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PT4024 > L9 Targeting NLRP3 Inflammasome > Flashcards

L9 Targeting NLRP3 Inflammasome Flashcards

1
Q

__ tend to activate the inflammasome

A

DAMPs

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2
Q

The priming signal leads to…

A

increased transcription of NLRP3 gene (via NF-κβ activation)

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3
Q

Post-translational modifications that stabilise the inflammasome

A

Phosphorylation and ubiquitylation

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4
Q

NLRP3 inflammasome activation leads to release of which pro-inflammatory cytokines?

A

IL-1β and IL-18

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5
Q

NLRP3 contains an amino-terminal __ domain

A

pyrin

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6
Q

NLRP3 inflammasome components

A
  • sensor molecule (NLRP3)
  • adaptor molecule (ASC)
  • effector molecule (caspase 1)
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7
Q

NLRP3 NACHT domain contains __ activity

A

ATPase

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8
Q

ASC proteolytically cleaves __ , which cleaves pro-IL-1β and pro-IL-18

A

caspase 1

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9
Q

NLRP3 binds to __ to secure structure and recruit ASC

A

NEK7

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10
Q

Inflammatory cell death

A

pyroptosis

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11
Q

Rate-limiting step in activating the inflammasome

A

The amount of NLRP3 expressed (abundance of NLRP3 gene)

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12
Q

Predominant function of a secondary signal

A

Help recruit ASC component and ultimately cleave procaspase 1

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13
Q

Most abundance and best described secondary signal

A

Efflux of K⁺ out of primed cell to activate NLRP3 inflammasome

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14
Q

Caspase 1 also cleaves __ , which inserts into the membrane and forms pores.

A

Gasdermin D (GSDMD)

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15
Q

__ position in LRR domain inhibits activation of NLRP3

A

Y861

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16
Q

Phosphorylation at S295 in NACHT domain by __ inhibits NLRP3

A

PKA (while PKD activates NLRP3)

17
Q

__ at S198 in linker region between NACHT and pyrin domains inhibits NLRP3

A

Dephosphorylation

18
Q

Unifying factor of NLRP3 activators

A

they all induce cellular stress, which is then sensed by NLRP3

19
Q

Most common activating stimuli for NLRP3

A
  • Potassium efflux
  • Cathepsin release
  • Mitochondrial dysfunction
  • Metabolic changes
20
Q

Examples of second signals

A
  • K⁺ efflux and pore formation
  • Lysosomal disruption
  • Mitochondrial dysfunction
  • Metabolic changes e.g. SCFAs
21
Q

Saturated fatty acid, palmitate, __ NLRP3 priming

A

activates

22
Q

SCFAs, butyrate and propionate, __ NLRP3 priming

A

inhibit

23
Q

Example of a ketone body that inhibits NLRP3

A

β-hydroxybutyrate (BHB) (via inhibition of K⁺ efflux)

24
Q

What is CAPS?

A

Cryopryin-associated periodic syndromes (caused by gain-of function mutations in NLRP3 gene)

25
Q

Increased IL-18 found in patients with __

A

Crohn’s disease

26
Q

NLRP3-activating crystals in atherosclerosis

A

Cholesterol crystals

27
Q

NLRP3-activating crystals in gout

A

Monosodium urate crystals

28
Q

NLRP3-activating crystals in kidney dysfunction

A

Calcium oxalate crystals

29
Q

3 biologics that target the IL-1 signalling pathway

A
  • Anakinra (IL-1R antagonist)
  • Rilonacept (soluble decoy receptor that binds both IL-1β & IL-1α)
  • Canakinumab (IL-1β nAb)
30
Q

Advantage of Canakinumab over Anakinra

A

Longer half-life (26h vs 4-6h) - less frequent dosing

31
Q

Pharmacological agents that directly inhibit NLRP3 activation

A
  • MCC950
  • Glyburide
  • OLT1177 (Dapansutrile)
32
Q

What is Dapansutrile?

A
  • Orally active β-sulfonyl nitrile molecule that inhibits NLRP3 activation (upstream of ASC), which reduces caspase 1 activity & subsequent IL-1β release
  • Good safety profile in patients with gout but quite a high dose needed
33
Q

What is glyburide?

A
  • Potently inhibits NLRP3 activation (by blocking K⁺ efflux), but requires high doses
  • Commonly used to treat T2DM (associated hypoglycaemia)
34
Q

What is MCC950?

A
  • Diarylsulfonylurea small molecule compound – most potent and specific NLRP3 inhibitor
  • Binds NLRP3 and blocks its ability to hydrolyse ATP (causing instability)
  • Inhibits ATP-triggered, NLRP3-mediated IL-1β release in monocytes
35
Q

Main issue with MCC950

A

Hepatotoxicity

PT4024 (12 decks)

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