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Phα1β

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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.

Phα1β
Identifiers
3D model (JSmol)
  • InChI=1S/C248H382N74O78S12/c1-14-120(6)192-240(393)301-152(88-129-44-21-18-22-45-129)215(368)283-142(52-29-36-80-255)209(362)308-170-113-411-412-117-174(243(396)322-85-41-57-177(322)244(397)320-83-39-55-175(320)238(391)271-101-183(334)277-160(103-323)225(378)303-161(104-324)226(379)293-148(86-119(4)5)200(353)269-102-185(336)316-192)315-218(371)151(90-131-60-64-134(328)65-61-131)296-232(385)168-111-407-410-116-173-237(390)319-195(127(13)326)242(395)302-159(97-191(347)348)223(376)299-158(96-190(345)346)224(377)312-167-110-406-405-109-166(230(383)286-139(49-26-33-77-252)204(357)279-136(46-23-30-74-249)202(355)275-126(12)246(399)400)307-208(361)141(51-28-35-79-254)282-210(363)146(68-72-187(339)340)287-205(358)138(48-25-32-76-251)280-203(356)137(47-24-31-75-250)281-206(359)143(54-38-82-267-248(263)264)285-220(373)156(94-181(260)332)298-233(386)169-112-404-402-107-164(229(382)300-157(95-189(343)344)222(375)297-155(93-180(259)331)221(374)288-145(211(364)309-168)66-70-178(257)329)278-184(335)100-270-201(354)163(106-401-409-115-172(305-196(349)123(9)256)236(389)318-194(122(8)16-3)245(398)321-84-40-56-176(321)239(392)290-135(53-37-81-266-247(261)262)199(352)268-99-182(333)276-144(67-71-186(337)338)213(366)317-193(121(7)15-2)241(394)314-173)306-235(388)171(310-212(365)147(289-231(167)384)69-73-188(341)342)114-408-403-108-165(313-227(380)162(105-325)304-234(170)387)228(381)274-125(11)197(350)291-153(91-132-98-265-118-272-132)214(367)273-124(10)198(351)292-154(92-179(258)330)219(372)284-140(50-27-34-78-253)207(360)294-150(89-130-58-62-133(327)63-59-130)216(369)295-149(217(370)311-169)87-128-42-19-17-20-43-128/h17-22,42-45,58-65,98,118-127,135-177,192-195,323-328H,14-16,23-41,46-57,66-97,99-117,249-256H2,1-13H3,(H2,257,329)(H2,258,330)(H2,259,331)(H2,260,332)(H,265,272)(H,268,352)(H,269,353)(H,270,354)(H,271,391)(H,273,367)(H,274,381)(H,275,355)(H,276,333)(H,277,334)(H,278,335)(H,279,357)(H,280,356)(H,281,359)(H,282,363)(H,283,368)(H,284,372)(H,285,373)(H,286,383)(H,287,358)(H,288,374)(H,289,384)(H,290,392)(H,291,350)(H,292,351)(H,293,379)(H,294,360)(H,295,369)(H,296,385)(H,297,375)(H,298,386)(H,299,376)(H,300,382)(H,301,393)(H,302,395)(H,303,378)(H,304,387)(H,305,349)(H,306,388)(H,307,361)(H,308,362)(H,309,364)(H,310,365)(H,311,370)(H,312,377)(H,313,380)(H,314,394)(H,315,371)(H,316,336)(H,317,366)(H,318,389)(H,319,390)(H,337,338)(H,339,340)(H,341,342)(H,343,344)(H,345,346)(H,347,348)(H,399,400)(H4,261,262,266)(H4,263,264,267)/t120-,121-,122-,123-,124-,125-,126-,127+,135-,136-,137-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,167-,168-,169-,170-,171-,172-,173-,174-,175-,176-,177-,192-,193-,194-,195-/m0/s1
    Key: QGMVGSCZYUDILO-FPHUJEMDSA-N
  • N[C@@]([H])(C)C(=O)N[C@@]([H])(CS7)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N1[C@@]([H])(CCC1)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)NCC(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(CS2)C(=O)N[C@@]([H])([C@]([H])(O)C)C(=O)N[C@@]([H])(CC(=O)O)C(=O)N[C@@]([H])(CC(=O)O)C(=O)N[C@@]([H])(CS3)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])(CS4)C(=O)N[C@@]([H])(CS7)C(=O)NCC(=O)N[C@@]([H])(CS5)C(=O)N[C@@]([H])(CC(=O)O)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CCC(=O)N)C(=O)N[C@@]([H])(CS2)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])(CS6)C(=O)N1[C@@]([H])(CCC1)C(=O)N1[C@@]([H])(CCC1)C(=O)NCC(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CC(C)C)C(=O)NCC(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CS6)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CS4)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(CS5)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CS3)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(C)C(=O)O
Properties
C248H382N74O78S12
Molar mass 6032.94 g·mol−1
Related compounds
Related compounds
 PnTx3-4, PLTX-II, ω-Aga-IIIA, ICK-OtTx-1A, DW-13.3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Source and Etymology

