Selective Voltage-Gated Sodium Channel Peptide Toxins from Animal

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Selective voltage-gated sodium channel peptide toxins from animal venom: pharmacological probes and analgesic drug development Ying Wu, Hui Ma, Fan Zhang, Chun-Lei Zhang, Xiaohan Zou, and Zhengyu Cao ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00406 • Publication Date (Web): 21 Nov 2017 Downloaded from http://pubs.acs.org on November 24, 2017

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ACS Chemical Neuroscience

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Selective voltage-gated sodium channel peptide toxins from animal

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venom: pharmacological probes and analgesic drug development

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Ying Wu1, Hui Ma1, Fan Zhang, Chunlei Zhang, Xiaohan Zou, and Zhengyu Cao

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Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational

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Development, China Pharmaceutical University, Nanjing 211198, China

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1

Equally contributed

Corresponding author:

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E-mail addresses: [email protected] (F. Zhang), [email protected]

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(Z. Cao); Tel.: +86-25-8618-5955 (F.Z. & Z.C.)

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Abstract:

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Voltage-gated sodium channels (Navs) play critical roles in action potential generation

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and propagation. Nav channelopathy as well as pathological sensitization contribute

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to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles

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of Nav subtypes (Nav1.3, 1.7, 1.8 and 1.9) in nociceptive transduction and therefore

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these Navs may represent attractive targets for analgesic drug discovery. Animal

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toxins are structurally diverse peptides that are highly potent yet selective on ion

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channel subtypes and therefore representing valuable probes to elucidate the

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structures, gating properties and cellular functions of ion channels. In this review, we

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summarized recent advance of peptide toxins from animal venom that selectively

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target Nav1.3, 1.7, 1.8, and 1.9, along with their potentials in analgesic drug

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discovery.

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Keywords: voltage-gated sodium channels; pain; animal toxins; peptide therapeutic

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1. Voltage-gated sodium channel structure and function

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2. Navs involved in pain

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3. Animal toxins targeting Nav subtypes associated with pain

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3.1 Nav1.3 and animal toxins

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4. Prospects of animal toxins in analgesic drug discovery

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Abbreviations:

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AP

Action potential

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CIP

Congenital indifference to pain

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CNS

Central nervous system

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DRG

Dorsal root ganglion

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GEFS+ Genetic epilepsy with febrile seizures plus

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IEM

Inherited erythromelalgia

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Na+

Sodium ion

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Navs

Voltage-gated sodium channels

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PEPD

Paroxysmal extreme pain disorder

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PNS

Peripheral nervous system

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SFN

Small fiber neuralgia

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SNI

spinal nerve injury

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STX

Saxitoxin

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TTX

Tetrodotoxin

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TTX-R TTX-resistant

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TTX-S TTX-sensitive

56 57 58 59 2


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1. Voltage-gated sodium channel structure and function

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Voltage-gated sodium channels (Navs) are transmembrane proteins that conduct

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sodium ion (Na+) into cytosol upon activation. Navs play a central role for action

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potential (AP) generation and propagation in excitable cells, including cardiac

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myocytes, skeletal muscle cells, and neurons.1,2 Navs are also marginally expressed in

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non-excitable cells, involved in noncanonical roles in regulating multiple

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pathophysiological functions.1,3

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An Nav comprises a highly sequence-conserved α-subunit (220-260 kDa) and

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one or two auxiliary β-subunits (30-40 kDa).4,5 The Nav α-subunit consists of four

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homologous domains (DI-DIV), each containing six transmembrane α-helixes (S1-S6)

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and a short membrane reentry loop between S5 and S6. The α-subunit comprises

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multiple domains, which are involved in pore-forming, voltage-sensing and Na+

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selectivity.6 The S4 transmembrane segment in each domain contains four to seven

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positively charged tri-amino acid repeats, in each of which an arginine or lysine is

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commonly followed by two hydrophobic amino acids. This positively charged motif

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in the S4 segment serves as the voltage sensor that moves outward to the extracellular

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part in a sliding-helix model upon depolarization.7 The movement of the S4 results in

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conformational change of the channel to an open state.6,7 Three hydrophobic amino

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acid residues, IFM, situated between transmembrane DIII-S6 and DIV-S1 form the

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inactivation gate which quickly plugs into the pore and prevents additional Na+

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influx.8,9 Four amino acids, DEKA, located between S5 and S6 form the selectivity

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filter for Na+ ions.9

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A variety of toxins have been found to target Navs. Combined with radioligand

