Snake Venom Neurotoxins Targeting Voltage-Gated Potassium Channels: Comparison
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The venom derived from various sources of snakes represents a vast collection of predominantly protein-based toxins that exhibit a wide range of biological actions, including but not limited to inflammation, pain, cytotoxicity, cardiotoxicity, and neurotoxicity. The venom of a particular snake species is composed of several toxins, while the venoms of around 600 venomous snake species collectively encompass a substantial reservoir of pharmacologically intriguing compounds. Findings have demonstrated the potential application of neurotoxins derived from snake venom in selectively targeting voltage-gated potassium channels (Kv). These neurotoxins include BPTI-Kunitz polypeptides, PLA2 neurotoxins, CRISPs, SVSPs, and various others.

  • BPTI-Kunitz polypeptides
  • CRISPs
  • dendrotoxins
  • Kv channels blockers
  • PLA2 neurotoxins
  • presynaptic neurotoxins
  • SVSPs
  • snake venom

1. Introduction

Throughout a span of over 120 million years, poisonous snakes belonging to the Order Squamata; namely, the suborder Serpentes, have developed a diverse array of venoms containing bioactive molecules. These snakes, which encompass approximately 600 species and are classified under the Elapidae, Viperidae, and Colubridae families, have undergone significant evolutionary adaptations in their venom composition [1]. These compounds exhibit a range of actions that target significant physiological pathways and organs, encompassing cytotoxic, neurotoxic, cardiotoxic, myotoxic, and other enzymatic activities [2,3][2][3]. Hence, snake envenomation poses a considerable health risk in numerous regions throughout. According to estimates, a total of 7400 individuals experience snake bites on a daily basis, resulting in an annual fatality count ranging from 81,000 to 138,000 [4,5][4][5]. Moreover, this unfortunate outcome leaves over 400,000 individuals with enduring bodily or psychological impairments, such as blindness, amputation, and post-traumatic stress disorder [4]. Snake venoms comprise intricate combinations of diverse chemicals, encompassing peptides and proteins, which serve as protective mechanisms, aid in prey acquisition, and/or discourage competition [2]. Nevertheless, several toxins derived from snake venom have demonstrated promising applications as diagnostic tools, therapeutic agents, or pharmacological candidates [3]. Through recent advanced in research and drug discovery, snake venom components gain in-depth attention as invaluable sources of therapeutics in many medical fields from antimicrobial to anti-cancer research, to name a few [6,7,8,9,10,11,12,13][6][7][8][9][10][11][12][13].
Potassium (Kv) channels are found in the membranes of numerous cell types due to their diverse physiological significance [14,15][14][15]. These potassium channels are tetrameric glycoproteins which have the ability to form pores through the membranes that selectively allow the passage of potassium ions in response to alterations in the voltage of the membrane. Moreover, they exhibit rapid activation and inactivation of potassium currents when the cell membrane is depolarized [16,17][16][17]. The study of animal peptide toxins, such as those found in snake venom, and their interaction with Kv channels has yielded significant insights into the physiological properties of potassium (K+) channels. These compounds are predominantly found in the venoms of several species, including sea anemones, spiders, scorpions, honeybees, and snails belonging to the Conus genus [18,19][18][19]. These substances have well-established modes of action [20]. Extensive examination of the structures and functionalities of many animal toxins has yielded numerous advantages, notably the development of medicines derived from snake toxins [18]. The modification of their chemical groups can lead to the acquisition of therapeutic properties through the manipulation of pharmacological selectivity, specificity, and potency [21,22][21][22].

