Group of modified nucleosides synthesis

Laboratory of biotechnology

Head: Anatoliy Miroshnikov, member of the academy of sciences
aiv@ibch.ru

One of the main areas of work is a development of the fundamental and applied aspects of biotechnology for the production of drugs, based on modified nucleoside, for subsequent deployment into biopharmaceuticals production. The other area is a development of biocatalytic technologies of new modified nucleosides for the study of their antiviral and antitumor activities.

 

Partners:

  • Postovsky Institute of Organic Synthesis Ural Branch of the Russian Academy of Sciences FASO Russia – Synthesis of new benzoimidazole bases.
  • Lomonosov Institute of Fine Chemical Technologies, Moscow Technical University, Laboratory of Biotechnology - Synthesis of new 1,2,4-triazole bases.
  • Institute of Bioorganic Chemistry of National Academy of Sciences, Belarus - Collaboration in field of cascade technologies for synthesis of modified nucleosides.
  • Engelgardt Institute of Molecular Biology - Synthesis of feximeric heterocyclic bases for obtaining of new nucleosides.
  • Institute of Experimental Diagnostics and Therapy of Tumors RONC - investigation of cytotoxicity of series of new modified nucleosides.
  • Ivanovsky Institute of Virology - Testing of antivirus activity of new nucleosides in vitro and in vivo.

Patents:

  • Konstantinova I.D., Esipov R.S., Muravieva T.I., et all. A method of producing 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin). Patent RU № 2230118, 10.07.2004.
  • Berzin V.B., Dorofeeva Е.V., Leonov V.N., et all. A method of producing 2,6-dichloro-9-(2',3',5'-tri-О-acetyl-β-D–ribofuranosyl)purine. Patent RU № 2324699, 05.02.2008.
  • Berzin V.B., Dorofeeva Е.V., Leonov V.N., et all. A method of producing 2-chloroadenosine. Patent RU № 2324698, 05.02.2008.
  • Berzin V.B., Dorofeeva Е.V., Leonov V.N., Miroshnikov А.I. A method of producing 2-amino-6-azido-9-(2',3',5'-tri-О-acetyl-β-D–ribofuranosyl)purine. Patent RU № 2326124, 05.02.2008.
  • Berzin V.B., Dorofeeva Е.V., Leonov V.N., et all. A method of producing 2',3',5'-tri-О-acetyl-2-fluoroadenosine. Patent RU № 2325395, 05.02.2008.
  • Konstantinova I.D., Antonov К.V., Berzin V.B., et all. A method of producing 9-(β-D-arabinofuranosyl)-2-fluoroadenosine. Patent RU № 2368662, 27.09.2009.
  • Konstantinova I.D., Fateev I.V., Miroshnikov А.I. A method of producing 1-beta-D-ribofuranosyl-1,2,4-triazol-3-carboxamide. Patent RU № 2480218, 27.04.2013.
  • Konstantinova I.D., Eletskaya B.Z., Dorofeeva Е.V., et all. A method of producing 9-beta-D-arabinofuranosyl-6-(Nα-L-serylamido)-2-chloropurine. Patent RU № 2563257, 21.08.2015.
  • Konstantinova I.D., Fateev I.V., Miroshnikov А.I. A method of producing purine nucleosides series of β-D-арабинофуранозы». Patent application RU № 201514771, 06.11.2015, decision from 30.03.2017.

1. The biotechnology laboratory has developed and tested technologies for the synthesis of drugs used in modern clinical practice for the treatment of oncohematological diseases:

  • Cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous infusion; Cladribine Tablets (CLARITY) are used for a treatment of multiple sclerosis for patients with relapsing–remitting form of disease.
  • Fludara - B-cell chronic lymphocytic leukemia, non-Hodgkin's lymphoma low grade and follicular B-cell lymphoma and lymphoma cells from the mantle zone (tablet form).
  • Nelarabine - T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma (in patients with refractory to chemotherapy or recurrent disease).
  • Clofarabine - treatment of acute lymphoblastic leukemia in children older than 1 year with relapse or refractory to therapy after application, at least two previous chemotherapy regimens and in the absence of other ways of achieving sustained remission.

The technologies have been scaled and tested in terms of the pharmaceutical production companies of OAO "Pharmsynthez" (St-Petersburg) and Zao "R-Pharm" (Moscow). The deployment of those technologies on those enterprises is constrained by the need to conduct clinical studies of the substances obtained and the small demand for the RF market (0.5 to 2 kg).

2. Metabolically resistant analogues of the nucleoside antibiotic cordycepin are obtained. Those substances are of great interest for the therapy of African human trypanosomiasis (HAT).