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Phα1β is purified from the venom of Phoneutria nigriventer, commonly known as the “armed spider”.[1] To ensure abundant supply and wide-scale therapeutic application of Phα1β, a recombinant peptide (CTK 01512-2) can be synthesized.[2] CTK 01512-2 showed a level of efficacy and potency equivalent to Phα1β.[3][2]

Chemistry

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Phα1β (PhTx3-6) is the sixth isoform of the PhTx3 neurotoxin, with a mature peptide of 55 amino acids, including 12 cysteines.[1] These cysteines form six disulfide bonds that contribute to the peptide's stable tertiary structure.[2] The molecular mass, calculated from its mature amino acid sequence, is approximately 6045.03 Da.[1]

The following sequence represents the mature peptide's chain of amino acids.[1]

ACIPRGEICT DDCECCGCDN QCYCPPGSSL GIFKCSCAHA NKYFCNRKKE KCKKA

Target and mode of action

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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.[4] Furthermore, the toxin acts as a specific TRPA1 antagonist. Its affinity within this context has not yet been accurately determined.[5]

Toxicity

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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.[5][6][7][8][9] Furthermore, it is known to be effective at doses that induce little to no side effects.[8][9] 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.[10] Nonetheless, its safety profile at effective doses suggests it as a promising candidate for therapeutic use.[9]

Therapeutic use

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Phα1β exhibits anti-nociceptive effects by inhibiting pro-nociceptive glutamate release induced by calcium (Ca2+) influx, reducing glutamate levels in the cerebral spinal fluid (CSF), or inhibiting TRPA1 channels.[11][5]

The cell bodies of sensory nerves, which are involved in neurogenic or inflammatory conditions, are primarily located in the Dorsal Root Ganglia (DRG).[12] Phα1β attenuates pain response by targeting synaptic transmission of these neurons in the following two ways.

1. Nociceptive modulation by voltage-gated calcium channels (VGCCs)

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Nociception is modulated by VGCCs.[13] In the context of inflammatory and neurogenic pain, VGCCs perform two key functions:

  1. Regulation of Ca2+, as calcium influx is known to enhance sensory activity by amplifying pain perception. An increase in calcium promotes greater excitability and intensifies the transmission of pain signals, which can lead to acute as well as chronic pain.[14]
  2. Enabling neurotransmitter (NTM) expression - specifically glutamate exocytosis - by selectively gating ionic flux of Ca2+ across the membrane.[9]

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.[9] Thus, they are central to analgesic research as they constitute the primary source of Ca2+ influx, and are upregulated in response to chronic pain.[15][16]

Phα1β inhibits N-type channels and therefore Ca2+ concentrations, resulting in a decrease of glutamate influx and consequently reduced pain perception.[9]

2. Nociceptive modulation by non-selective cation channels

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Phα1β also affects the signal transmission of sensory neurons by targeting TRPA1 channels, which are non-selective cation channels predominantly found in the DRG.[12][5] TRPA1 channels constitute a major pain conduction pathway.[17][18] Phα1β acts as an antagonist for TRPA1, effectively inhibiting the excitatory calcium response induced by TRPA1 agonists like allyl isothiocyanate (AITC).[5]

