Exploring Venom Toxins as Molecular Models for Chronic Pain Treatment

Authors

DOI:

https://doi.org/10.47611/jsrhs.v11i1.2365

Keywords:

Opioids, Analgesia, Sodium Channels, Venom, Toxins, Chronic Pain, Molecular Model

Abstract

The purpose of this project is to propose venomous animal toxins as molecular models for pain medication. Chronic pain is a prevalent health problem among the general population, and current pharmacological treatments are oftentimes ineffective or limited due to undesirable side-effects. This project explores the role of specific Voltage- Gated Sodium Channels, such as Sodium Channel 1.7 (NaV 1.7), in setting the stage for proposing analgesics with binding properties in peripheral pain-sensing neurons. Sodium Channels, notably NaV 1.7, play a major role in human pain signaling pathways that propagate action potentials in excitable cells. By inhibiting and blocking them, analgesic effects are known to be achievable. Through means of bioinformatic tools, we explore amino acid sequence alignments, Motif scans, tertiary structure modeling, and molecular docking of venomous animal toxins for in-silico new drug discovery research. Cysteine residues in toxins were reviewed as a possible link between acting upon the receptor and their analgesic effects. This led to the questioning of cysteine's role in the search for potential antagonists of NaV 1.7. Eventually, the attempt for a further investigation prompted the consideration for molecular docking between selected toxins and the receptor, aiming to seize chronic pain.

Downloads

Download data is not yet available.

Author Biography

Dr. Olga Chaim , University of California San Diego, School of Medicine, La Jolla, CA

Advisor

Olga Meiri Chaim, Pharm. D., Ph.D. 

Assistant Project Scientist 

Department of Pharmacology - School of Medicine 

University of California San Diego, La Jolla, CA. 

References or Bibliography

Harvey A. L. (2014). Toxins and drug discovery. Toxicon : official journal of the International Society on Toxinology, 92, 193–200. https://doi.org/10.1016/j.toxicon.2014.10.020

Scholz J. (2014). Mechanisms of chronic pain. Molecular Pain, 10(Suppl 1), O15. https://doi.org/10.1186/1744- 8069-10-S1-O15

Salsitz E. A. (2016). Chronic Pain, Chronic Opioid Addiction: a Complex Nexus. Journal of medical toxicology : official journal of the American College of Medical Toxicology, 12(1), 54–57. https://doi.org/10.1007/s13181-015- 0521-9

Spahr, N., Hodkinson, D., Jolly, K., Williams, S., Howard, M., & Thacker, M. (2017). Distinguishing between nociceptive and neuropathic components in chronic low back pain using behavioural evaluation and sensory examination. Musculoskeletal science & practice, 27, 40–48. https://doi.org/10.1016/j.msksp.2016.12.006

Montero-Homs J. (2009). Dolor nociceptivo, dolor neuropático y memoria de dolor [Nociceptive pain, neuropathic pain and pain memory]. Neurologia (Barcelona, Spain), 24(6), 419–422.

Jan, F. K., & Wilson, P. E. (2004). A survey of chronic pain in the pediatric spinal cord injury population. The journal of spinal cord medicine, 27 Suppl 1, S50–S53. https://doi.org/10.1080/10790268.2004.11753785

Cummins, T. R., Sheets, P. L., & Waxman, S. G. (2007). The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain, 131(3), 243–257. https://doi.org/10.1016/j.pain.2007.07.026

Gold, M. S., & Gebhart, G. F. (2010). Nociceptor sensitization in pain pathogenesis. Nature medicine, 16(11), 1248– 1257. https://doi.org/10.1038/nm.2235

Levinson, S. R., Luo, S., & Henry, M. A. (2012). The role of sodium channels in chronic pain. Muscle & nerve, 46(2), 155–165. https://doi.org/10.1002/mus.23314

Wie, C. S., & Derian, A. (2021). Ziconotide. In S tatPearls. StatPearls Publishing. Animal-World. (n.d.). Vietnamese Centipede. Animal World. https://animal-world.com/encyclo/reptiles/centipedes/VietnameseCentipede.php.

Ian. (2019, October 26). Peruvian green Velvet (THRIXOPELMA PRURIENS). Tarantula Friendly.

https://tarantulafriendly.com/peruvian-green-velvet/.

Australian tarantulas. The Australian Museum. (n.d.). https://australian.museum/learn/animals/spiders/australian-

tarantulas/.

Kerley, C. (2019, November 22). Poisonous spiders in China. Sciencing. https://sciencing.com/poisonous-spiders-

china-6059950.html.