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binding, electrophysiological approach and site-directed mutagenesis, at least seven

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distinct neurotoxin binding sites have been recognized in the Nav α-subunit (Table

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1).10 According to their electrophysiological properties and binding sites, generally,

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Nav toxins can be classified into three groups: (1) pore-blocking toxins which block

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Na+ conductance by interacting with neurotoxin site 1, including tetrodotoxin (TTX),

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µ-conotoxins, and saxitoxin (STX); (2) toxins negatively shift the activation voltage

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and produce a persistent activation by binding to membrane-embedded neurotoxin site 3



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2 (such as veratridine, grayanotoxin, and batrachotoxin), or 5 (such as ciguatoxin and

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brevetoxin). These toxins prefer to interact with the open state of channel; (3) toxins

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delay inactivation by binding to extracellular neurotoxin site 3, such as sea-anemone

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toxins and α-scorpion toxins. In addition to these well characterized toxins, some

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other toxins have distinct modes of action and/or neurotoxin binding sites. Spider

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toxins and β-scorpion toxins shift activation voltage to either depolarized or

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hyperpolarized direction by interacting with neurotoxin site 4. Delta-conotoxin

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prolongs channel inactivation similar to that of α-scorpion toxins, by binding to

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neurotoxin site 6. Although the neurotoxin binding sites are topologically distinct,

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allosteric coupling has been demonstrated between sites 3 and 6 and between sites 2

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and 5.11,12

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In mammals, four β-subunits (β1-β4; encoded by SCN1B-4B genes) have been

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discovered. The β-subunits are type I transmembrane proteins, containing an

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extracellular signal peptide in the N-terminus, a transmembrane segment and an

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immunoglobulin domain.9,13 Both excitable and non-excitable cells have considerable

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amounts of β-subunit expression which plays critical roles in modulating the

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localization, kinetics, and gating of Nav α-subunits.1,11,13,14

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Based on similarity of their amino acid sequences, Navs can be classified into

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nine subtypes, Nav1.1-Nav1.9, encoded by genes SCN1A-5A and SCN8A-11A in

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mammals (Table 2).1,14 In addition to sequence homology which is greater than 50%

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in identify, different subtypes of Navs display distinct gating kinetics. The nine

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subtypes can be categorized to be tetrodotoxin-sensitive (TTX-S, Nav1.1-1.4, Nav1.6

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and 1.7) and tetrodotoxin-resistant (TTX-R, Nav1.5, 1.8 and 1.9) according to their

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sensitivities to TTX blocking. Nav expressions are tissue and development

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dependent.2,11,15 Navs1.1-1.3 and 1.6 are primarily expressed in central nervous

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system (CNS). Navs1.4-1.5 are predominately expressed in skeletal and cardiac

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muscles, respectively. Navs1.7-1.9 are the major subtypes in peripheral nervous

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system (PNS).2

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2. Navs involved in pain

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Chronic pain affects approximately 20% of people worldwide.16 In general, 4


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chronic pain is categorized as neuropathic and nociceptive (nociceptor sensitization).

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Neuropathic pain, as a debilitating chronic pain condition, is often followed by nerve

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injury or malfunction derived from diseases such as cancer, diabetes mellitus,

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infection, autoimmune disease, and trauma. Clinical symptoms of neuropathic pain

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are characterized by hyperalgesia (increased pain perception of noxious stimuli), and

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mechanical allodynia (pain hypersensitivity to normally innocuous stimuli).17

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The molecular basis of chronic pain is complicated. Sensitization or changes in

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expression levels of ion channels, including Navs contribute to chronic pain. Several

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sodium channel subtypes such as Navs1.3, 1.7, 1.8, and 1.9 are preferentially

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expressed in nociceptors where they propagate electric signals. These Nav subtypes

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play pivotal roles in the pathobiological progression of pain.18 Navs channelopathies

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derived from gene mutations are associated with many painful disorders.19 Local

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anesthetics such as lidocaine20 and anti-epileptic drugs such as carbamazepine21

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targeting Navs have been used for pain relief. However, these drugs provide limited

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analgesic efficacy in most cases due to lack of selectivity at inhibiting Navs including

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those expressed in brain and heart.22,23 Therefore, discovering Nav subtype selective

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inhibitors may provide promising analgesics with less side effects.

