Phα1β
{{Short description|Spider neurotoxin}}
{{Chembox
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| StdInChIKey=QGMVGSCZYUDILO-FPHUJEMDSA-N
}}
|Section2={{Chembox Properties
|C=248|H=382|N=74|O=78|S=12
}}
|Section8={{Chembox Related
| OtherCompounds=PnTx3-4, PLTX-II, ω-Aga-IIIA, ICK-OtTx-1A, DW-13.3
}}
}}
Phα1β (also known as PnTx3-6; PhTx3-6; Phalpha1beta) is a peptide toxin that blocks various types of voltage-gated calcium channels (VGCCs) and is a specific receptor antagonist of the TRPA1 cation channel. The peptide is derived from the venom of the armed spider Phoneutria nigriventer and possesses wide-ranging analgesic and anti-nociceptive effects in animal models.
Source and Etymology
Phα1β is purified from the venom of Phoneutria nigriventer, commonly known as the “armed spider”.{{Cite journal |last1=Cordeiro |first1=Marta do Nascimento |last2=de Figueiredo |first2=Suely Gomes |last3=Valentim |first3=Ana do Carmo |last4=Diniz |first4=Carlos Ribeiro |last5=von Eickstedt |first5=Vera Regina D. |last6=Gilroy |first6=John |last7=Richardson |first7=Michael |date=1993 |title=Purification and amino acid sequences of six Tx3 type neurotoxins from the venom of the Brazilian 'armed' spider Phoneutria Nigriventer (keys.) |url=https://linkinghub.elsevier.com/retrieve/pii/004101019390354L |journal=Toxicon |volume=31 |issue=1 |pages=35–42 |doi=10.1016/0041-0101(93)90354-L |pmid=8446961 |bibcode=1993Txcn...31...35C |issn=0041-0101|url-access=subscription }} A recombinant peptide (CTK 01512-2) has been synthesized.{{Cite journal |last1=Lyukmanova |first1=Ekaterina N. |last2=Mironov |first2=Pavel A. |last3=Kulbatskii |first3=Dmitrii S. |last4=Shulepko |first4=Mikhail A. |last5=Paramonov |first5=Alexander S. |last6=Chernaya |first6=Elizaveta M. |last7=Logashina |first7=Yulia A. |last8=Andreev |first8=Yaroslav A. |last9=Kirpichnikov |first9=Mikhail P. |last10=Shenkarev |first10=Zakhar O. |date=2023 |title=Recombinant Production, NMR Solution Structure, and Membrane Interaction of the Phα1β Toxin, a TRPA1 Modulator from the Brazilian Armed Spider Phoneutria nigriventer |journal=Toxins |language=en |volume=15 |issue=6 |pages=378 |doi=10.3390/toxins15060378 |doi-access=free |pmid=37368679 |issn=2072-6651 |pmc=10305275}} CTK 01512-2 showed a level of efficacy and potency equivalent to Phα1β.{{Cite journal |last1=de Souza |first1=A. H. |last2=Lima |first2=M. C. |last3=Drewes |first3=C. C. |last4=da Silva |first4=J. F. |last5=Torres |first5=K. C. L. |last6=Pereira |first6=E. M. R. |last7=de Castro |first7=C. J. |last8=Vieira |first8=L. B. |last9=Cordeiro |first9=M. N. |last10=Richardson |first10=M. |last11=Gomez |first11=R. S. |last12=Romano-Silva |first12=M. A. |last13=Ferreira |first13=J. |last14=Gomez |first14=M. V. |date=2011 |title=Antiallodynic effect and side effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer: Comparison with ω-conotoxin MVIIA and morphine |journal=Toxicon |volume=58 |issue=8 |pages=626–633 |doi=10.1016/j.toxicon.2011.09.008 |pmid=21967810 |issn=0041-0101|doi-access=free |bibcode=2011Txcn...58..626D }}
Chemistry
Phα1β (PhTx3-6) is the sixth isoform of the PhTx3 neurotoxin, with a mature peptide of 55 amino acids, including 12 cysteines. These cysteines form six disulfide bonds that contribute to the peptide's stable tertiary structure. The molecular mass, calculated from its mature amino acid sequence, is approximately 6045.03 Da.[https://www.aatbio.com/tools/calculate-peptide-and-protein-molecular-weight-mw]
The following sequence represents the mature peptide's amino acid sequence.