2. Voltage-Gated Potassium (Kv) Channels

Potassium channels are the most extensive and heterogeneous group of ion channels. The voltage-gated potassium channels (Kv) are the most significant subfamily among K+ channels. Potassium ions play a crucial role in various physiological processes, as they facilitate the controlled movement of ions along the electrochemical gradient [23]. These processes include the regulation of excitability and the modulation of neuronal action potentials [24[24][25],25], as well as the facilitation of muscular contraction [26,27,28][26][27][28] and the regulation of calcium signaling pathways, among others [29]. These functions have been extensively reviewed by previous studies [14,15][14][15]. The genes responsible for encoding Kv channel α-subunits have been identified and can be categorized into twelve distinct subfamilies [15]. These subfamilies include Kv1 (Shaker) with eight members, Kv2 (Shab) with two members, Kv3 (Shaw) with four members, Kv4 (Shal) having five members, Kv7 (KvLQT) with five members, Kv10 (HERG) with two members, Kv11 (also known as EAG) with three members, and Kv12 (ELK) with three members, as well as the modulatory subfamilies Kv5 (consisting of one member), Kv6 (consisting of four members), Kv8 (consisting of two members), and Kv9 (consisting of three members). This classification system has been established based on the identified genes for Kv channel α-subunits. These channels have been found to be involved in a wide range of neurological, cardiac, and immunological illnesses, making them significant targets for therapeutic interventions [30]. The number of transmembrane domains (TMD) observed in K+ channels has been determined through genetic and structural investigation, revealing the presence of two, four, or six TMD. The majority of Kv channels exhibit a six-TMD arrangement in their functional assembly (see Figure 1A). The regulation of the pore opening is governed by the voltage-sensing domain, which is composed of transmembrane segments S1–S4. This domain, also known as the voltage-sensor domain (VSD), is coupled to the pore domain (PD) through the intracellular loop between segments S4 and S5 [31] (Figure 1B). The latter domain consists of transmembrane proteins S5 and S6, which feature a re-entrant pore loop containing the K+ selectivity motif TVGYG [32]. Following the repolarization phase, the voltage-sensitive domain (VSD) undergoes deactivation, wherein the channel gate is closed, thereby impeding the passage of ions and restoring the VSD to its original resting state. Channels have the ability to be revived, however, if the stimulation caused by depolarization lasts longer than a few milliseconds, inactivation occurs and stops the permeability of potassium ions. Kv channels undergo recovery from the inactivation state exclusively following a short duration at a hyperpolarized potential [33]. C-type inactivation, also known as slow inactivation, is occurring after tens or hundreds of milliseconds from channel activation and is observed in the majority of Kv rectifying channels [34]. Recent research findings provide evidence for a mechanism in which the reorganization of amino acids within the inner cavity and outer vestibule of a channel is accompanied by the redistribution of structural water molecules. This process ultimately results in the collapse of the permeation pathway in C-type inactivation. This mechanism has been extensively discussed and reviewed in Ref. [35]. Several types of Kv channels exhibit rapid inactivation or N-type inactivation, which happens shortly after channel activation. This inactivation is primarily caused by an intracellular blockage by the channel’s intracellular N-terminus, also known as the inactivation particle [36,37][36][37].
Figure 1. The structure of Kv channels. (A) Schematic side-view presentation of a Kv1.2-2.1 chimeric channel obtained from a single-particle cryo-EM structure (PDB: 6EBK, [38]) showing the four α and four β auxiliary subunits. Shaded areas are the cell membrane. The image was generated using BIOVIA Discovery Studio Visualizer software (v21.1.0). (B) Schematic illustration of Kv channel membrane topology (two, four, or six transmembrane domains; TMDs). The majority of Kv channels have six TM domains. Here, the side-view depicts one of the four transmembrane α subunits: each subunit includes the voltage-sensing domain (in gray, S1–S4: VSD) and the pore domain between S5 and S6 segments (the loop between orange parts: PD).
Functional Kv1 channels consist of four α subunits and four cytoplasmic auxiliary Kvβ subunits [39,40][39][40] (Figure 1B) once they are expressed as a cell membrane molecule. Previous research has demonstrated that in heterologous expression systems, Kv1 α and Kvβ subunits have the ability to form both homo- and heteromeric complexes in a promiscuous manner [39,41][39][41]. The generation of functional Kv1 channels is attributed to the diverse combinations of eight distinct subtypes of Kv1 α subunits and three subtypes of Kvβ subunits expressed in the mammalian brain. These subunits exhibit unique biophysical and pharmacological features, as discussed in a comprehensive study [15]. Nevertheless, Kv1 channels derived from the mammalian brain display a restricted range of subunit composition [42,43][42][43].