3. Biotechnological approaches to synthesis of pharmaceutical substances of antiviral drugs - ribavirin, vidarabine, didanosine - have been developed.

NamePositionContacts
Irina Konstantinova, Ph.D.s. r. f.kid1968@yandex.ru+7(495)330-72-47#102
Aleksej Kayushin, Ph.D.s. r. f.kaushin@ibch.ru+7(495)3366833
Vladimir Leonov, Ph.D.s. r. f.+7(495)3362922
Elena Dorofeeva, Ph.D.r. f.iegol2013@gmail.com+7(495)336-29-22
Inessa Muzykar. f.mis_kou@mail.ru+7(916)126-78-63
Ilya Fateev, Ph.D.r. f.ifateev@gmail.com
Maria Kharitonovaj. r. f.
Maria BerzinaPhD stud.berzina_maria@mail.ru
Ol'ga Tikhomirovaeng.obtikh@mail.ru+7(330)336-29-22
Barbara Eletskayseng.fraubarusya@gmail.com
Olga Smirnovaeng.gescheites@gmail.com
A Denisovaeng.
Ol'ga Lutoninares. eng.ATRegister@mail.ru+7(495)727-38-67
Konstantin Antonovproc. eng.+7(495)330-72-47#102

Selected publications

  1. Shelukhina IV, Zhmak MN, Lobanov AV, Ivanov IA, Garifulina AI, Kravchenko IN, Rasskazova EA, Salmova MA, Tukhovskaya EA, Rykov VA, Slashcheva GA, Egorova NS, Muzyka IS, Tsetlin VI, Utkin YN (2018). Azemiopsin, a selective peptide antagonist of muscle nicotinic acetylcholine receptor: Preclinical evaluation as a local muscle relaxant. Toxins (Basel) 10 (1),
  2. Timofeev VI, Zhukhlistova NE, Abramchik YA, Fateev II, Kostromina MA, Muravieva TI, Esipov RS, Kuranova IP (2018). Crystal structure of Escherichia coli purine nucleoside phosphorylase in complex with 7-deazahypoxanthine. Acta Crystallogr F Struct Biol Commun 74 (0), 355–362
  3. Zhurilo NI, Chudinov MV, Matveev AV, Smirnova OS, Konstantinova ID, Miroshnikov AI, Prutkov AN, Grebenkina LE, Pulkova NV, Shvets VI (2017). Isosteric ribavirin analogues: Synthesis and antiviral activities. Bioorg Med Chem Lett 28 (1), 11–14
  4. Denisova AO, Tokunova YA, Fateev IV, Breslav AA, Leonov VN, Dorofeeva EV, Lutonina OI, Muzyka IS, Esipov RS, Kayushin AL, Konstantinova ID, Miroshnikov AI, Stepchenko VA, Mikhailopulo IA (2017). The Chemoenzymatic Synthesis of 2-Chloro- and 2-Fluorocordycepins. Synthesis (Stuttg) 49 (21), 4853–4860
  5. Kharitonova MI, Dntonov KV, Fateev IV, Berzina MY, Kaushin AL, Paramonov AS, Kotovskaya SK, Dndronova VL, Konstantinova ID, Galegov GA, Charushin VN, Miroshnikov AI (2017). Chemoenzymatic Synthesis of Modified 2′-Deoxy-2′-fluoro-β- d -arabinofuranosyl Benzimidazoles and Evaluation of Their Activity Against Herpes Simplex Virus Type 1. Synthesis (Stuttg) 49 (5), 1043–1052
  6. Kharitonova MI, Denisova AO, Andronova VL, Kayushin AL, Konstantinova ID, Kotovskaya SK, Galegov GA, Charushin VN, Miroshnikov AI (2017). New modified 2-aminobenzimidazole nucleosides: Synthesis and evaluation of their activity against herpes simplex virus type 1. Bioorg Med Chem Lett 27 (11), 2484–2487
  7. Esipov RS, Abramchik YA, Fateev IV, Muravyova TI, Artemova KG, Konstantinova ID, Kuranova IP, Miroshnikov AI (2016). Recombinant phosphoribosyl pyrophosphate synthetases from Thermus thermophilus HB27: Isolation and properties. Russ. J. Bioorganic Chem. 42 (5), 512–521
  8. Konstantinova ID, Fateev IV, Miroshnikov AI (2016). The arsenolysis reaction in the biotechnological method of synthesis of modified purine β-D-arabinonucleosides. Russ. J. Bioorganic Chem. 42 (4), 372–380
  9. Esipov RS, Abramchik YA, Fateev IV, Konstantinova ID, Kostromina MA, Muravyova TI, Artemova KG, Miroshnikov AI (2016). A Cascade of Thermophilic Enzymes As an Approach to the Synthesis of Modified Nucleotides. Acta Naturae 8 (4), 82–90
