Item request has been placed!
×
Item request cannot be made.
×
Processing Request
The road to evolution of ProTx2: how to be a subtype-specific inhibition of human Na v 1.7.
Item request has been placed!
×
Item request cannot be made.
×
Processing Request
- Additional Information
- Source:
Publisher: Frontiers Media] Country of Publication: Switzerland NLM ID: 101548923 Publication Model: eCollection Cited Medium: Print ISSN: 1663-9812 (Print) Linking ISSN: 16639812 NLM ISO Abbreviation: Front Pharmacol Subsets: PubMed not MEDLINE
- Publication Information:
Original Publication: [Lausanne : Frontiers Media]
- Abstract:
The human voltage-gated sodium channel Na v 1.7 is a widely proven target for analgesic drug studies. ProTx2, a 30-residue polypeptide from Peruvian green tarantula venom, shows high specificity to activity against human Na v 1.7, suggesting its potential to become a non-addictive analgesic. However, its high sensitivity to human Na v 1.4 raises concerns about muscle side effects. Here, we engineered three mutants (R13A, R13D, and K27Y) of ProTx2 to evaluate their pharmacological activities toward Na v 1.7 and Na v 1.4. It is demonstrated that the mutant R13D maintained the analgesic effect in mice while dramatically reducing its muscle toxicity compared with ProTx2. The main reason is the formation of a strong electrostatic interaction between R13D and the negatively charged amino acid residues in DII/S3-S4 of Na v 1.7, which is absent in Na v 1.4. This study advances our understanding and insights on peptide toxins, paving the way for safer, effective non-addictive analgesic development.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Zhao, Liu, Liu, Ye, Yang, Gui and Song.)
- References:
Neuropharmacology. 2007 Feb;52(2):291-6. (PMID: 17074372)
J Biol Chem. 2007 Apr 27;282(17):12687-97. (PMID: 17339321)
J Chem Theory Comput. 2015 Aug 11;11(8):3696-713. (PMID: 26574453)
J Phys Chem B. 2012 Apr 26;116(16):4796-800. (PMID: 22471309)
Drug Discov Today Technol. 2012 Spring;9(1):e1-e70. (PMID: 24064239)
J Chem Inf Model. 2011 Jan 24;51(1):69-82. (PMID: 21117705)
Sci Rep. 2017 Jan 20;7:40883. (PMID: 28106092)
Sci Rep. 2017 Jan 03;7:39662. (PMID: 28045073)
Neuron. 2006 Dec 7;52(5):767-74. (PMID: 17145499)
J Biochem. 2020 Dec 26;168(6):633-641. (PMID: 32730584)
Adv Sci (Weinh). 2023 Apr;10(11):e2206602. (PMID: 36722732)
Cell. 2019 Feb 21;176(5):1238-1239. (PMID: 30794776)
Protein Sci. 2020 Aug;29(8):1851-1857. (PMID: 32557917)
Int J Mol Sci. 2019 Jan 08;20(1):. (PMID: 30626119)
Handb Exp Pharmacol. 2018;246:271-306. (PMID: 29532179)
J Mol Graph. 1996 Feb;14(1):33-8, 27-8. (PMID: 8744570)
J Biol Chem. 2020 Jan 31;295(5):1315-1327. (PMID: 31871053)
Front Pharmacol. 2019 Apr 11;10:366. (PMID: 31031623)
J Med Chem. 2015 Sep 24;58(18):7093-118. (PMID: 25927480)
J Ethnopharmacol. 2021 Nov 15;280:114457. (PMID: 34329712)
J Mol Biol. 1995 Sep 29;252(4):492-503. (PMID: 7563068)
Sci Rep. 2021 Dec 24;11(1):24412. (PMID: 34952900)
Phys Rev E Stat Nonlin Soft Matter Phys. 2006 Dec;74(6 Pt 1):061901. (PMID: 17280090)
FEBS Lett. 2005 Jul 18;579(18):3881-4. (PMID: 15990094)
Sci Rep. 2016 May 13;6:25974. (PMID: 27174182)
J Med Chem. 2018 Nov 8;61(21):9500-9512. (PMID: 30346167)
Neuropharmacology. 2002 Sep;43(3):457-65. (PMID: 12243776)
Nature. 2011 Jul 10;475(7356):353-8. (PMID: 21743477)
J Gen Physiol. 2014 May;143(5):645-56. (PMID: 24778431)
J Mol Biol. 2021 Aug 20;433(17):166967. (PMID: 33794261)
Pain. 2022 Feb 1;163(2):e328-e332. (PMID: 33990113)
Channels (Austin). 2014;8(3):264-77. (PMID: 24632677)
J Am Chem Soc. 2017 Sep 20;139(37):13063-13075. (PMID: 28880078)
ACS Chem Neurosci. 2014 Sep 17;5(9):749-51. (PMID: 25111714)
Biochemistry. 2015 May 19;54(19):2988-96. (PMID: 25919575)
Nat Rev Neurol. 2020 Dec;16(12):689-705. (PMID: 33110213)
Mol Pharmacol. 2008 Nov;74(5):1476-84. (PMID: 18728100)
Nature. 1977 Apr 21;266(5604):730-2. (PMID: 559941)
J Chem Theory Comput. 2013 Jul 9;9(7):3084-95. (PMID: 26583988)
Mol Med Rep. 2019 Jul;20(1):709-718. (PMID: 31180563)
J Chem Phys. 2022 May 7;156(17):174105. (PMID: 35525663)
Mol Pharmacol. 2008 Mar;73(3):1020-8. (PMID: 18156314)
ACS Pharmacol Transl Sci. 2021 Jun 07;4(4):1362-1378. (PMID: 34423271)
Int J Biol Macromol. 2020 Jul 1;154:634-643. (PMID: 32156541)
Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2208211119. (PMID: 35858452)
J Biol Chem. 2017 Nov 3;292(44):18270-18280. (PMID: 28924048)
Nature. 2006 Dec 14;444(7121):894-8. (PMID: 17167479)
Methods Mol Biol. 2022;2349:259-289. (PMID: 34718999)
- Contributed Indexing:
Keywords: ProTx2; analgesia; structure optimization; toxin; voltage-gated sodium ion channel
- Publication Date:
Date Created: 20240517 Latest Revision: 20240518
- Publication Date:
20240518
- Accession Number:
PMC11096480
- Accession Number:
10.3389/fphar.2024.1374183
- Accession Number:
38756380
No Comments.