Hall, M. (n.d.). Conus GEOGRAPHUS (GEOGRAPHY Cone snail). Animal Diversity Web.

https://animaldiversity.org/accounts/Conus_geographus/.

Huntsman spider - Facts, bite & Habitat Information. Animal Corner. (2017, February 8).

https://animalcorner.org/animals/huntsman-spider/.

Animal-World. (n.d.). Panther puffer. Animal World. https://animal-world.com/encyclo/marine/puffers/panther.php.

Broadbent, S. (2018, August 2). About the manchurian scorpion. EntoBlog. https://www.entoblog.com/about-the- manchurian-scorpion/.

Animal-World. (n.d.). Striped scorpion. Animal World. https://animal- world.com/encyclo/reptiles/scorpions/StripedScorpion.php.

Drake, N. (2021, May 3). Science still can't explain why these tarantulas are blue. Animals. https://www.nationalgeographic.com/animals/article/151127-blue-tarantula-science-explain-animals.

(n.d.). Pubmed. National Center for Biotechnology Information. https://pubmed.ncbi.nlm.nih.gov/.

(n.d.). UniProt consortium. UniProt ConsortiumEuropean Bioinformatics Institute Protein Information Resource SIB Swiss Institute of Bioinformatics. https://www.uniprot.org/.

(n.d.). COBALT:Multiple alignment tool. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/tools/cobalt/re_cobalt.cgi.

Motif: Searching protein sequence motifs. GenomeNet icon. (n.d.). https://www.genome.jp/tools/motif/. Motif scan. (1970, January 1). https://myhits.sib.swiss/cgi-bin/motif_scan.

Model. SWISS. (n.d.). https://swissmodel.expasy.org/.

Bank, R. C. S. B. P. D. (n.d.). The Protein Data Bank. RCSB PDB. https://www.rcsb.org/.

Desta IT, Porter KA, Xia B, Kozakov D, Vajda S. Performance and Its Limits in Rigid Body Protein-Protein Docking. Structure. 2020 Sep; 28 (9):1071-1081. doi Vajda S, Yueh C, Beglov D, Bohnuud T, Mottarella SE, Xia B, Hall DR, Kozakov D. New additions to the ClusPro server motivated by CAPRI. Proteins: Structure, Function, and Bioinformatics. 2017 Mar; 85(3):435-444. pdf Kozakov D, Hall DR, Xia B, Porter KA, Padhorny D, Yueh C, Beglov D, Vajda S. The ClusPro web server for protein-protein docking. Nature Protocols. 2017 Feb;12(2):255-278. pdf Kozakov D, Beglov D, Bohnuud T, Mottarella S, Xia B, Hall DR, Vajda, S. How good is automated protein docking? Proteins: Structure, Function, and Bioinformatics. 2013 Dec; 81(12):2159-66. pdf

AutoDock Vina. AutoDock Vina - molecular docking and virtual screening program. (n.d.). http://vina.scripps.edu/.

UCSF Chimera . UCSF chimera home page. (n.d.). https://www.cgl.ucsf.edu/chimera/.

Wang, C., Shan, B., Wang, Q., Xu, Q., Zhang, H., & Lei, H. (2017). Fusion of Ssm6a with a protein scaffold retains selectivity on NaV 1.7 and improves its therapeutic potential against chronic pain. Chemical biology & drug design, 89(6), 825–833. https://doi.org/10.1111/cbdd.12915

Cardoso, F. C., Dekan, Z., Rosengren, K. J., Erickson, A., Vetter, I., Deuis, J. R., Herzig, V., Alewood, P. F., King, G. F., & Lewis, R. J. (2015). Identification and Characterization of ProTx-III [μ-TRTX-Tp1a], a New Voltage- Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens. Molecular pharmacology, 88(2), 291–303. https://doi.org/10.1124/mol.115.098178

Chow, C. Y., Cristofori-Armstrong, B., Undheim, E. A., King, G. F., & Rash, L. D. (2015). Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula. Toxins, 7(7), 2494–2513. https://doi.org/10.3390/toxins7072494

Liu, Z., Cai, T., Zhu, Q., Deng, M., Li, J., Zhou, X., Zhang, F., Li, D., Li, J., Liu, Y., Hu, W., & Liang, S. (2013). Structure and function of hainantoxin-III, a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels isolated from the Chinese bird spider Ornithoctonus hainana. The Journal of biological chemistry, 288(28), 20392–20403. https://doi.org/10.1074/jbc.M112.426627

