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PHAL303 > Peptides > Flashcards

Peptides Flashcards

1
Q

Peptide

A

A compound consisting of two or amino acids linked in a chain, joined by covalent bonding of the amino region of one amino acid with the carboxyl region of another

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2
Q

Neuropeptides

A

Small peptide proteins (3-40AA) produced in and released from neurons

There are ~100 distinct neuropeptides, some of which arise from different processing of the same gene

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3
Q

Peptide families

A

Peptides are groups into families based on shared genetic code, which results in shared structures and release patterns

eg: calcitonin CGRP family

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4
Q

What are the three key concepts of this module?

A
  1. Mature peptides are derived from sequential processing events from a larger precursor peptide, creating substantial diversity from each gene
  2. neuropeptides are neuromodulators, not neurotransmitters
  3. Peptide-receptor systems can be targeted in many different ways for therapeutic benefit
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5
Q

Neuropeptide processing

A
  1. Pre-pro-peptide is inserted into the ER via signal sequence, which facilitates its own cleavage by signal peptidase
  2. Pro-peptides undergo endoproteolytic cleavage in vesicles, whereby junk sequences are removed by prohormone convertases. The cleavage sites are signalled by dibasic amino acid sequences (RR/RK/KK).
  3. Further processing of pro-peptides is accomplished via carboxypeptidases
  4. This may be aided by action of cathespin L or Arg/Lys aminopeptidase
  5. Post-translational modification may be required to achieve a C-terminal amide or a disulphide bond.. etc
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6
Q

Diversity from pro-peptides (3)

A
  1. Pro-peptides can contain multiple copies of a neuropeptide
  2. Pro-peptides can contain several different neuropeptides with different functions
  3. Pro-peptides undergo tissue specific processing, resulting in different mature neuropeptides produced in different tissues
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7
Q

how are neuropeptides packaged and released?

A

neuropeptides are packaged in large dense core vesicles, which are released in bolus

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8
Q

What characteristics of neuropeptides implicates their role as neuromodulators, rather than neuropeptides

A

Neuropeptides undergo volume transmission/dispersion whereby they can act at extra-synaptic receptors
- This is aided by a high receptor affinity, that allows action at diffuse concentrations
- Allows action both pre/post-synaptically
- No reuptake, instead slow degradation by proteases, which can create different bioactive peptides

Signalling occurs primarily through GPCRs, which are relatively slow acting comparative to ion channels

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9
Q

Example of a neuropeptide acting as a neuromodulator

A

NPY acts
- pre-synaptically on Y2R to reduce release of GABA and glutamate
- post-synaptically on Y1R to inhibit hypocretin/orexin cells

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10
Q

Four general ways of therapeutically targeting neuropeptides

A
  1. Biosynthetic pathway
  2. Release mechansm
  3. Peptide
  4. Receptor
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11
Q

List two ways of targeting a peptide post-release

A
  1. Monoclonal antibodies that bind released peptides, thus preventing them from activating receptors
  2. Inhibiting proteolytic degradation to increase intensity and duration of endogenous peptide release
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12
Q

List 4 ways of targeting neuropeptide receptors

A
  1. Small molecule agonist/antagonist
  2. Monoclonal antibody agonist/antagonist
  3. Synthetic/recombinant form of peptide to supplement endogenous activity
  4. Using a variant of the peptide that is protected from proteolytic breakdown by proteases, thus prolonging duration and intensity of effect
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13
Q

What is pain?

A

Pain is a protective subjective experience that facilitates response to injury. It can be described as acute or chronic. Overall there is an unmet clinical need for pain management.

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14
Q

List three types of pain

A
  1. Pain associated with tissue pathology (trauma, inflammation, tumour)
  2. Pain associated with nervous system pathology, aka neuropathic pain (diabetes)
  3. Musculo-skeletal pain
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15
Q

Type of nociceptive fibres

A

unmyelinated C fibres and myelinated A-delta fibres

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16
Q

Neural pathway for bodily pain

A
  • nociceptive input to nerve ending
  • signal travels up spinothalamic tract via the dorsal root ganglion
  • travels via spinal cord to higher brain centres
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17
Q

Neural pathway for face/head pain

A
  • nociceptive input to nerve ending
  • signal travels to cell body in trigeminal ganglion
  • travels via spinal nucleus of trigeminal nerve to higher brain centres
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18
Q

How can neuropeptides modulate pain?