ACIPRGEICT DDCECCGCDN QCYCPPGSSL GIFKCSCAHA NKYFCNRKKE KCKKA
Target and mode of action
The peptide reversibly blocks a variety of voltage-gated calcium channels (VGCCs), including N-type (Cav2.2), R-type (Cav2.3), P/Q-type (Cav2.1), and L-type (Cav1.2) channels, with varying potencies that correspond to IC50 values of 122, 136, 263, and 607 nM, respectively. It induces a complete blockade of N-type-based currents and an incomplete blockade of R-, P/Q- and L-type-based currents. The exact mechanism by which Phα1β influences the functional properties of these ion channels remains unclear. However, it has been suggested that the peptide blocks VGCCs by physically occluding the pore, which could account for its varying effects across this family of channels.{{Cite journal |last1=Vieira |first1=Luciene B. |last2=Kushmerick |first2=Christopher |last3=Hildebrand |first3=Michael E. |last4=Garcia |first4=Esperanza |last5=Stea |first5=Antony |last6=Cordeiro |first6=Marta N. |last7=Richardson |first7=Michael |last8=Gomez |first8=Marcus Vinicius |last9=Snutch |first9=Terrance P. |date=2005 |title=Inhibition of High Voltage-Activated Calcium Channels by Spider Toxin PnTx3-6 |url=https://jpet.aspetjournals.org/content/314/3/1370 |journal=Journal of Pharmacology and Experimental Therapeutics |language=en |volume=314 |issue=3 |pages=1370–1377 |doi=10.1124/jpet.105.087023 |issn=0022-3565 |pmid=15933156|url-access=subscription }} Furthermore, the toxin acts as a specific TRPA1 antagonist. Its affinity within this context has not yet been accurately determined.{{Cite journal |last1=Tonello |first1=Raquel |last2=Fusi |first2=Camilla |last3=Materazzi |first3=Serena |last4=Marone |first4=Ilaria M |last5=De Logu |first5=Francesco |last6=Benemei |first6=Silvia |last7=Gonçalves |first7=Muryel C |last8=Coppi |first8=Elisabetta |last9=Castro-Junior |first9=Celio J |last10=Gomez |first10=Marcus Vinicius |last11=Geppetti |first11=Pierangelo |last12=Ferreira |first12=Juliano |last13=Nassini |first13=Romina |date=2017 |title=The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice |journal=British Journal of Pharmacology |language=en |volume=174 |issue=1 |pages=57–69 |doi=10.1111/bph.13652 |issn=0007-1188 |pmc=5341489 |pmid=27759880}}
Toxicity
Phα1β possesses wide-ranging analgesic and anti-nociceptive effects in animal models, that can be attributed to its modulatory action on VGCCs and TRPA1 receptors.{{Cite journal |last1=Ricardo Carvalho |first1=Vanice Paula |last2=Figueira da Silva |first2=Juliana |last3=Buzelin |first3=Marcelo Araújo |last4=Antônio da Silva Júnior |first4=Cláudio |last5=Carvalho dos Santos |first5=Duana |last6=Montijo Diniz |first6=Danuza |last7=Binda |first7=Nancy Scardua |last8=Borges |first8=Márcia Helena |last9=Senna Guimarães |first9=André Luiz |last10=Rita Pereira |first10=Elizete Maria |last11=Gomez |first11=Marcus Vinicius |date=2021 |title=Calcium channels blockers toxins attenuate abdominal hyperalgesia and inflammatory response associated with the cerulein-induced acute pancreatitis in rats |url=https://linkinghub.elsevier.com/retrieve/pii/S0014299920307640 |journal=European Journal of Pharmacology |volume=891 |pages=173672 |doi=10.1016/j.ejphar.2020.173672 |pmid=33190801 |issn=0014-2999|url-access=subscription }}{{Cite journal |last1=Garcia Mendes |first1=Mariana Peluci |last2=Carvalho dos Santos |first2=Duana |last3=Rezende |first3=Márcio Júnior S. |last4=Assis Ferreira |first4=Luana Caroline |last5=Rigo |first5=Flavia Karine |last6=José de Castro Junior |first6=Célio |last7=Gomez |first7=Marcus Vinicius |date=2021 |title=Effects of intravenous administration of recombinant Phα1β toxin in a mouse model of fibromyalgia |url=https://linkinghub.elsevier.com/retrieve/pii/S004101012100091X |journal=Toxicon |volume=195 |pages=104–110 |doi=10.1016/j.toxicon.2021.03.012 |pmid=33753115 |bibcode=2021Txcn..195..104G |issn=0041-0101|url-access=subscription }}{{Cite