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3. Animal toxins targeting Nav subtypes associated with pain

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Venoms from deadly venomous animal are a complex mixture containing a

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variety of peptides for defense and prey capture. Due to the critical roles of ion

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channels in the regulation of heart beating and neuronal excitability,24 many peptide

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toxins from animal venoms have been demonstrated to modulate ion channel

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(including but not limited to sodium, potassium, and calcium channels) activities,

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often with exquisite potency and selectivity.25

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The expression of TTX-S Nav1.3 depends on the development stage. While

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Nav1.3 expression level is significant in embryonic or neonatal dorsal root ganglion

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(DRG) neurons, adult sensory neurons have very low expression.26 Nav1.3 displays

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fast activation and inactivation kinetics and quick recovery from inactivation at

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membrane potentials < −80 mV, suggesting the roles of Nav1.3 in repetitive firing. 5



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Upon slow ramp depolarization, Nav 1.3 produces large ramp currents.27 Nav1.3

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contributes to accelerated repriming of TTX-S sodium currents within axotomized

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DRG neurons. This unique electrophysiological property may contribute to neuron

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development and altered neuronal excitability in injured neurons.18,27

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In human injured neurons and painful neuromas, Nav1.3 expression, however, is

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significantly up-regulated.28,29,30 Antisense knock-down of Nav1.3 in nerve-injured

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rats attenuates neuropathic pain.31 However, controversy exists. Deletion of Nav1.3

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either specifically from nociceptors or globally did not affect the abnormal discharges

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in injured nerves, nor did it alter the threshold of mechanical stimuli in neuropathic

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pain model suggesting a possible compensation mechanism in Nav1.3 knock-out

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mice.32

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Although controversy exists, Nav1.3 selective inhibitors are likely to be useful

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analgesics. Several Nav1.3 gating modifiers have been identified from animal venoms

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(Table 3). A peptide termed µ-conotoxin BuIIIB (µ-BuIIIB), discovered from the cone

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snail Conus bullatus, potently blocks Nav1.3 (IC50 = 0.2 µM),33 while another two

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structurally similar peptides, µ-KIIIA and µ-SIIIA are less potent (IC50 = 8 and 11 µM,

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respectively).34 Structure-activity relationship studies of µ-BuIIIB revealed the critical

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roles of C-terminal residues (Trp16, Arg18 and His20) for Nav inhibition.33 In addition

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to the C-terminal, the E3 to A replacement in the N-terminus of µ-BuIIIB significantly

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increased its potency. Another analog, ddSecBuIIIB, has been proven to display

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enhanced blockade to Nav1.3.33 However, whether the blockade of Nav1.3 by

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mutated µ-BuIIIB is useful in pain management needs further exploration. Indeed,

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ddSecBuIIIB also suppressed Nav1.4 activity which is responsible for the initiation of

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excitation-contraction coupling in skeletal muscle cells.

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BmK AS, a long-chain neurotoxic polypeptide purified from scorpion Buthus

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martensi Karsch,35 has been reported to suppress Nav1.3 peak currents at nanomolar

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concentrations

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hyperpolarized direction by modulating neurotoxin site 4.36 In rodent pain models,

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BmK AS produced significant analgesic effects on both inflammation-induced

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spontaneous pain and mechanical hyperalgesia.37

and

shift

the

voltage-dependent

6


activation/inactivation

to

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Although several toxins have been reported to be Nav1.3 selective, little in vivo

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information was available in the literature. The role of Nav1.3 on pain maintenance

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and/or progression remains unclear. Nevertheless, these discovered Nav1.3 selective

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peptide inhibitors may represent valuable tools to evaluate whether Nav1.3 can serve

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as a drug target for chronic pain management.

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TTX-S Nav1.7 expression is mainly found in the peripheral nociceptors.15,22 The

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kinetics of Nav1.7 activation and inactivation are quick and the closed-state

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inactivation is slow allowing it to amplify subthreshold depolarizations.18 Nav1.7 is

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therefore considered to be a threshold channel producing substantial ramp currents for

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firing APs.38 Nav1.7 also produces resurgent currents upon repolarization following a

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strong depolarization.39 The expression profile, together with its unique property in

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the actin potential generation, suggested that Nav1.7 may serve as a promising drug

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target for pain drug development.18,39

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Genetic evidences have further demonstrated the roles of Nav1.7 in pain onset

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and maintenance in humans and other mammals.39 In humans, gain-of-function

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mutations of Nav1.7 have been demonstrated to be the etiology of several painful

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disorders such as paroxysmal extreme pain disorder (PEPD),21 small fiber neuralgia

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(SFN),15 and inherited erythromelalgia (IEM).40 These mutated Nav1.7 displayed

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enhanced Na+ currents, lowered threshold for activation which resulted in increased

