 10.3389/fimmu.2019.02578 . ISSN   1664-3224. PMC   6839275 . PMID   31736980.
  15. ↑ Ragab, Gaafar; Elshahaly, Mohsen; Bardin, Thomas (2017-09-01). "Gout: An old disease in new perspective – A review". Journal of Advanced Research. 8 (5): 495–511. doi:10.1016/j.jare.2017.04.008. ISSN   2090-1232. PMC   5512152 . PMID   28748116.
  16. ↑ Wen, Haitao; Ting, Jenny P.-Y.; O'Neill, Luke A. J. (April 2012). "A role for the NLRP3 inflammasome in metabolic diseases—did Warburg miss inflammation?". Nature Immunology. 13 (4): 352–357. doi:10.1038/ni.2228. ISSN   1529-2916. PMC   4090390 . PMID   22430788.
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  18. 1 2 3 "SARS-CoV-2 infection: NLRP3 inflammasome as plausible target to prevent cardiopulmonary complications?". European Review. 2020-09-14. Retrieved 2020-11-15.
  19. ↑ Tang, Yujun; Liu, Jiajia; Zhang, Dingyi; Xu, Zhenghao; Ji, Jinjun; Wen, Chengping (2020-07-10). "Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies". Frontiers in Immunology. 11: 1708. doi: 10.3389/fimmu.2020.01708 . ISSN   1664-3224. PMC   7365923 . PMID   32754163.
  20. ↑ Zahid, Ayesha; Li, Bofeng; Kombe, Arnaud John Kombe; Jin, Tengchuan; Tao, Jinhui (2019). "Pharmacological Inhibitors of the NLRP3 Inflammasome". Frontiers in Immunology. 10: 2538. doi: 10.3389/fimmu.2019.02538 . ISSN   1664-3224. PMC   6842943 . PMID   31749805.
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