Treatment

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Compared to similar toxins (MVIIA, which is a ω-conotoxin), Phα1β has a significantly wider therapeutic index, no side effects in controlled settings, and longer-lasting analgesic effects.[9] 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.[9] 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.[3] Additionally, its analgesic and anti-inflammatory properties could also be utilized for pain treatment in cancer patients.[19] Interestingly, Phα1β also appears to mitigate or even prevent symptoms of Huntington’s Disease, where it may exhibit neuroprotective effects and improve motor performance.[20][21]

Phα1β shows considerable promise for the treatment of various pain conditions, including acute and chronic inflammatory or neuropathic pain.[3][9] Additionally, its potential may extend to neurodegenerative diseases such as Huntington's disease.[20][21] While present findings are encouraging, further research is required to explore its broader therapeutic applications and efficacy across different neurological conditions.

References

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  1. ^ a b c Cordeiro, Marta do Nascimento; de Figueiredo, Suely Gomes; Valentim, Ana do Carmo; Diniz, Carlos Ribeiro; von Eickstedt, Vera Regina D.; Gilroy, John; Richardson, Michael (1993). "Purification and amino acid sequences of six Tx3 type neurotoxins from the venom of the Brazilian 'armed' spider Phoneutria Nigriventer (keys.)". Toxicon. 31 (1): 35–42. doi:10.1016/0041-0101(93)90354-L. ISSN 0041-0101. PMID 8446961.
  2. ^ a b c Lyukmanova, Ekaterina N.; Mironov, Pavel A.; Kulbatskii, Dmitrii S.; Shulepko, Mikhail A.; Paramonov, Alexander S.; Chernaya, Elizaveta M.; Logashina, Yulia A.; Andreev, Yaroslav A.; Kirpichnikov, Mikhail P.; Shenkarev, Zakhar O. (2023). "Recombinant Production, NMR Solution Structure, and Membrane Interaction of the Phα1β Toxin, a TRPA1 Modulator from the Brazilian Armed Spider Phoneutria nigriventer". Toxins. 15 (6): 378. doi:10.3390/toxins15060378. ISSN 2072-6651. PMC 10305275. PMID 37368679.
  3. ^ a b c de Souza, A. H.; Lima, M. C.; Drewes, C. C.; da Silva, J. F.; Torres, K. C. L.; Pereira, E. M. R.; de Castro, C. J.; Vieira, L. B.; Cordeiro, M. N.; Richardson, M.; Gomez, R. S.; Romano-Silva, M. A.; Ferreira, J.; Gomez, M. V. (2011). "Antiallodynic effect and side effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer: Comparison with ω-conotoxin MVIIA and morphine". Toxicon. 58 (8): 626–633. doi:10.1016/j.toxicon.2011.09.008. ISSN 0041-0101. PMID 21967810.
  4. ^ Vieira, Luciene B.; Kushmerick, Christopher; Hildebrand, Michael E.; Garcia, Esperanza; Stea, Antony; Cordeiro, Marta N.; Richardson, Michael; Gomez, Marcus Vinicius; Snutch, Terrance P. (2005). "Inhibition of High Voltage-Activated Calcium Channels by Spider Toxin PnTx3-6". Journal of Pharmacology and Experimental Therapeutics. 314 (3): 1370–1377. doi:10.1124/jpet.105.087023. ISSN 0022-3565. PMID 15933156.
  5. ^ a b c d e Tonello, Raquel; Fusi, Camilla; Materazzi, Serena; Marone, Ilaria M; De Logu, Francesco; Benemei, Silvia; Gonçalves, Muryel C; Coppi, Elisabetta; Castro-Junior, Celio J; Gomez, Marcus Vinicius; Geppetti, Pierangelo; Ferreira, Juliano; Nassini, Romina (2017). "The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice". British Journal of Pharmacology. 174 (1): 57–69. doi:10.1111/bph.13652. ISSN 0007-1188. PMC 5341489. PMID 27759880.
