Synthesis and biological activity study of the retro-isomer of RhTx against TRPV1

  • RSC Adv. 2020 Jan 10;10(4):2141-2145. doi: 10.1039/c9ra08829f.
Rilei Yu  1  2 ,  Huijie Liu  3 ,  Baishi Wang  1 ,  Peta J Harvey  4 ,  Ningning Wei  3 ,  Yanyan Chu  1  2
Affiliations
  • 1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China Qingdao 266003 China [email protected].
  • 2. Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology Qingdao 266003 China.
  • 3. Department of Pharmacology, School of Pharmacy, Qingdao University Qingdao 266021 China [email protected].
  • 4. Institute for Molecular Bioscience, The University of Queensland Brisbane QLD 4072 Australia.
PMID: 35494567 DOI: 10.1039/c9ra08829f
Abstract

TRPV1 is a ligand-gated ion channel and plays an important role in detecting noxious heat and pain with an unknown mechanism. RhTx from Chinese red-headed centipede activates the TRPV1 channel through the heat activation pathway by binding to the outer pore region, and causes extreme pain. Here, we synthesized RhTx and its retro-isomer RL-RhTx. Their structures were investigated by their circular dichroic spectra and NMR spectra. The effect of RhTx and RL-RhTx on the currents of wild-type and mutants of TRPV1 indicated that RL-RhTx have comparable TRPV1 activation responses to RhTx. A mutagenesis study showed that four TRPV1 residues, including Leu461, Asp602, Tyr632 and Thr634, significantly contributed to the activation effects of RL-RhTx and RhTx, and both peptides probably bind with TRPV1 in similar binding modes. As a novel TRPV1 activator, RL-RhTx provides an essential powerful tool for the investigation of activation mechanisms of TRPV1.

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