Assessment of the antiviral activity of 2HCl*H-His-Rim compound compared to the anti-influenza drug Arbidol for influenza caused by A/duck/Novosibirsk/56/05 (H5N1) (Influenza A virus, Alphainfluenzavirus, Orthomyxoviridae)

Deryabin, P. G.; Garaev, T. M.; Финогенова, М. П.; Odnovorov, A I

doi:10.36233/0507-4088-2019-64-6-268-273

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…The formation of a peptide bond between the carbocycle of rimantadine and di- tert -butyloxycarbonyl-L-histidine was carried out in a single stage under the conditions of mixed anhydride method in the equimolar ratio according to the procedure described. 6 - 8 The removal of protective tert -butyloxycarbonyl groups was carried out in a solution of 4 N HCl in ethyl acetate followed by vacuum drying to a dry foam. Yield: 92%.…”

Section: Methodsmentioning

confidence: 99%

Studying the Effect of Amino Acid Substitutions in the M2 Ion Channel of the Influenza Virus on the Antiviral Activity of the Aminoadamantane DerivativeIn VitroandIn Silico

et al. 2020

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Purpose: The aminoadamantane derivative of L-histidyl-1-adamantayl ethylamine hydrochloride (HCl*H-His-Rim) has showed a high inhibition level against influenza A virus strains in vitro. The aim of this work is to search and establish evidence of the direct effect of the drug on influenza A virus proton channel M2. Methods: The compound HCl*H-His-Rim was obtained by classical peptide synthesis methods. Influenza A virus mutants of A/PuertoRico/8/34(H1N1) strain were obtained by reverse genetics methods. The mutant samples of the virus were cultured on chicken embryos with a virus titer in the hemagglutination test. ELISA was carried out on Madin-Darby canine kidney (MDCK) monolayer cells when multiplying the virus 10-4-10-6. The binding stability of HCl*H-His-Rim was compared to those of M2 (S31N) and M2 (S31N_A30T) channels by molecular dynamic (MD) modeling. The calculation was performed taking into account the interaction with the model lipid bilayer (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) in the presence of water molecules in accordance with the three-center model. Results: It was found that HCl*H-His-Rim is a direct action drug against influenza A. The most likely conformation of drug binding to target protein has been shown. It has been found that the A30T mutation reduces the binding energy of the drug, and the results obtained in vitro have confirmed the data calculated in silico. Conclusion: The mechanism of action of HCl*H-His-Rim is directly related to the suppression of the function of the proton channel M2 of influenza A virus.

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Section: Methodsmentioning

confidence: 99%

Studying the Effect of Amino Acid Substitutions in the M2 Ion Channel of the Influenza Virus on the Antiviral Activity of the Aminoadamantane DerivativeIn VitroandIn Silico

et al. 2020

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“…The substance H-His-Rim•2HCl•H2O, synthesized in laboratory conditions by the classical peptide synthesis method [14], rimantadine hydrochloride, 99% (Zhejiang Kangyu Pharmaceutical Co, China), ethanol 96% (purity category "Lux"); N, N-dimethylformamide anhydrous, 99.8% and n-hexane anhydrous, 95% (Sigma-Aldrich, USA); deionized high resistance water (18.2 MΩ•cm at 25 °C, Milli-Q system); silver nitrate (chemically pure, Himmed, Russia).…”

Section: Methodsmentioning

confidence: 99%

“…The identification of the new substance and the determination of its properties are crucial for further testing. Some characteristics of the compound (NMR spectrum, mass spectrum) were presented previously [14].…”

Section: Fig 1: Structural Formula Of L-histidyl-1-adamantylethylamin...mentioning

confidence: 99%

Physicochemical Properties and Biological Activity of the New Antiviral Substance