3. Snake Venom

The composition of snake venoms is characterized by a complex mixture of peptides, proteins, and non-protein components [2,44][2][44]. Despite the variations seen among different snake species and their geographical distribution, it is noteworthy that a significant proportion of the protein component in snakes exhibits enzymatic activity. The pro-inflammatory effects of the venom are commonly ascribed mostly to metalloproteases (SVMPs) and phospholipases A2 (PLA2s) [2,3][2][3]. Conversely, non-enzymatic proteins exacerbate the intensity of the envenomation. The venoms produced by snakes have the ability to selectively target particular receptors, ion channels, or plasma proteins, or extracellular components, thereby functioning as agonists, antagonists, or modulators. The pharmaceutical effects described would disrupt the individual’s physiological processes, leading to a variety of hazardous outcomes [45]. Included in this group of proteins, besides SVMPs and PLA2s, are disintegrins, C-type lectins, three-finger toxins, bradykinin-potentiating peptides (BPPs), Kunitz-type polypeptide, cysteine-rich secretory proteins (CRISPs), serpins, ICK peptides, and serine proteases (SVSPs) [9]. The components that specifically target Kv channels aim to disrupt the normal functioning of these channels, resulting in a decrease in the excitability of the affected tissues and ultimately leading to paralysis in the individual.

4. Snake Venom Neurotoxins as Therapeutics

Snake venom is composed of a diverse combination of proteins and peptides, several of which have demonstrated promising medicinal possibilities [6,8,10,11,13,190,191][6][8][10][11][13][46][47]. The potential therapeutic applications of snake venom neurotoxins have been investigated owing to their capacity to selectively bind to certain receptors within the nervous system [192][48]. Neurotoxins possess the potential for both therapeutic and deleterious effects, contingent upon their distinct method of action and administered dosage. Nonetheless, the process of generating therapeutic treatments using neurotoxins derived from snake venom has numerous hurdles. One of the primary obstacles encountered in the development of snake venom neurotoxins as therapeutic agents lies in the attainment of adequate quantities suitable for clinical application [193][49]. The difficulties in acquiring adequate quantities of purified toxins from crude snake venom for scientific investigation and therapeutics can be mitigated by implementing venomics technologies, such as reverse-phase high-performance liquid chromatography (RP-HPLC) and followed by LC-MS/MS-based toxin identification [8]. Moreover, the future of advancements and discoveries lies in the use of efficient biotechnologies, such as cloning and large-scale toxin expression systems, and the optimization of drug delivery by toxin conjugation to monoclonal antibodies and nanoparticles [6,12][6][12]. Other approaches could involve the rational design of modified venom toxins with reduced toxicity and increased protection against proteolytic degradation [6,12][6][12]. A further obstacle lies in the imperative task of guaranteeing the safety of these toxins, given their high potency and the inherent risk of injury if mishandled [194][50]. In spite of the aforementioned hurdles, certain neurotoxins derived from snake venom have already been transformed into medicinal agents [9]. The utilization of snake venom neurotoxins exhibits considerable potential as a medicinal intervention for pain management. For instance, the antihypertensive drug Captopril (Capoten) was the first peptide derived from the venom of the Bothrops jararaca snake to receive FDA approval in 1981 [12,195][12][51]. This was then followed by the approval of Enalapril by the FDA in 1985 [9]. Both drugs are generated from bradykinin-potentiating peptides and function as angiotensin-converting enzyme inhibitors. They are administered to regulate hypertension and to avoid or ameliorate congestive heart failure [8,9][8][9]. This paved the way for more drug discoveries, such as Tirofiban and Eptifibatide, the selective competitive inhibitors for fibrinogen receptors [10]. Certain neurotoxins contained in snake venom have been discovered to specifically inhibit particular types of ion channels in sensory neurons, effectively impeding the transmission of pain signals to the brain [196][52]. These ion channels play a crucial role in a diverse range of pain syndromes, encompassing neuropathic pain, inflammatory pain, and cancer pain. In addition to the neurotoxins discussed in this review from various protein families (Table 1), DTXs exhibited notable efficacy and specificity against Kv1 channels. Such criteria of DTX make them useful tools to study the presynaptic Kv1 channel populations in healthy tissue and the integrity of brain’s connectomes in neurodegenerative diseases [7]. The synthesis of selective ligands against Kv1 channels, which are commonly seen in demyelinated neurons, has been achieved by rational design using a chemo-informatic approach. This strategy involves the design of chemical analogs to increase neural conduction in these neurons [197][53]. Nevertheless, there have been no reports of any pharmaceutical medication derived from a neurotoxic found in snake venom that specifically targets Kv channels for therapeutic purposes. Notably, Kv channel modulators derived from snake venom of various sizes (Table 1) show promise for biological uses. Due to their ability to precisely modulate various Kv channels, they have considerable potential as cardiovascular and neurological disease treatments and research tools. More research is needed to identify the molecular targets for several toxins, such as the members of PLA2, CRISPs, and three-finger toxins families.
Table 1.
The list of protein neurotoxins isolated from snake venom and their Kv channel targets.