  6. ^ Ricardo Carvalho, Vanice Paula; Figueira da Silva, Juliana; Buzelin, Marcelo Araújo; Antônio da Silva Júnior, Cláudio; Carvalho dos Santos, Duana; Montijo Diniz, Danuza; Binda, Nancy Scardua; Borges, Márcia Helena; Senna Guimarães, André Luiz; Rita Pereira, Elizete Maria; Gomez, Marcus Vinicius (2021). "Calcium channels blockers toxins attenuate abdominal hyperalgesia and inflammatory response associated with the cerulein-induced acute pancreatitis in rats". European Journal of Pharmacology. 891: 173672. doi:10.1016/j.ejphar.2020.173672. ISSN 0014-2999. PMID 33190801.
  7. ^ Garcia Mendes, Mariana Peluci; Carvalho dos Santos, Duana; Rezende, Márcio Júnior S.; Assis Ferreira, Luana Caroline; Rigo, Flavia Karine; José de Castro Junior, Célio; Gomez, Marcus Vinicius (2021). "Effects of intravenous administration of recombinant Phα1β toxin in a mouse model of fibromyalgia". Toxicon. 195: 104–110. doi:10.1016/j.toxicon.2021.03.012. ISSN 0041-0101. PMID 33753115.
  8. ^ a b Rigo, Flavia Karine; Trevisan, Gabriela; De Prá, Samira Dal-Toé; Cordeiro, Marta Nascimento; Borges, Marcia Helena; Silva, Juliana Figueiredo; Santa Cecilia, Flavia Viana; de Souza, Alessandra Hubner; de Oliveira Adamante, Gabriela; Milioli, Alessandra Marcon; de Castro Junior, Célio José; Ferreira, Juliano; Gomez, Marcus Vinicius (2017). "The spider toxin Phα1β recombinant possesses strong analgesic activity". Toxicon. 133: 145–152. doi:10.1016/j.toxicon.2017.05.018. ISSN 0041-0101. PMID 28526335.
  9. ^ a b c d e f g h i Souza, Alessandra H.; Ferreira, Juliano; Cordeiro, Marta do Nascimento; Vieira, Luciene Bruno; De Castro, Celio J.; Trevisan, Gabriela; Reis, Helton; Souza, Ivana Assis; Richardson, Michael; Prado, Marco A. M.; Prado, Vânia F.; Gomez, Marcus Vinicius (2008). "Analgesic effect in rodents of native and recombinant Phα1β toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom". PAIN. 140 (1): 115–126. doi:10.1016/j.pain.2008.07.014. ISSN 0304-3959. PMID 18774645.
  10. ^ de Lima, Maria Elena; Figueiredo, Suely Gomes; Matavel, Alessandra; Nunes, Kenia Pedrosa; da Silva, Carolina Nunes; De Marco Almeida, Flávia; Diniz, Marcelo Ribeiro Vasconcelos; do Cordeiro, Marta Nascimento; Stankiewicz, Maria (2016), Gopalakrishnakone, P.; Corzo, Gerardo A.; de Lima, Maria Elena; Diego-García, Elia (eds.), "Phoneutria nigriventer Venom and Toxins: A Review", Spider Venoms, Dordrecht: Springer Netherlands, pp. 71–99, doi:10.1007/978-94-007-6389-0_6, ISBN 978-94-007-6389-0, retrieved 2024-10-22
  11. ^ de Souza, A. H.; Lima, M. C.; Drewes, C. C.; da Silva, J. F.; Torres, K. C. L.; Pereira, E. M. R.; de Castro, C. J.; Vieira, L. B.; Cordeiro, M. N.; Richardson, M.; Gomez, R. S.; Romano-Silva, M. A.; Ferreira, J.; Gomez, M. V. (2011). "Antiallodynic effect and side effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer: Comparison with ω-conotoxin MVIIA and morphine". Toxicon. 58 (8): 626–633. doi:10.1016/j.toxicon.2011.09.008. ISSN 0041-0101. PMID 21967810.
  12. ^ a b Staton, Penny C.; Wilson, Alex W.; Bountra, Chas; Chessell, Iain P.; Day, Nicola C. (2007). "Changes in dorsal root ganglion CGRP expression in a chronic inflammatory model of the rat knee joint: Differential modulation by rofecoxib and paracetamol". European Journal of Pain. 11 (3): 283–289. doi:10.1016/j.ejpain.2006.03.006. ISSN 1090-3801. PMID 16690336.