Odnovorov

GREBENNIKOVA²,

Pleteneva³

et al. 2020

Int J App Pharm

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Objective: To develop a set of quality control procedures for the promising antiviral pharmaceutical substance L-histidyl-1-adamantylethylamine dihydrochloride monohydrate, a derivative of rimantadine. Methods: Substances and solvents: synthesized in laboratory L-histidyl-1-adamantylethylamine dihydrochloride monohydrate (H-His-Rim•2HCl•H2O), rimantadine hydrochloride (Rim•HCl), 99%, ethanol 96%, N, N-dimethylformamide (DMF) anhydrous, 99.8% and n-hexane anhydrous, 95%, deionized high-resistance water (18.2 MΩ•cm at 25 °C, Milli-Q system), silver nitrate. Infrared (IR) Spectroscopy–Cary 630 Fourier Transform IR Spectrometer, elemental analysis–elemental composition analyzer CHNS-O EuroEA3000, ultraviolet (UV) spectrometry–Cary-60 spectrophotometer, polarimetry–POL-1/2 polarimeter with an external Peltier module, granulometric analysis by optical microscopy (Altami BIO 2 microscope) and low-angle laser light scattering (LALLS)–Master Sizer 3600, measurement of potential for hydrogen–potentiometer PB-11, Spirotox method–the study of temperature dependences of Spirostomum ambiguum lifetime to characterize the biological activity of the studied compounds. Results: The substance H-His-Rim•2HCl•H2O is an amorphous yellowish powder, slightly soluble in water, soluble in ethanol, freely soluble in N, N-dimethylformamide, and practically insoluble in n-hexane. A study of the elemental composition has confirmed the authenticity of H-His-Rim•2HCl•H2O. Comparison of the spectral characteristics of H-His-Rim•2HCl•H2O and Rim•HCl by IR spectroscopy and UV spectrometry confirmed the authenticity of the substance. The racemic form of the substance Rim•HCl with an insignificant amount of impurity of the levorotatory enantiomer was proved polarimetrically: α =-0.0126±0.0003 (1% aqueous solution, 20±0.5 °С). The specific optical rotation of 1% aqueous solution H-His-Rim•2HCl•H2O . In 1% ethanol solution -10.32±0.12. Using the method of laser light diffraction for a substance H-His-Rim•2HCl•H2O, the dimensional spectra «fraction of particles, %-d, μm» were characterized, the maximum of which in hexane is in the region of 40–50 μm. Arrhenius’s kinetics on the Spirotox model established statistically significant differences in ligand-receptor interactions, which are characterized by values of observed apparent activation energy °bsEa, kJ/mol: 132.36±1.55 for H-His-Rim•2HCl•H2O and 176.15±0.48 for Rim•HCl. Conclusion: The developed set of methods for assessment of physical and chemical properties and biological activity of a new antiviral substance H-His-Rim•2HCl•H2O is the basis for establish of regulatory documentation.

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“…Umifenovir (Arbidol) is a broad-spectrum antiviral that acts against viral HA specifically [10]. Developed in the 1970s by the collaborative efforts of the Chemical-Pharmaceutical Scientific Research Institute of Russia, the Scientific Research Institute of Medical Radiology in Obninsk, and the Leningrad-Pasteur Scientific Research Institute for Epidemiology and Microbiology, Umifenovir is currently only approved in Russia and China for treatment of influenza A and B, prophylaxis, and post-influenza complications [11][12][13], though it does exhibit anti-influenza C activity as well [10]. Umifenovir is a controversial drug; due to a lack of reproducible lab results [14] and limited toxicity data outside of Russia, it has yet to gain global use, and remains unapproved for influenza treatment in many countries.…”

Section: Umifenovirmentioning

confidence: 99%

Popular Influenza Antiviral Drugs: Mechanisms, Efficacy, and Resistance

Ley¹

2023

Preprint

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Influenza viruses cause acute respiratory infections responsible for significant mortality and morbidity around the world. Because factors such as antigenic drift allow influenza strains to avoid being fully suppressed by seasonal vaccines, public interest has led to increased scrutiny of antivirals as treatment and prophylaxis options for seasonal outbreaks and potential pandemics. Unfortunately, many influenza antivirals suffer from a lack of sufficient clinical trials, as well as a lack of toxicity data; this is especially true of umifenovir (Arbidol), a popularly used drug for the prevention and treatment of influenza strains in China and Russia. Neuraminidase inhibitors, though widely prescribed, display a potential for future resistance. Adamantanes, while proven to be effective in treating influenza A, are already encountering rapid, widespread cross-resistance, and are effectively obsolete. Baloxavir marboxil, a newer antiviral, shows promise in treating acute uncomplicated influenza and may avoid the development of resistance when coadministered with other antiviral drugs. Indeed, the low genetic barriers to resistance faced by influenza antivirals may be surmounted by coadministration with other antivirals. This review explores the most widely prescribed antivirals for influenza treatment, their mechanisms of action, and current data on their susceptibility to resistance and efficacy at this time.

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Assessment of the antiviral activity of 2HCl*H-His-Rim compound compared to the anti-influenza drug Arbidol for influenza caused by A/duck/Novosibirsk/56/05 (H5N1) (Influenza A virus, Alphainfluenzavirus, Orthomyxoviridae)

Cited by 7 publications

References 11 publications

Studying the Effect of Amino Acid Substitutions in the M2 Ion Channel of the Influenza Virus on the Antiviral Activity of the Aminoadamantane DerivativeIn VitroandIn Silico

Studying the Effect of Amino Acid Substitutions in the M2 Ion Channel of the Influenza Virus on the Antiviral Activity of the Aminoadamantane DerivativeIn VitroandIn Silico

Physicochemical Properties and Biological Activity of the New Antiviral Substance

Popular Influenza Antiviral Drugs: Mechanisms, Efficacy, and Resistance

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