Polypeptide azemiopsin miorelaxant properties study

Azemiopsin is a linear peptide from the viper Azemiops feae venom. It has high affinity and selective inhibitor of the muscle nicotinic acetylcholine receptor (nAChR) and can be considered as a potentially useful nondepolarizing muscle relaxant. This peptide does not contain disulfide bonds, which facilitates its synthesis and modification in comparison with other snake neurotoxins. Within the framework of the State Contract No. 14.N08.12.1025 of April 28, 2015, "Preclinical studies of a polypeptide blocking neuromuscular transmission-based drug for the treatment of muscular dystonia", a study was conducted of the preclinical profile of azemiopsin for in vitro and in vivo efficacy, acute and chronic toxicity, pharmacokinetics, allergenic ability, immunotoxicity and mutagenic activity. The peptide showed high efficiency of muscle relaxation with intramuscular injection in mice. The peptide did not possess immunotoxic, allergenic or mutagenic properties. In general, the results show that azemiopsin has good drug-like properties for use as a local muscle relaxant and in its parameters is not inferior to the relaxants that are currently used. However, rodent tests do not provide enough information on the distribution of azemiopsin molecules in muscle tissue, as well as the applicability of this muscle relaxant in various surgical operations that require different durations of action and release rates of the drug. There is always the possibility that real surgery may exhibit properties that were not predicted by preclinical testing. Within the framework of the proposed project, we plan to carry out a research study consisting of the synthesis of several azemiopsin derivatives with presumably altered pharmacokinetic and pharmacodynamic properties, obtaining characteristics of their interaction with mammalian muscle nAChRs in vitro, and researching the properties of the azemiopsin and its new derivatives in surgical operations on individual representatives of ruminant and/or non-ruminant artiodactyls. The advantage of working with relatively large animals is their greater similarity with humans, the possibility of estimating the distribution and biodegradation of the studied molecules more carefully than in the case of rodents and rabbits. The implementation of such a project is possible only within the framework of a hybrid study involving the interaction of biochemical and veterinary teams that can together perform a full cycle of work from the rational design of new aziompsin derivatives, their synthesis and in vitro testing, before testing large animals with monitoring of various biological parameters.

July 1, 2018 — June 30, 2021

Kudryavtsev D.S. (PI), Ivanov I.A. (Co-PI), Son L.V. (Co-PI), Shelukhina I.V. (Co-PI), Siniavin A.E.

Laboratory of ligand-receptor interactions

Grant, RSF, 15000000 rub.

List of publications

  1. Akimov MG, Kudryavtsev DS, Kryukova EV, Fomina-Ageeva EV, Zakharov SS, Gretskaya NM, Zinchenko GN, Serkov IV, Makhaeva GF, Boltneva NP, Kovaleva NV, Serebryakova OG, Lushchekina SV, Palikov VA, Palikova Y, Dyachenko IA, Kasheverov IE, Tsetlin VI, Bezuglov VV (2020). Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System. Biomolecules 10 (2),
  2. Lebedev D, Kryukova E, Ivanov I, Egorova N, Timofeev N, Spirova E, Tufanova E, Siniavin A, Kudryavtsev D, Kasheverov I, Zouridakis M, Katsarava R, Zavradashvili N, Iagorshvili I, Tzartos S, Tsetlin V (2019). Oligoarginine Peptides, a New Family of nAChR Inhibitors. Mol Pharmacol 96 (5), 664–673
  3. Kudryavtsev DS, Tabakmakher VМ, Budylin GS, Egorova NS, Efremov RG, Ivanov IA, Belukhina SY, Jegorov AV, Kasheverov IE, Kryukova EV, Shelukhina IV, Shirshin EA, Zhdanova NG, Zhmak MN, Tsetlin VI (2020). Complex approach for analysis of snake venom α-neurotoxins binding to HAP, the high-affinity peptide. Sci Rep 10 (1), 3861
  4. Kudryavtsev D, Isaeva A, Barkova D, Spirova E, Mukhutdinova R, Kasheverov I, Tsetlin V (2021). Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia. Molecules 26 (5),