  13. ^ ALTIER, C; ZAMPONI, G (2004). "Targeting Ca channels to treat pain: T-type versus N-type". Trends in Pharmacological Sciences. 25 (9): 465–470. doi:10.1016/j.tips.2004.07.004. ISSN 0165-6147. PMID 15559248.
  14. ^ Gribkoff, Valentin K; Winquist, Raymond J (2005). "Modulators of peripheral voltage-gated sodium channels for the treatment of neuropathic pain". Expert Opinion on Therapeutic Patents. 15 (12): 1751–1762. doi:10.1517/13543776.15.12.1751. ISSN 1354-3776.
  15. ^ Miljanich, G P; Ramachandran, J (1995). "Antagonists of Neuronal Calcium Channels: Structure, Function, and Therapeutic Implications". Annual Review of Pharmacology and Toxicology. 35 (1): 707–734. doi:10.1146/annurev.pa.35.040195.003423. ISSN 0362-1642. PMID 7598513.
  16. ^ Cizkova, Dasa; Marsala, Jozef; Lukacova, Nadezda; Marsala, Martin; Jergova, Stanislava; Orendacova, Judita; Yaksh, Tony L. (2002). "Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury". Experimental Brain Research. 147 (4): 456–463. doi:10.1007/s00221-002-1217-3. ISSN 1432-1106. PMID 12444477.
  17. ^ Andrade, E. L.; Meotti, F. C.; Calixto, J. B. (2012). "TRPA1 antagonists as potential analgesic drugs". Pharmacology & Therapeutics. 133 (2): 189–204. doi:10.1016/j.pharmthera.2011.10.008. ISSN 0163-7258. PMID 22119554.
  18. ^ Nassini, Romina; Materazzi, Serena; Benemei, Silvia; Geppetti, Pierangelo (2014), Nilius, Bernd; Gudermann, Thomas; Jahn, Reinhard; Lill, Roland (eds.), "The TRPA1 Channel in Inflammatory and Neuropathic Pain and Migraine", Reviews of Physiology, Biochemistry and Pharmacology, Vol. 167, vol. 167, Cham: Springer International Publishing, pp. 1–43, doi:10.1007/112_2014_18, ISBN 978-3-319-11920-5, PMID 24668446, retrieved 2024-10-23
  19. ^ Rigo, Flavia Karine; Trevisan, Gabriela; Rosa, Fernanda; Dalmolin, Gerusa D.; Otuki, Michel Fleith; Cueto, Ana Paula; de Castro Junior, Célio José; Romano-Silva, Marco Aurelio; Cordeiro, Marta do N.; Richardson, Michael; Ferreira, Juliano; Gomez, Marcus V. (2013). "Spider peptide Phα1β induces analgesic effect in a model of cancer pain". Cancer Science. 104 (9): 1226–1230. doi:10.1111/cas.12209. ISSN 1347-9032. PMC 7657190. PMID 23718272.
  20. ^ a b Joviano-Santos, Julliane V.; Valadão, Priscila A.C.; Magalhães-Gomes, Matheus P.S.; Fernandes, Lorena F.; Diniz, Danuza M.; Machado, Thatiane C.G.; Soares, Kivia B.; Ladeira, Marina S.; Miranda, Aline S.; Massensini, Andre R.; Gomez, Marcus V.; Guatimosim, Cristina (2021). "Protective effect of a spider recombinant toxin in a murine model of Huntington's disease". Neuropeptides. 85: 102111. doi:10.1016/j.npep.2020.102111. ISSN 0143-4179. PMID 33333486.
  21. ^ a b Joviano-Santos, Julliane V.; Valadão, Priscila A. C.; Magalhães-Gomes, Matheus P. S.; Fernandes, Lorena F.; Diniz, Danuza M.; Machado, Thatiane C. G.; Soares, Kivia B.; Ladeira, Marina S.; Massensini, Andre R.; Gomez, Marcus V.; Miranda, Aline S.; Tápia, Juan C.; Guatimosim, Cristina (2022). "Neuroprotective effect of CTK 01512-2 recombinant toxin at the spinal cord in a model of Huntington's disease". Experimental Physiology. 107 (8): 933–945. doi:10.1113/EP090327. ISSN 0958-0670. PMID 35478205.
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