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firing frequency in response to graded supra-threshold stimuli,39 thereby enhancing

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hyperexcitability in DRG neurons. By contrast, Nav1.7 loss-of-function mutations are

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associated with congenital indifference to pain (CIP).41 Importantly, CIP patients has

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no aberrant cognitive and motor development.39 In addition, manipulation of Nav1.7

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expression in rodent models also supports the notion. Globally knock-down of mouse

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Nav1.7 ameliorated diabetic pain42 and thermal hyperalgesia induced by complete

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Freund’s adjuvant administration.43 Conditional knock-out of Nav1.7 in DRG neurons

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normalized inflammatory pain and thermal hyperalgesia induced by burn injury,

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without affecting neuropathic pain.39,44 DRG neurons from Nav1.7 knock-out mice

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displayed similar peak amplitude of AP, however, the rising phase was slowed. A 7



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population of 30% of DRG neurons from Nav1.7 knock-out animals failed to generate

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APs.45 Therefore, Nav1.7 is one of the promising drug targets for analgesic

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development with broad interests.15,46

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Many selective Nav1.7 toxins have been reported (Table 4). Mu-SLPTX-Ssm6a,

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a peptide containing 46 amino acid residues with three disulfide bonds has been

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isolated from the centipede Scolopendra subspinipes mutilans. Mu-SLPTX-Ssm6a

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potently inhibited Nav1.7 (IC50 = 25 nM) by shifting voltage-dependent activation to

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more depolarized potentials which is 150-fold more potent than its effect on other

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Navs except for Nav1.2 which is 32-fold.47 In thermal- and acid-induced pain models,

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µ-SLPTX-Ssm6a produced comparable analgesic effect with morphine without

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adverse effects on cardiovascular system and CNS.15,47

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In addition to centipede toxin, several spider toxins have been identified to

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potently and selectively inhibit Nav1.7.15 The best-known example is protoxin II

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(ProTx-II), isolated from Thrixopelma pruriens. The IC50 value (0.3 nM) for ProTx-II

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inhibiting Nav1.7 was ~100-fold more potent than that on other Nav subtypes.48

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ProTx-II inhibited Nav1.7 peak current by shifting the activation potentials to

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depolarized direction. It is interesting that local or systematic administrations of

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ProTx-II failed to produce analgesic effect in an inflammatory pain model. The

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explanation that ProTxII lacks analgesic effect is due to its inability to penetrate blood

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brain barrier48 is unlikely to be true since Nav1.7 is predominantly expressed in

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peripheral nociceptors. Nevertheless, the selectivity on Nav1.7 of this peptide does

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provide a valuable tool to study the cellular function of Nav1.7.45,48

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GpTx-1, a 34-residue, C-terminal amidated peptide toxin with three-disulfide

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bounds, was reported to inhibit Nav 1.7 with less selectivity. Using multi-attribute

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positional scan analoging, an engineered GpTx-1 analog was reported to inhibit

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Nav1.7 with IC50 values of ~1.6 nM, which was over 1000-fold more potent than that

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on Nav1.4 and Nav1.5.49,50 Local administration of GpTx-1 significantly reduced the

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pain behavior induced by scorpion toxin OD1. However, systematically delivered

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GpTx-1 had no efficacy on rodent pain models.51

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Recently, Shcherbatko et al. engineered a potent and selective Nav1.7 inhibitor 8


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using the template, tarantula ceratotoxin-1 (CcoTx1), an Nav toxin isolated from

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Ceratogyrus cornuatus. The CcoTx1 was further modified to achieve more potent and

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selective microproteins using semirational approaches. The microprotein suppressed

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Nav1.7 with an IC50 value of 2.5 nM, over 1000-fold selectivity on Nav1.4 and

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Nav1.5, 80- and 20-fold selectivity on Nav1.2 and Nav1.6, respectively.52 However,

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no in vivo data were available regarding the efficacy of the microprotein on pain

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models.