Snake Polypeptides

Source

Molecular Mass (kDa)

Potassium Channel Targets

References

BPTI-Kunitz type

        

DTXs

Dendroapis angusticeps

Dendroapis polylepis

Dendroapis viridis

7

Kv1.1, Kv1.2, and Kv1.6 antagonists

[43,50,57,58,59][43][54][55][56][57]

BF9

Bungarus fasciatus

9

Kv1.3 antagonist

[81][58]

PLA2

        

Crotamine

Crotalus durissus terrificus

4.8

Kv1.1, Kv1.2, and Kv1.3 antagonists

[93,106][59][60]

β-Bungarotoxin

Bungarus multicinctus

22

Inhibition of Kv currents (including Kv1.2 and Kv1.1).

[123,124,135,136,137][61][62][63][64][65]

Natratoxin

Naja atra

13

A-type Kv channels antagonist

[140][66]

MiDCA1

Micrurus dumerilii carinicauda

15.5

Kv2.1 antagonist

[154,155][67][68]

Taipoxin

Oxyuranus s. scutellatus

4.6

Inhibition of slowly activating Kv channels

[133,158,69][70]159,[71]160][[72]

Notexin

Oxyuranus s. scutellatus

  

Inhibition of slowly activating Kv channels

  

Crotoxin

Crotalus durissus terrificus

24

Inhibition of slowly activating Kv channels

  

CRISPs

        

BaltCRP

Bothrops alternatus

24

Inhibition of Kv1.1, Kv1.3, Kv2.1, and Shaker channels

[165][73]

Natrin

Naja atra

25

Inhibition of the Kv1.3 and BKCa channels

[163,164][74][75]

Stecrisp

Trimeresurus stejnegeri

25

Possible Kv channels

[166][76]

SVSPs

        

Collinein-1

Crotalus durissus collilineatus

29.5

Inhibitor for hEAG1 (Kv10.1) channel (anticancer effect)Mild inhibitor for hERG1 (Kv11.1) channel

[174,175][77][78]

Gyroxin_B1.3

Crotalus durissus terrificus

28

Inhibitor for hEAG1 (Kv10.1) channel

  

BjSP

Bothrops jararaca

28

Inhibitor for hEAG1 (Kv10.1) channel

  

Three-finger toxins

        

Cardiotoxin-I

Naja kaouthia

6.7

Possible antagonist for KATP channel involved in stimulating insulin release

[179,182][79][80]