  10. Chudinov MV, Matveev AV, Prutkov AN, Konstantinova ID, Fateev IV, Prasolov VS, Smirnova OA, Ivanov AV, Galegov GA, Deryabin PG (2016). Novel 5-alkyl(aryl)-substituted ribavirine analogues: Synthesis and antiviral evaluation. MENDELEEV COMMUN 26 (3), 214–216
  11. Kharitonova MI, Fateev IV, Kayushin AL, Konstantinova ID, Kotovskaya SK, Andronova VL, Galegov GA, Charushin VN, Miroshnikov AI (2016). Chemoenzymatic Synthesis and Antiherpes Activity of 5-Substituted 4,6-Difluorobenzimidazoles Ribo- and 2′-Deoxyribonucleosides. Synthesis (Stuttg) 48 (3), 394–406
  12. Chudinov MV, Prutkov AN, Matveev AV, Grebenkina LE, Konstantinova ID, Berezovskaya YV (2016). An alternative route to the arylvinyltriazole nucleosides. Bioorg Med Chem Lett 26 (14), 3223–3225
  13. Eletskaya BZ, Konstantinova ID, Paramonov AS, Esipov RS, Gruzdev DA, Vigorov AY, Levit GL, Miroshnikov AI, Krasnov VP, Charushin VN (2016). Chemoenzymatic arabinosylation of 2-aminopurines bearing the chiral fragment of 7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazines. MENDELEEV COMMUN 26 (1), 6–8
  14. Fateev IV, Kharitonova MI, Antonov KV, Konstantinova ID, Stepanenko VN, Esipov RS, Seela F, Temburnikar KW, Seley-Radtke KL, Stepchenko VA, Sokolov YA, Miroshnikov AI, Mikhailopulo IA (2015). Recognition of Artificial Nucleobases by E. coli Purine Nucleoside Phosphorylase versus its Ser90Ala Mutant in the Synthesis of Base-Modified Nucleosides. Chemistry 21 (38), 13401–13419
  15. Ozhukil Kollath V, Van Den Broeck F, Fehér K, Martins JC, Luyten J, Traina K, Mullens S, Cloots R (2015). A Modular Approach to Study Protein Adsorption on Surface Modified Hydroxyapatite. Chemistry 21 (29), 10497–10505
  16. Sakharov V, Baykov S, Konstantinova I, Esipov R, Dorogov M (2015). An Efficient Chemoenzymatic Process for Preparation of Ribavirin. International Journal of Chemical Engineering 2015 (0),
  17. Fateev IV, Antonov KV, Konstantinova ID, Muravyova TI, Seela F, Esipov RS, Miroshnikov AI, Mikhailopulo IA (2014). The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: The electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases. Beilstein J Org Chem 10 (0), 1657–1669
  18. Deryabin PG, Galegov GA, Konstantinova ID, Muzyka IS, Miroshnikov AI, Lvov DK (2014). The combination of ribavirin and ozeltamivir effectively inhibits reproduction of influenza a virus resistant to rimantadine (Amantadine) in vitro and in vivo. Dokl Biochem Biophys 455 (1), 80–83
  19. Konstantinova ID, Fateev IV, Galegov GA, Deryabin PG, Botikov AG, Muzyka IS, LVov DK, Miroshnikov AI (2013). The arsenolysis reaction in the biotechnological synthesis of ribavirin. the in vitro and in vivo inhibition of influenza A virus replication with a combination of ribavirin and ozeltamivir. Russ. J. Bioorganic Chem. 39 (5), 530–538
  20. Timofeev VI, Abramchik YA, Fateev IV, Zhukhlistova NE, Muraveva TI, Kuranova IP, Esipov RS (2013). Three-Dimensional Structure of Thymidine Phosphorylase from E. coli in Complex with 3'-Azido-2'-Fluoro-2',3'- Dideoxyuridine. CRYSTALLOGR REP+ 58 (6), 842–853
  21. Konstantinova ID, Chudinov MV, Fateev IV, Matveev AV, Zhurilo NI, Shvets VI, Miroshnikov AI (2013). Chemoenzymatic method of 1,2,4-triazole nucleoside synthesis: Possibilities and limitations. Russ. J. Bioorganic Chem. 39 (1), 53–71
  22. Konstantinova ID, Selezneva OM, Fateev IV, Balashova TA, Kotovskaya SK, Baskakova ZM, Charushin VN, Baranovsky AV, Miroshnikov AI, Balzarini J, Mikhailopulo IA (2013). Chemo-enzymatic synthesis and biological evaluation of 5,6-disubstituted benzimidazole ribo- and 2′-deoxyribonucleosides. Synthesis (Stuttg) 45 (2), 272–280