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Huwentoxin (HWTX)-IV, a 35-residue peptide purified from the spider

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Selenocosmia huwena, containing three disulfide bridges, was reported to inhibit

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hNav1.7 (IC50 = 17±2 nM) without effects on Nav1.5 even at a concentration of 10

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µM. HWTX-IV bound to neurotoxin site 4 of hNav1.7 in the closed state and trapped

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the voltage sensor in its inward position. A triple mutant, E1G, E4G, Y33W-HwTx-IV,

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displayed a 42-fold (IC50 = 0.4±0.1 nM) selectivity of Nav 1.7 over other Navs.53,54

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HWTX-IV showed anti-nociceptive effects in murine neuropathic pain models. The

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analgesic effect of HWTX-IV in spinal nerve injury (SNI) model lasted longer and

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displayed higher efficacy than Mexiletine.55

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Hainantoxin (HNTX)-IV (also termed β-TRTX-Hn2a), a typical cystine knot

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peptide purified from Ornithoctonus hainana, selectively inhibited TTX-S, but not

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TTX-R Na+ currents.56,57 HNTX-IV preferentially blocked hNav1.7 (IC50 ~ 21 nM)

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with little effect on rNav1.4 and hNav1.5. HNTX-IV also blocked the rNav1.2 and

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rNav1.3 (IC50 = 36 and 375 nM, respectively).58 HNTX-IV modification of Nav1.7

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was dependent on depolarization potentials. At depolarization potentials below +70

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mV, HNTX-IV suppressed Nav1.7 activity. However, partial agonism was observed at

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the depolarization potentials above +70 mV.58 Nevertheless, in physiological and

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pathological conditions, no evidence shows that the membrane potential can reach

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+70 mV. HNTX-IV administration alleviated acute inflammatory pain and

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SNI-induced neuropathic pain.59 HNTX-III, another toxin from the spider

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Ornithoctonus hainana, inhibited Nav1.7, Nav1.2 and Nav1.3 with similar potency

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although the selectivity against Nav1.4 and 1.5 was over 100-fold. Although it was

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bound to neurotoxin site 4, the mode of action of HNTX-III was distinct from 9



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β-scorpion toxins and other β-spider toxins. HNTX-III trapped the domain II voltage

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sensor in the closed state therefore suppressed the Nav1.7 Na+ current.60 The in vivo

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analgesic data of HNTX-III are not available.

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Novel peptides µ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, from Australian Phlogius

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sp. tarantula, modified hNav1.7 at concentrations ranged from high nanomolar to

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sub-micromolar. Phlo1a and Phlo1b both contain 35 amino acid residues with only

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one residue difference. Phlo1a and Phlo1b belong to NaSpTx family 2 with marginal

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inhibition on Nav1.2 and Nav1.5 therefore are selective Nav1.7 inhibitors. Phlo2a was

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less selective, as it robustly inhibited rNav1.2 and hNav1.5 as well at similar

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concentration range. Although the selectivities on Nav1.7 are different, these three

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peptides all shifted activation voltage to depolarized direction rendering Nav1.7 more

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difficult to open.61

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Other species like corn snails also contain a diverse range of Nav1.7 inhibitors,

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however, their selectivities on Nav1.7 were relatively poor. Mu-conotoxin PIIIA,

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isolated from Conus purpurascens was a hNav1.7 inhibitor with an IC50 value of 3.1

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µM. Mu-conotoxin PIIIA also blocked Nav1.4.62,63 Another Nav1.7 inhibitor,

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µ-conotoxin KIIIA, isolated from Conus kinoshitai, suppressed Nav1.7, Nav1.2 and

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Nav1.4 at comparable concentration ranges. Nevertheless, µ-conotoxin KIIIA

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significantly attenuated mouse pain behaviors induced by formalin, most like through

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its action on Nav1.7.64,65

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In conclusion, venom-derived peptides have provided a broad range of Nav1.7

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inhibitors most of which displayed significant analgesic effect in murine pain models.

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Further investigation on structure-activity relationships in combination with point

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mutation and electrophysiology may provide highly potent yet selective Nav1.7

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inhibitors with metabolic stability for analgesics development targeting Nav1.7.

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Similar to Nav1.7, TTX-R Nav1.8 is preferentially expressed in PNS nociceptors

297

including small-diameter DRG neurons, nodose and trigeminal ganglia neurons.66

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Nav1.8 displays a fast activation, slow inactivation and rapid repriming kinetics.66,67

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Nav1.8 is responsible for the majority of inward Na+ current contributing to the 10


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upstroke of neuronal APs, supporting the repetitive firing in depolarized neurons.22,68

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Nav1.8 is also responsible for subthreshold membrane oscillations,69 which contribute

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significantly to hyperexcitability following injury of sensory neurons.