A

Enhance nociceptive pathways
eg: capsaicin activates the TRPV1 receptor, causing release of CGRP on nerve fibres, which excites pain transmission neurons

Inhibit nociceptive pathways
eg: enkephalins inhibit pain transmission neurons

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19
Q

List 5 endogenous opioid peptides

A

b-endorphin
leu-enkaphalin
met-enkaphalin
dynorphin
nociceptin

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20
Q

Enkephalin processing

A

pro-enkephalin is cleaved by action of proenkephalin convertases guided by dibasic AA sequences
- This can give rise to leu or met enkaphalin depending on tissue specific processing

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21
Q

Why is measuring gene expression of pro-peptides not accurate?

A

Measuring expression of pro-peptides does not inform which mature peptides are acting in the system
- this only gets more complex due to cellular processing and post-release processing

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22
Q

µ-opioid receptor

A

most abundant opioid receptor in pain-related regions of the brain
- high affinity for b-endorphin and L/M-enkephalin

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23
Q

k-opioid receptor

A

has a preference for dynorphin1

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24
Q

NOP opioid receptor

A

selective for nociceptin

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25
Q

List 5 ways opioids can modulate nociception

A
  1. reduce sensitisation (reduce sensitivity to pain)
  2. modify gene expression
  3. reduce neurotransmitter release from noceptive neurons
  4. reduce excitability of spinal neurons (through decreasing cAMP)
  5. reduce nociception (by acting on K+/Ca2+ channels to dampen EPSPs)
26
Q

What are the downstream effects of opioid receptor activation

A
  • Gai reduces cAMP
  • Gby inhibits voltage-gated calcium channel opening and activates GIRKs

= reduced neurotransmitter release and membrane hyperpolarisation

27
Q

exogenous µ-opioid agonists

A

derived from p.somniferum: morphine, codeine
synthetic: fentanyl, tramadol, pethidine

28
Q

What is the opioid epidemic?

A

The increase in opioid related deaths in the U.S. occurring due to
- incentivised prescription of opioids
- inappropriate long-term prescription of opioids leading to addiction

29
Q

What is the future direction for targeting pain?

A

Biased ligands: Targeting G protein signalling of µ-opioid receptors and not arrestin signalling to obtain pain relief without euphoria and other side effects

Targeting delta/k-opioid receptors: These receptors are also analgesic and lack the side effect of euphoria and thus avoid physical dependence

30
Q

Side effects of µ-opioid agonism (3)

A
  • euphoria
  • respiratory depression
  • physical dependence
31
Q

RAMPs

A

receptor activity-modifying proteins
- chaperones; aid trafficking of receptors to the cell surface
- pharmacological switches; alter ligand selectivity
- signalling switch; alter downstream signalling
- trafficking switch; mediate trafficking of GPCRs away from the membrane and determine whether the receptor is recycled or degraded

32
Q

Class B GPCRs

A

peptide hormone receptors that can be agonised by
- glucagon, PACAP, calcitonin, CGRP, amylin, etc…

33
Q

What is migraine?

A

Migraine is a disabling primary headache disorder that can be classified into numerous subtypes with complex symptoms including:
- severe headache
- hypersensitivity to light, sound, smell, touch
- nausea/vomiting

34
Q

Clinical need for migraine therapy

A
  • Migraine can develop into a chronic condition that often affects individuals throughout their adult life
  • Is a leading cause of emergency department visits, which strains healthcare system
  • more common that diabetes, epilepsy, and asthma combined
  • lack of knowledge on mechanism means it is poorly treated
  • many do not seek treatment because of this
  • annual cost of 17 billion in US alone
35
Q

CGRP

A

a 37 AA peptide that is part of the calcitonin family
- all have a C-terminal for ligand affinity and a cysteine loop for receptor activation
- abundant in sensory neurons, and also found at NMJ

36
Q

Processing of CGRP

A

The CGRP gene (CALCA) undergoes tissue-specific mRNA processing, whereby alternative splicing of mRNA results in distinct pro-peptides depending on tissue (thyroid/neurons)
- CGRP
- Calcitonin

37
Q

CGRP receptor

A

An obligatory dimer of the class B GPCR calcitonin-like receptor (CLR) and RAMP1

38
Q

Downstream consequences of CGRP receptor activation

A
  • Gas increases cAMP production

Acts to modulate glutamate neurotransmission and increase neuronal excitability through cAMP

39
Q

Location of CGRP receptors

A

CGRP receptors are found at many anatomical location relevant to the processing of head pain
- Found on glutamate neurons and surrounding glia and pre-synaptic neurons

40
Q

What is the link between CGRP and migraine

A

In migraine the CGRP system is overactive
- peripheral and central sensitisation to CGRP, supporting by higher plasma CGRP in plasma/saliva of those with migraine
- CGRP infusion causes migraine attacks in those who suffer from migraine, but only mild headaches in others