journal |last1=Rigo |first1=Flavia Karine |last2=Trevisan |first2=Gabriela |last3=De Prá |first3=Samira Dal-Toé |last4=Cordeiro |first4=Marta Nascimento |last5=Borges |first5=Marcia Helena |last6=Silva |first6=Juliana Figueiredo |last7=Santa Cecilia |first7=Flavia Viana |last8=de Souza |first8=Alessandra Hubner |last9=de Oliveira Adamante |first9=Gabriela |last10=Milioli |first10=Alessandra Marcon |last11=de Castro Junior |first11=Célio José |last12=Ferreira |first12=Juliano |last13=Gomez |first13=Marcus Vinicius |date=2017 |title=The spider toxin Phα1β recombinant possesses strong analgesic activity |url=https://linkinghub.elsevier.com/retrieve/pii/S0041010117301563 |journal=Toxicon |volume=133 |pages=145–152 |doi=10.1016/j.toxicon.2017.05.018 |pmid=28526335 |bibcode=2017Txcn..133..145R |issn=0041-0101|url-access=subscription }}{{Cite journal |last1=Souza |first1=Alessandra H. |last2=Ferreira |first2=Juliano |last3=Cordeiro |first3=Marta do Nascimento |last4=Vieira |first4=Luciene Bruno |last5=De Castro |first5=Celio J. |last6=Trevisan |first6=Gabriela |last7=Reis |first7=Helton |last8=Souza |first8=Ivana Assis |last9=Richardson |first9=Michael |last10=Prado |first10=Marco A. M. |last11=Prado |first11=Vânia F. |last12=Gomez |first12=Marcus Vinicius |date=2008 |title=Analgesic effect in rodents of native and recombinant Phα1β toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom |url=https://journals.lww.com/pain/abstract/2008/11150/analgesic_effect_in_rodents_of_native_and.13.aspx |journal=PAIN |language=en-US |volume=140 |issue=1 |pages=115–126 |doi=10.1016/j.pain.2008.07.014 |pmid=18774645 |issn=0304-3959|url-access=subscription }} Furthermore, it is known to be effective at doses that induce little to no side effects in animal models. While Phoneutria nigriventer venom is highly neurotoxic and can cause a range of symptoms that may include agitation, hypertension, perspiration, excessive salivation, nausea, profuse vomiting, lacrimation, somnolence, tachycardia, tachypnea, spasms, tremors, and priapism, the toxicity of Phα1β has not been sufficiently characterized to provide estimates of its LD50 or specific side effects.{{Citation |last1=de Lima |first1=Maria Elena |title=Phoneutria nigriventer Venom and Toxins: A Review |date=2016 |work=Spider Venoms |pages=71–99 |editor-last=Gopalakrishnakone |editor-first=P. |url=https://link.springer.com/referenceworkentry/10.1007/978-94-007-6389-0_6 |access-date=2024-10-22 |place=Dordrecht |publisher=Springer Netherlands |language=en |doi=10.1007/978-94-007-6389-0_6 |isbn=978-94-007-6389-0 |last2=Figueiredo |first2=Suely Gomes |last3=Matavel |first3=Alessandra |last4=Nunes |first4=Kenia Pedrosa |last5=da Silva |first5=Carolina Nunes |last6=De Marco Almeida |first6=Flávia |last7=Diniz |first7=Marcelo Ribeiro Vasconcelos |last8=do Cordeiro |first8=Marta Nascimento |last9=Stankiewicz |first9=Maria |editor2-last=Corzo |editor2-first=Gerardo A. |editor3-last=de Lima |editor3-first=Maria Elena |editor4-last=Diego-García |editor4-first=Elia|url-access=subscription }}
Therapeutic use
Phα1β exhibits anti-nociceptive effects by inhibiting pro-nociceptive glutamate release induced by influx of calcium ions (Ca2+) or by inhibiting TRPA1 channels.{{Cite journal |last1=de Souza |first1=A. H. |last2=Lima |first2=M. C. |last3=Drewes |first3=C. C. |last4=da Silva |first4=J. F. |last5=Torres |first5=K. C. L. |last6=Pereira |first6=E. M. R. |last7=de Castro |first7=C. J. |last8=Vieira |first8=L. B. |last9=Cordeiro |first9=M. N. |last10=Richardson |first10=M. |last11=Gomez |first11=R. S. |last12=Romano-Silva |first12=M. A. |last13=Ferreira |first13=J. |last14=Gomez |first14=M. V. |date=2011 |title=Antiallodynic effect and side effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer: Comparison with ω-conotoxin MVIIA and morphine |journal=Toxicon |volume=58 |issue=8 |pages=626–633 |doi=10.1016/j.toxicon.2011.09.008 |pmid=21967810 |issn=0041-0101|doi-access=free |bibcode=2011Txcn...58..626D }}