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The fundamental neurophysiological role of Nav1.8 in nociceptive neurons

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suggests that Nav1.8 has significant effect on nociceptor excitability, thus linking to

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pain management in humans. Although genetic loss-of-function mutations were not

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yet described in humans, gain-of-function mutations of Nav1.8 were shown to

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produce hyperexcitability and inappropriate spontaneous firing in neurons. These

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gain-of-function mutations were thought to be the etiology of painful peripheral

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neuropathy observed in human.70,71 Nav1.8 has been confirmed to be involved in cold,

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inflammatory and neuropathic pain in knock-out67,72 and knock-down73,74 murine

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models. Bierhaus et al. reported that methylglyoxal modification of Nav1.8 increased

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nociceptor firing, contributing to hyperalgesia in mouse diabetic neuropathy. These

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studies provided evidence for a previously unidentified pathway in which

314

methylglyoxal directly induced hyperalgesia and may suggest that Nav1.8 was a valid

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therapeutic target for diabetic pain.75 Moreover, some small molecular inhibitors, such

316

as A-803467 and PF-01247324, which are potent and selective Nav1.8 blockers, were

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reported to produce significant anti-nociceptive effect in neuropathic and

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inflammatory pain models.76,77 Overall, although the relationship between Nav1.8

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expression and neuropathic signaling is not as clear as Nav1.7, electrophysiological

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properties, together with its tissue distribution, suggest that Nav1.8 is crucial in

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nociceptive signaling.

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To date, several selective Nav1.8 inhibitors have been identified from animal

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venom (Table 5). The µO-conotoxin, MrVIA, from freshwater snail Conus

324

marmoreus was reported to block TTX-R Na+ current with an IC50 value of 82.8 nM

325

which was 10-fold more potent than that on TTX-S Na+ currents in DRG neurons.78

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The inhibition of Na+ current was voltage-dependent. The inhibition was significantly

327

diminished with more depolarized voltage steps.79 The other µO-conotoxin, MrVIB,

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displayed 10-fold selectivity in inhibiting TTX-R Na+ currents than for TTX-S Na+

329

current in nociceptive DRG neurons. Further studies demonstrated that MrVIB 11



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330

blocked human Nav1.8 with 10-fold selectivity to other Navs.80 MrVIB displayed

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efficacious long-lasting analgesic effects in animal models of persistent pain.80,81

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MrVIB (0.03-3 nmol) intrathecal administration significantly reduced mechanical

333

allodynia and hyperalgesia although motor activity deficits were observed at a much

334

higher dose.80 Thus, MrVIB may represent a promising lead compound to develop

335

Nav1.8-selective inhibitor for treating inflammatory and neuropathic chronic pain.

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Another µO-conotoxin, MfVIA, a hydrophobic 32-residue peptide, isolated from

337

Conus magnificus, potently inhibited Nav1.4 and Nav1.8 with much lower affinity to

338

other Navs.79 However, there are no in vivo data available due to its action on Nav1.4.

339

APETx2, a toxin from the sea anemone Anthopleura elegantissima, was reported

340

to be an acid-sensing ion channel 3 (ASIC3) modulator. APETx2 moralized

341

inflammatory and acid-induced pain was initially proposed to be through inhibiting

342

ASIC3. Recent studies demonstrated that APETx2 also inhibited the TTX-R Nav1.8

343

Na+ currents in DRG neurons (IC50 = 2.6 µM) with marginal effect on TTX-S Na+

344

currents. APETx2 shifted activation voltage of Nav1.8 rightward therefore reducing

345

the maximal macroscopic conductance. Thus, in vivo analgesic effect of APETx2 was

346

possible through inhibition of both Nav1.8 and ASIC3 channels, two promoting pain

347

targets.82

348

ProTx-I, identified from tarantula Thrixopelma pruriens, was the first highly

349

potent TTX-R Nav1.8 inhibitor, however, with poor selectivity.83 Many spider toxins

350

have been demontarated to inhibit Nav1.8 currents with low affinity or without

351

selectivity. Ceratotoxins (CcoTx)1-3 and phrixotoxin 3 (PaurTx3) inhibited Nav1.8

352

Na+ current at micromolar concentrations.84 JZTX-V85 and JZTX-IX86 inhibited rat

353

Nav1.8 without selectivity.87 Recently discovered µ-TRTX-Hl1a from Haplopelma

354

lividum appeared to suppress TTX-R Na+ current rather than TTX-S Na+ current

355

suggesting the selectivity of µ-TRTX-Hl1a on Nav.18. The comparable analgesic

356

effect of µ-TRTX-Hl1a with morphine in both neuropathic inflammatory pain

357

suggests its usefulness in pain drug discovery.88

358 359

As described above, the search for Nav1.8 selective inhibitors is relatively lagging

when

compared

to

Nav1.7.