Crotalphine

Crotalus durissus terrificus

1.5

Possible agonist for K+ channels mediating antinociceptive effect

[184,185][81][82]
Numerous toxins and derivatives resulting from the venom of snakes and other animals have demonstrated efficacy in the treatment of various medical ailments. The presence of α-cobrotoxin, a neurotoxic protein, has been identified in the venom of Naja naja atra, commonly referred to as the Chinese cobra [196][52]. This particular substance is classified as a postsynaptic neurotoxic that effectively inhibits the activity of acetylcholine at the neuromuscular junction. Shi et al. [198][83] examined the pain-relieving properties of α-cobrotoxin in a rat model of formalin-induced inflammatory pain. The study showed that injecting α-cobrotoxin into rats through the intraperitoneal route could reduce the inflammatory pain in a dose-dependent manner. This effect is achieved by activating the cholinergic rather than the opioid system. The beneficial antinociceptive effect of α-cobrotoxin is achieved through the activation of muscarinic and α7-necotinic acetylcholine receptors. This is in contrast to atropine, a common anticholinergic drug that acts as a nonselective antagonist for both central and peripheral muscarinic acetylcholine receptors. The drug (cobratide), derived from α-cobrotoxin, has been granted approval in China for its utilization as an analgesic in cases of moderate to severe pain [199][84]. Nevertheless, the considerable bioactivity of the substance may give rise to potential adverse consequences, including respiratory arrest. However, ziconotide, a pharmaceutical compound derived from the venom of the cone snail, has been authorized by both the FDA and the EMA for the purpose of managing severe chronic pain [200][85]. Ziconotide is a synthetic peptide that is synthesized based on the venom of the cone snail species Conus magus [200][85]. This substance serves as a non-opioid analgesic and is employed in the treatment of severe chronic pain among those who exhibit inadequate response to alternative therapeutic interventions. Ziconotide functions through the inhibition of N-type calcium channels located in the spinal cord, which play a crucial role in the transmission of pain signals [201][86]. Research has demonstrated the efficacy of this intervention in mitigating pain among individuals with severe and chronic conditions, such as neuropathic pain, cancer pain, and complicated regional pain syndrome [200][85]. In addition to the management of pain, there is ongoing research on various neurotoxins found in snake venom for its potential therapeutic applications, including the treatment of epilepsy, stroke, and hypertension [202,203][87][88]. Certain neurotoxins have demonstrated the ability to regulate the functioning of ion channels within the brain. These ion channels play a crucial role in the initiation and transmission of neuronal activity. An instance of α-neurotoxin can be observed within the venom of some snake species, such as the green mamba (Dendroaspis angusticeps). The α7 nicotinic acetylcholine receptor, which plays a role in modulating neuronal excitability in the brain, is specifically targeted by this neurotoxic [204,205][89][90]. The α-neurotoxin has the ability to attach to a specific receptor and inhibit its function, so mitigating the hyperexcitability that is causally linked to the occurrence of seizures. The efficacy of α-neurotoxin in mitigating seizures in rats with experimentally produced temporal lobe epilepsy has been demonstrated in preclinical investigations. Furthermore, the observed anti-seizure effects have exhibited a prolonged duration, persisting for a period of up to three days subsequent to treatment. In addition to its Kv-blocking properties, taipoxin has demonstrated the ability to inhibit Nav channels inside the cerebral region, which play a crucial role in the initiation and transmission of neuronal action potentials. Through the process of channel blockade, taipoxin has the capacity to diminish the excitability of neurons, hence impeding the occurrence of aberrant neuronal activity that precipitates seizures. The presence of natriuretic peptide (NP), a neurotoxin, has been detected in the venom of Calloselasma rhodostoma, a pit viper species native to Southeast Asia. Studies have demonstrated that NP exhibits vasodilatory properties, leading to the relaxation of blood vessels and enhancement of blood circulation [191,203,206][47][88][91]. The relaxation of smooth muscle cells in the blood arteries is facilitated through the activation of cyclic guanosine monophosphate (cGMP) synthesis. Another illustration is contortrostatin, a neurotoxin included in the venom of the southern copperhead snake (Agkistrodon contortrix contortrix). The anti-angiogenic characteristics of contortrostatin have been demonstrated through its ability to suppress neovascularization [207,208][92][93]. The significance of this finding lies in its implications for the management of hypertension, as neovascularization has been identified as a potential factor in the pathogenesis of elevated blood pressure. In preclinical investigations, the administration of NP and contortrostatin have shown a notable capacity to effectively diminish blood pressure levels in rats that were experimentally produced with hypertension. Several studies have indicated that some constituents present in snake venom, such as neurotoxins, exhibit promising characteristics as possible anti-cancer agents [75,180,209,210][94][95][96][97]. The neurotoxins have demonstrated the capacity to trigger apoptosis in cancer cells and may hinder angiogenesis, the process of blood vessel formation that sustains tumor growth.

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