The cell bodies of sensory nerves, which are involved in neurogenic or inflammatory conditions, are primarily located in the Dorsal Root Ganglia (DRG).{{Cite journal |last1=Staton |first1=Penny C. |last2=Wilson |first2=Alex W. |last3=Bountra |first3=Chas |last4=Chessell |first4=Iain P. |last5=Day |first5=Nicola C. |date=2007 |title=Changes in dorsal root ganglion CGRP expression in a chronic inflammatory model of the rat knee joint: Differential modulation by rofecoxib and paracetamol |url=https://onlinelibrary.wiley.com/doi/10.1016/j.ejpain.2006.03.006 |journal=European Journal of Pain |language=en |volume=11 |issue=3 |pages=283–289 |doi=10.1016/j.ejpain.2006.03.006 |pmid=16690336 |issn=1090-3801|url-access=subscription }} Phα1β attenuates the pain response by targeting synaptic transmission in these neurons in the following two ways.
= 1. Nociceptive modulation by voltage-gated calcium channels (VGCCs) =
Upon activation of L, N, and P/Q type VGCCs in response to painful stimuli, glutamate is released. N-type channels (Cav2.2) respond most potently to painful stimuli. Thus, they are central to analgesic research as they constitute the primary source of Ca2+ influx, and are upregulated in response to chronic pain.{{Cite journal |last1=Miljanich |first1=G P |last2=Ramachandran |first2=J |date=1995 |title=Antagonists of Neuronal Calcium Channels: Structure, Function, and Therapeutic Implications |url=https://www.annualreviews.org/doi/10.1146/annurev.pa.35.040195.003423 |journal=Annual Review of Pharmacology and Toxicology |language=en |volume=35 |issue=1 |pages=707–734 |doi=10.1146/annurev.pa.35.040195.003423 |pmid=7598513 |issn=0362-1642|url-access=subscription }}{{Cite journal |last1=Cizkova |first1=Dasa |last2=Marsala |first2=Jozef |last3=Lukacova |first3=Nadezda |last4=Marsala |first4=Martin |last5=Jergova |first5=Stanislava |last6=Orendacova |first6=Judita |last7=Yaksh |first7=Tony L. |date=2002 |title=Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury |url=https://link.springer.com/article/10.1007/s00221-002-1217-3 |journal=Experimental Brain Research |language=en |volume=147 |issue=4 |pages=456–463 |doi=10.1007/s00221-002-1217-3 |pmid=12444477 |issn=1432-1106|url-access=subscription }} Phα1β inhibits N-type channels, resulting in a decrease of glutamate influx and consequently reduced pain perception.
= 2. Nociceptive modulation by non-selective cation channels =
Phα1β also affects the signal transmission of sensory neurons by targeting TRPA1 channels, which are non-selective cation channels predominantly found in the DRG. TRPA1 channels constitute a major pain conduction pathway.{{Cite journal |last1=Andrade |first1=E. L. |last2=Meotti |first2=F. C. |last3=Calixto |first3=J. B. |date=2012 |title=TRPA1 antagonists as potential analgesic drugs |url=https://linkinghub.elsevier.com/retrieve/pii/S016372581100204X |journal=Pharmacology & Therapeutics |volume=133 |issue=2 |pages=189–204 |doi=10.1016/j.pharmthera.2011.10.008 |pmid=22119554 |issn=0163-7258|url-access=subscription }}{{Citation |last1=Nassini |first1=Romina |title=The TRPA1 Channel in Inflammatory and Neuropathic Pain and Migraine |date=2014 |work=Reviews of Physiology, Biochemistry and Pharmacology, Vol. 167 |volume=167 |pages=1–43 |editor-last=Nilius |editor-first=Bernd |url=https://link.springer.com/10.1007/112_2014_18 |access-date=2024-10-23 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/112_2014_18 |isbn=978-3-319-11920-5 |last2=Materazzi |first2=Serena |last3=Benemei |first3=Silvia |last4=Geppetti |first4=Pierangelo |pmid=24668446 |editor2-last=Gudermann |editor2-first=Thomas |editor3-last=Jahn |editor3-first=Reinhard |editor4-last=Lill |editor4-first=Roland|url-access=subscription }} Phα1β acts as an antagonist for TRPA1, effectively inhibiting the calcium responses induced by TRPA1 agonists such as allyl isothiocyanate (AITC).