Nevertheless,

12


genetic

evidence

and

Page 13 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


360

pharmacological data all suggest the potential of Nav1.8 selective inhibitors for pain

361

drug development.

362


363

TTX-R Nav1.9 is preferentially expressed in intrinsic myenteric sensory

364

nociceptors, small-diameter (100-fold selectivity)

137

rNav1.3 >> hNav1.5 > rNav1.4 Nav1.7 (IC50 = 10 nM) > Nav1.4 >> Nav1.5 Gating modifier hNav1.7 (IC50 ~ 21 nM) > rNav1.2 > rNav1.3 >> hNav1.5 > rNav1.4

52

61

61

53, 54

50

57, 58

Binds to site 4 in the closed state Nav1.7 (IC50 = 232 nM) > Nav1.2 >

60

Nav1.3 >> Nav1.5 > Nav1.4 Shifts activation to depolarizing direction hNav1.7 (IC50 = 25 nM) > hNav1.2 >

47

hNav1.1 >> hNav1.3, 1.4, 1.5 ZRLCCGFOKSCRSRQCKOHRCC#

Blocks current

62,

Nav1.4 (IC50 = 41 nM) >> hNav1.7 (3.1 µM)

63

Blocks current

CCNCSSKWCRDHSRCC#

(Cone snail)

501

48,

to depolarizing direction

hNav1.7 (IC50 = 17 nM) > rNav1.2 >

(Cone snail) µ-conotoxin KIIIA

Inhibits Na+ conductance and shifts activation

Blocks current

Huwentoxin-IV

Ref.

rNav1.2 > rNav1.4 > rNav1.7 >> rNav1.5

(#, C-terminal amidation; Z, pyroglutamate; O, 4-hydroxyproline)

502 503 504 505 506 507 508 19


64


Page 20 of 31

509

Table 5. Primary structures and electrophysiological properties of Nav1.8 and Nav1.9

510

toxins from animal venoms Major pharmacology,

Toxin (species)

Amino acid sequences

µO-conotoxin MrVIA

ACRKKWEYCIVPIIGFIYCCP

Gating modifier

78,

(Cone snail)

GLICGPFVCV

TTX-R Nav (rat DRG) (IC50 = 82.8 nM)

79

µO-conotoxin MrVIB

ACSKKWEYCIVPILGFVYCC

(Cone snail)

PGLICGPFVCV

µO-conotoxin MfVIA

RDCQEKWEYCIVPILGFVYC

Blocks current

(Cone snail)

CPGLICGPFVCV

Nav1.4 > rNav1.8 (IC50 = 95.9 nM) > Nav1.5

ProTx-I

ECRYWLGGCSAGQTCCKHL

Shifts activation to depolarizing direction

(Tarantula)

VCSRRHGWCVWDGTFS

Nav1.2 ~ Nav1.5 ~ Nav1.7 ~ Nav1.8

GTACSCGNSKGIYWFYRPSC

Blocks current and shifts activation to

PTDRGYTGSCRYFLGTCCTP

depolarizing direction

AD

rNav1.8 (IC50 = 2.6 µM) > TTX-S Nav

Blocks current hNav1.8 (IC50 = 102 nM) > rNav1.2, rNav1.3, hNav1.5, hNav1.7 >> rNav1.9

APETx2 (Sea anemone)

subtype selectivity

µ-conotoxin SmIIIA

ZRCCNGRRGCSSRWCRDHS

(Cone snail)

RCC#

Blocks TTX-R Na+ current Blocks TTX-R Na+ current in rat DRG

µ-conotoxin TsIIIA GCCRWPCPSRCGMARCCSS

(Cone snail)

(IC50 = 2.6 µM)

Ref.

80, 81

79

83

82

138

139

KEGYLMDHEGCKLSCFIRPS

Dramatic facilitation of rNav1.9 currents

TsVII

GYCGRECGIKKGSSGYCAW

(Scorpion)

PACYCYGLPNWVKVWDRA TNKC#

511

while only modest inhibition of rNav1.8 at 100 nM

(#, C-terminal amidation; Z, pyroglutamate; O, 4-hydroxyproline)