41
Q

List three ways that the CGRP system can be targeted

A
  1. Small molecule antagonists of the CGRP receptor
  2. Antibody antagonists of the CGRP receptor
  3. Antibodies against CGRP that prevent receptor activation
42
Q

What are shortcoming in clinical trials targeting CGRP

A
  • high placebo response
  • variable responses to treatment across patients
  • low empirical data for females, despite migraine being 3x more prevalent in females
43
Q

PACAP and migraine

A

pituitary adenylate cyclase-activating polypeptide

  • High receptor expression at migraine relevant sites
  • Elevated plasma PACAP during migraine
  • PACAP infusion precipitates attack in those with migraine
44
Q

Issues with targeting PACAP

A
  • Pro-peptide processing gives rise to two forms of PACAP, although it is not known which form is associated with migraine
  • The PACAP receptor is complex, and exists in multiple forms
  • The specific role of PACAP in migraine is not understood, therefore effects and side effects cannot be predicted
45
Q

Diabetes

A

A chronic metabolic disorder characterised by high blood glucose that can be separated into two forms
- Type 1: insulin deficiency
- Type 2: insulin resistance

46
Q

Causes of type II diabetes

A
  • genetic predispositions
  • increase in sedentary life style combined with abundant poor quality, calorie-rich food
  • environmental obesogens
47
Q

Name three ways peptides can influence metabolic control

A
  1. Act as hormones, thus are secreted peripherally (eg: amylin)
  2. Act as classical neuropeptides
  3. Trigger effects via nodose ganglia/vagal nerve (eg:
48
Q

Nodose ganglia

A

Ganglia which receive input from the vagal nerve, which allows connection of peripheral information in nutrient status from stomach, intestine, and portal vein to the hindbrain

49
Q

Amylin

A

A 37 amino acid peptide that is co-secreted with insulin from pancreatic beta cells in response to food intake

Plays a complementary role to insulin in decreasing blood glucose and reducing food intake

50
Q

Area postrema

A

A circumventricular organ that allows peripheral agents to exert influence on the brain without crossing the BBB
- mediates food intake
- associated with nausea

51
Q

Peripheral amylin pathway

A

Secreted from beta cells of pancreas and acts on nodose ganglia to
- decrease food intake
- increase energy expenditure

52
Q

Orexigenic hormones

A

Hormones that act to enhance appetite
- ghrelin, orexin

53
Q

An-orexigenic hormones

A

Hormones that act to suppress food intake
- leptin, insulin, serotonin, MSH, GLP-1

54
Q

Describe the hypothalamic melanocortin system

A

There exist two key neuronal populations in the arcuate nucleus
- AGRP/NPY
- POMC/a-MSH

AGRP/NPY neurons are stimulated by an-orexigenic hormones, and act to inhibit the POMC/a-MSH neurons whilst inhibiting upstream PVN neurons via inverse agonism of MC4R
= HUNGER

POMC/a-MSH neurons are stimulated by orexigenic hormones and act to stimulate upstream PVN neurons via agonism of MC4R
= SATIETY

55
Q

a-MSH

A

a-melanocyte stimulating hormone is a neuropeptide derived from POMC which acts to suppress appetite through agonist action on MC4R

56
Q

POMC

A

pro-opiomelanocortin, a pro-peptide that can give rise to
- a-MSH
- b-MSH
- y-MSH
- ACTH

57
Q

MSH receptors

A

All coupled to Gs
- MC1/MC5 (a-MSH)
- MC2 (ACTH)
- MC3 (y-MSH)
- MC4 (b-MSH)

58
Q

AGRP

A

Agouti-related peptide that is produced in NPY neurons and opposes the action of MSH by acting as an inverse agonist at MC4R

59
Q

Clinical treatment of POMC deficiency

A

POMC deficiency is linked to severe obesity, as it results in an absence of a-MSH signalling and ACTH deficiency

Hydrocortisone mimics downstream action of ACTH, lacks full efficacy

Setmelanotide replaces a-MSH, reduces hunger and weight

60
Q

Therapeutic application of amylin for obesity

A

Amylin analogues are used (due to aggregating nature of human amylin) and are shown to be effective at controlling food intake and thus body weight

61
Q

Therapeutical application of Amylin and GLP-1

A

Cagrilinitide = amylin receptor agonist
+
Semaglutide = GLP-1 receptor agonist

Shows safety and efficacy of combined treatment for weight loss in a phase 1b trial

62
Q

delta opioid receptor

A

Has high affinity for b-endorphin and Leu/met-enkephalin

PHAL303 (10 decks)

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