Compared to similar toxins (MVIIA, which is a ω-conotoxin), Phα1β has a significantly wider therapeutic index, no evident side effects in controlled settings in animal models, and longer-lasting analgesic effects. Phα1β achieves maximum pain relief comparable to other analogs (MVIIA), with a higher effective dose (ED50) and lower inhibitory dose (ID50), indicating enhanced safety and potency at lower concentrations. Importantly, Phα1β has the potential to prevent and reverse chronic pain conditions, such as those induced by complete Freund’s adjuvant (CFA), and alleviate symptoms of allodynia and hyperalgesia. Additionally, its analgesic and anti-inflammatory properties could also be utilized for pain treatment in cancer patients.{{Cite journal |last1=Rigo |first1=Flavia Karine |last2=Trevisan |first2=Gabriela |last3=Rosa |first3=Fernanda |last4=Dalmolin |first4=Gerusa D. |last5=Otuki |first5=Michel Fleith |last6=Cueto |first6=Ana Paula |last7=de Castro Junior |first7=Célio José |last8=Romano-Silva |first8=Marco Aurelio |last9=Cordeiro |first9=Marta do N. |last10=Richardson |first10=Michael |last11=Ferreira |first11=Juliano |last12=Gomez |first12=Marcus V. |date=2013 |title=Spider peptide Phα1β induces analgesic effect in a model of cancer pain |journal=Cancer Science |language=en |volume=104 |issue=9 |pages=1226–1230 |doi=10.1111/cas.12209 |issn=1347-9032 |pmc=7657190 |pmid=23718272}} Interestingly, Phα1β also appears to mitigate or even prevent symptoms in a mouse model of Huntington’s Disease, where it may exhibit neuroprotective effects and improve motor performance.{{Cite journal |last1=Joviano-Santos |first1=Julliane V. |last2=Valadão |first2=Priscila A.C. |last3=Magalhães-Gomes |first3=Matheus P.S. |last4=Fernandes |first4=Lorena F. |last5=Diniz |first5=Danuza M. |last6=Machado |first6=Thatiane C.G. |last7=Soares |first7=Kivia B. |last8=Ladeira |first8=Marina S. |last9=Miranda |first9=Aline S. |last10=Massensini |first10=Andre R. |last11=Gomez |first11=Marcus V. |last12=Guatimosim |first12=Cristina |date=2021 |title=Protective effect of a spider recombinant toxin in a murine model of Huntington's disease |url=https://linkinghub.elsevier.com/retrieve/pii/S0143417920301293 |journal=Neuropeptides |volume=85 |pages=102111 |doi=10.1016/j.npep.2020.102111 |pmid=33333486 |issn=0143-4179|url-access=subscription }}{{Cite journal |last1=Joviano-Santos |first1=Julliane V. |last2=Valadão |first2=Priscila A. C. |last3=Magalhães-Gomes |first3=Matheus P. S. |last4=Fernandes |first4=Lorena F. |last5=Diniz |first5=Danuza M. |last6=Machado |first6=Thatiane C. G. |last7=Soares |first7=Kivia B. |last8=Ladeira |first8=Marina S. |last9=Massensini |first9=Andre R. |last10=Gomez |first10=Marcus V. |last11=Miranda |first11=Aline S. |last12=Tápia |first12=Juan C. |last13=Guatimosim |first13=Cristina |date=2022 |title=Neuroprotective effect of CTK 01512-2 recombinant toxin at the spinal cord in a model of Huntington's disease |url=https://physoc.onlinelibrary.wiley.com/doi/10.1113/EP090327 |journal=Experimental Physiology |language=en |volume=107 |issue=8 |pages=933–945 |doi=10.1113/EP090327 |pmid=35478205 |issn=0958-0670|url-access=subscription }}
Phα1β is potentially useful for the treatment of various pain conditions, including acute and chronic inflammatory or neuropathic pain. Additionally, its potential may extend to neurodegenerative diseases such as Huntington's disease. Studies in human subjects would be required to explore its broader therapeutic applications and efficacy across different neurological conditions.