Peigneur, S., Cheneval, O., Maiti, M., Leipold, E., Heinemann, S. H., Lescrinier, E., Herdewijn, P., De Lima, M. E., Craik, D. J., Schroeder, C. I., & Tytgat, J. (2019). Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33(3), 3693–3703. https://doi.org/10.1096/fj.201801909R

Wu, X., Wang, Z., Chen, Y., Xu, D., Zhang, P., & Wang, X. (2019). Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia. Toxins, 11(12), 680. https://doi.org/10.3390/toxins11120680

Tsukamoto, T., Chiba, Y., Wakamori, M., Yamada, T., Tsunogae, S., Cho, Y., Sakakibara, R., Imazu, T., Tokoro, S., Satake, Y., Adachi, M., Nishikawa, T., Yotsu-Yamashita, M., & Konoki, K. (2017). Differential binding of tetrodotoxin and its derivatives to voltage-sensitive sodium channel subtypes (Nav 1.1 to Nav 1.7). British journal of pharmacology, 174(21), 3881–3892. https://doi.org/10.1111/bph.13985

Zhao, F., Wang, J. L., Ming, H. Y., Zhang, Y. N., Dun, Y. Q., Zhang, J. H., & Song, Y. B. (2020). Insights into the binding mode and functional components of the analgesic-antitumour peptide from Buthus martensii Karsch to human voltage-gated sodium channel 1.7 based on dynamic simulation analysis. Journal of biomolecular structure & dynamics, 38(6), 1868–1879. https://doi.org/10.1080/07391102.2019.1620126

Rowe, A. H., Xiao, Y., Scales, J., Linse, K. D., Rowe, M. P., Cummins, T. R., & Zakon, H. H. (2011). Isolation and characterization of CvIV4: a pain inducing α-scorpion toxin. PloS one, 6(8), e23520. https://doi.org/10.1371/journal.pone.0023520

Mueller, A., Dekan, Z., Kaas, Q., Agwa, A. J., Starobova, H., Alewood, P. F., Schroeder, C. I., Mobli, M., Deuis, J. R., & Vetter, I. (2020). Mapping the Molecular Surface of the Analgesic NaV1.7-Selective Peptide Pn3a Reveals Residues Essential for Membrane and Channel Interactions. ACS pharmacology & translational science, 3(3), 535– 546. https://doi.org/10.1021/acsptsci.0c00002

Wright, Z., McCarthy, S., Dickman, R., Reyes, F. E., Sanchez-Martinez, S., Cryar, A., Kilford, I., Hall, A., Takle, A. K., Topf, M., Gonen, T., Thalassinos, K., & Tabor, A. B. (2017). The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx-II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Nav1.7. Journal of the American Chemical Society, 139(37), 13063–13075. https://doi.org/10.1021/jacs.7b06506

Truini, A., Piroso, S., Pasquale, E., Notartomaso, S., Di Stefano, G., Lattanzi, R., Battaglia, G., Nicoletti, F., & Cruccu, G. (2015). N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive transmission in humans. Molecular pain, 11, 14. https://doi.org/10.1186/s12990-015-0009-2

Bernabucci, M., Notartomaso, S., Zappulla, C., Fazio, F., Cannella, M., Motolese, M., Battaglia,

G., Bruno, V., Gradini, R., & Nicoletti, F. (2012). N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors. Molecular pain, 8, 77. https://doi.org/10.1186/1744-8069-8-77

Goldsztejn, G., Mundlapati, V. R., Brenner, V., Gloaguen, E., Mons, M., Cabezas, C., León, I., & Alonso, J. L. (2020). Intrinsic folding of the cysteine residue: competition between folded and extended forms mediated by the - SH group. Physical chemistry chemical physics : PCCP, 22(36), 20284–20294. https://doi.org/10.1039/d0cp03136d

Rao, S., Lynch, C. I., Klesse, G., Oakley, G. E., Stansfeld, P. J., Tucker, S. J., & Sansom, M. (2018). Water and hydrophobic gates in ion channels and nanopores. Faraday discussions, 209(0), 231–247. https://doi.org/10.1039/c8fd00013a

Published

02-28-2022

How to Cite

Shahriyar, K., & Chaim , O. . (2022). Exploring Venom Toxins as Molecular Models for Chronic Pain Treatment. Journal of Student Research, 11(1). https://doi.org/10.47611/jsrhs.v11i1.2365

Issue

Section

HS Research Projects