Full Antagonist of TRPV1 Receptor of Sea Anemone Heteractis crispa

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Full Antagonist of TRPV1 Receptor of Sea Anemone Heteractis crispa

January 14, 2021 Pharmaceutical 0

Sea anemone venom contains several biological target modulating peptides, such as ion channels or receptors. On the basis of the gene sequence obtained from the Heteractis crispa cDNA, the sequence of a new Kunitz-type peptide, HCRG21, belonging to the Heteractis crispa RG (HCRG) peptide subfamily was deduced. HCRG21 shares strong structural homology with APHC1-APHC3 Kunitz-type peptides from H. “Crispa and peptide clusters from the HCGS peptide subfamily, but form a separate branch on the NJ-phylogenetic tree from the so-called “analgesic cluster. HCRG21 is distinguished from other peptides of this cluster by three distinct point substitutions at the N-terminus of the molecule, Arg1, Gly2, and Ser5. The inhibitory activity of trypsin with recombinant HCRG21 (rHCRG21) was close to the activity of peptides in the same cluster. For trypsin and alpha-chymotrypsin, inhibition constants were 2.0 * 10−7 and 7.0 * 10−7 M, respectively. Electrophysiological studies have shown that rHCRG21 by transient receptor potential family member vanilloid 1 (TRPV1) inhibits 95 percent of the capsaicin-induced current and has a half-maximal inhibitory concentration of 6.9 ± 0.4 μM. HCRG21 is distinguished from the other peptides of this cluster by three distinct point substitutions at the N-terminus of the molecule, Arg1, Gly2, and Ser5. Recombinant HCRG21 (rHCRG21) trypsin inhibitory activity was comparable to the activity of peptides from the same cluster. Trypsin and alpha-chymotrypsin inhibition constants were 2.0 * 10−7 and 7.0 * 10−7 M, respectively. Electrophysiological studies have shown that rHCRG21 by transient receptor potential family member vanilloid 1 (TRPV1) inhibits 95 percent of the capsaicin-induced current and has a half-maximum inhibitory concentration of 6.9 ± 0.4 μM. HCRG21 is a promising instrument for the study of TRPV1 channels and may also be an interesting lead compound for the production of new analgesics. These data provide useful insights into bifunctional Kunitz-type peptides’ structural and functional relationships and pharmacological potential.

Author (s) Details

Margarita Monastyrnaya
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok, 690022, Russia.

Elena Zelepuga
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok, 690022, Russia.

Steve Peigneur
Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg O&N2, Herestraat 49, P.O.Box 922, Leuven B-3000, Belgium.

Valentin Tabakmakher
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Ulitsa Miklukho-Maklaya, Moscow, 117997, Russia.

Oksana Sintsova
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok, 690022, Russia.

Irina Gladkikh
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok, 690022, Russia.

Elena Leychenko
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok, 690022, Russia.

Marina Isaeva
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok, 690022, Russia.

Jan Tytgat
Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg O&N2, Herestraat 49, P.O.Box 922, Leuven B-3000, Belgium.

Emma Kozlovskaya
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok, 690022, Russia.

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