512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 20


105, 140

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528

References

529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570

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(127) Mantegazza, M., Gambardella, A., Rusconi, R., Schiavon, E., Annesi, F., Cassulini, R. R., Labate, A., Carrideo, S., Chifari, R., Canevini, M. P., Canger, R., Franceschetti, S., Annesi, G., Wanke, E., and Quattrone, A. (2005) Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. Proc. Natl. Acad. Sci. U. S. A. 102, 18177-18182. (128) Mullen, S. A., and Scheffer, I. E. (2009) Translational research in epilepsy genetics sodium channels in man to interneuronopathy in mouse. Arch. Neurol. 66, 21-26. (129) Sugawara, T., Tsurubuchi, Y., Agarwala, K. L., Ito, M., Fukuma, G., Mazaki-Miyazaki, E., Nagafuji, H., Noda, M., Imoto, K., Wada, K., Mitsudome, A., Kaneko, S., Montal, M., Nagata, K., Hirose, S., and Yamakawa, K. (2001) A missense mutation of the Na+ channel alpha(II) subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc. Natl. Acad. Sci. U. S. A. 98, 6384-6389. (130) Cannon, S. C. (1997) From mutation to myotonia in sodium channel disorders. Neuromuscul. Disord. 7, 241-249. (131) Wang, Q., Shen, J. X., Splawski, I., Atkinson, D., Li, Z. Z., Robinson, J. L., Moss, A. J., Towbin, J. A., and Keating, M. T. (1995) SCN5A mutations associated with an inherited cardiac-arrhythmia, long QT syndrome. Cell 80, 805-811. (132) Probst, V., Kyndt, F., Potet, F., Trochu, J. N., Mialet, G., Demolombe, S., Schott, J. J., Baro, I., Escande, D., and Le Marec, H. (2003) Haploinsufficiency in combination with aging causes SCN5A-linked hereditary lenegre disease. J. Am. Coll. Cardiol. 41, 643-652. (133) Schott, J. J., Alshinawi, C., Kyndt, F., Probst, V., Hoorntje, T. M., Hulsbeek, M., Wilde, A. A. M., Escande, D., Mannens, M., and Le Marec, H. (1999) Cardiac conduction defects associate with mutations in SCN5A. Nat. Genet. 23, 20-21. (134) Kohrman, D. C., Smith, M. R., Goldin, A. L., Harris, J., and Meisler, M. H. (1996) A missense mutation in the sodium channel Scn8a is responsible for cerebellar ataxia in the mouse mutant jolting. J. Neurosci. 16, 5993-5999. (135) Burgess, D. L., Kohrman, D. C., Galt, J., Plummer, N. W., Jones, J. M., Spear, B., and Meisler, M. H. (1995) Mutation of a new sodium-channel gene, Scn8a, in the mouse mutant motor end-plate disease. Nat. Genet. 10, 461-465. (136) Kuang, Z., Zhang, M. M., Gupta, K., Gajewiak, J., Gulyas, J., Balaram, P., Rivier, J. E., Olivera, B. M., Yoshikami, D., Bulaj, G., and Norton, R. S. (2013) Mammalian neuronal sodium channel blocker mu-conotoxin BuIIIB has a structured N-terminus that influences potency. ACS Chem. Biol. 8, 1344-1351. (137) Priest, B. T., Blumenthal, K. M., Smith, J. J., Warren, V. A., and Smith, M. M. (2007) ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon 49, 194-201. (138) Keizer, D. W., West, P. J., Lee, E. F., Yoshikami, D., Olivera, B. M., Bulaj, G., and Norton, R. S. (2003) Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA. J. Biol. Chem. 278, 46805-46813. (139) Yang, M., Zhao, S., Min, X., Shao, M., Chen, Y., Chen, Z., and Zhou, M. (2017) A novel mu-conotoxin from worm-hunting Conus tessulatus that selectively inhibit rat TTX-resistant sodium currents. Toxicon 130, 11-18. (140) Hassani, O., Mansuelle, P., Cestele, S., Bourdeaux, M., Rochat, H., and Sampieri, F. (1999) Role of lysine and tryptophan residues in the biological activity of toxin VII (Ts gamma) from the scorpion Tityus serrulatus. Eur. J. Biochem. 260, 76-86. 30


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Selective voltage-gated sodium channel peptide toxins from animal

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venom: pharmacological probes and analgesic drug development

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Ying Wu1, Hui Ma1, Fan Zhang, Chunlei Zhang, Xiaohan Zou, and Zhengyu Cao

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Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational

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Development, China Pharmaceutical University, Nanjing 211198, China

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1

Equally contributed

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Corresponding author:

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E-mail addresses: [email protected] (F. Zhang), [email protected]

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(Z. Cao); Tel.: +86-25-8618-5955 (F.Z. & Z.C.)

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For Table of Contents Use Only

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Selective Voltage-Gated Sodium Channel Peptide Toxins from Animal

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