  23. Kayushin A, Demekhina A, Korosteleva M, Miroshnikov A, Azhayev A (2011). Synthesis of biotin-containing phosphoramidite linker with polyether spacer arm. Nucleosides Nucleotides Nucleic Acids 30 (78), 490–502
  24. Konstantinova ID, Antonov KV, Fateev IV, Miroshnikov AI, Stepchenko VA, Baranovsky AV, Mikhailopulo IA (2011). A chemo-enzymatic synthesis of β-D-arabinofuranosyl purine nucleosides. Synthesis (Stuttg)  (10), 1555–1560
  25. Bregadze VI, Semioshkin AA, Laskova JN, Berzina MY, Lobanova IA, Sivaev IB, Grin MA, Titeev RA, Brittal DI, Ulybina OV, Chestnova AV, Ignatova AA, Feofanov AV, Mironov AF (2009). Novel types of boronated chlorin e6 conjugates via 'click chemistry'. Appl Organomet Chem 23 (9), 370–374
  26. Красильщикова МС, Леонов ВП, Зацепина ОВ, Дейгин ВИ (2009). Исследование иммуносупрессорных свойств Тимодепрессина в экспериментальной модели аутоиммунных заболеваний.  (0),
  27. Berzin VB, Dorofeeva EV, Leonov VN, Miroshnikov AI (2009). The preparative method for 2-fluoroadenosine synthesis. Russ. J. Bioorganic Chem. 35 (2), 193–196
  28. Yagodkin A, Azhayev A, Roivainen J, Antopolsky M, Kayushin A, Korosteleva M, Miroshnikov A, Randolph J, Mackie H (2007). Improved synthesis of trinucleotide phosphoramidites and generation of randomized oligonucleotide libraries. Nucleosides Nucleotides Nucleic Acids 26 (5), 473–497
  29. Chudinov MV, Konstantinova ID, Ryzhova OI, Esipov RS, Yurkevich AM, Shvets VI, Miroshnikov AI (2005). A new effective method for the synthesis of 1,2,4-triazole-3-carboxamide and ribavirin derivatives. PHARM CHEM J 39 (4), 212–215
  30. Streletskii AV, Kozlova AY, Esipov DS, Kayushin AL, Korosteleva MD, Esipov SE (2005). Determination of oligonucleotide molecular masses by MALDI mass spectrometry. Russ. J. Bioorganic Chem. 31 (2), 139–145
  31. Konstantinova ID, Leonteva NA, Galegov GA, Ryzhova OI, Chuvikovskii DV, Antonov KV, Esipov RS, Taran SA, Verevkina KN, Feofanov SA, Miroshnikov AI (2004). Ribavirin: Biotechnological synthesis and effect on the reproduction of Vaccinia virus. Russ. J. Bioorganic Chem. 30 (6), 553–560
  32. Mauriala T, Auriola S, Azhayev A, Kayushin A, Korosteleva M, Miroshnikov A (2004). HPLC electrospray mass spectrometric characterization of trimeric building blocks for oligonucleotide synthesis. J Pharm Biomed Anal 34 (1), 199–206
  33. Antonov KV, Esipov RS, Gurevich AI, Chuvikovsky DV, Mikulinskaya GV, Feofanov SA, Miroshnikov AI (2003). Chemical and chemoenzymatic synthesis of nucleoside 5′-α- thiotriphosphates. Russ. J. Bioorganic Chem. 29 (6), 560–565
  34. Petrovskaya LE, Kryukova EA, Kayushin AL, Rodina AV, Moskaleva EY, Korobko VG (2002). Deletion mutants of human granulocyte-macrophage colony-stimulating factor. Russ. J. Bioorganic Chem. 28 (5), 397–403
  35. Petrovskaya LE, Kryukova EA, Kayushin AL, Korobko VG (2001). Chaperone Caf1M Stabilizes Hybrid Proteins Containing Sequences of F1 Antigen Subunit from Yersinia pestis. Russ. J. Bioorganic Chem. 27 (4), 241–247
  36. Kayushin A, Korosteleva M, Miroshnikov A (2000). Large-scale solid-phase preparation of 3′-unprotected trinucleotide phosphotriesters - Precursors for synthesis of trinucleotide phosphoramidites. Nucleosides Nucleotides Nucleic Acids 19 (1012), 1967–1976
  37. Esipov RS, Gurevich AI, Kayushin AL, Korosteleva MD, Belova MA (1999). Dependence of the E. coli gene expression level on the structure of the translation initiation region (TIR). IV. Distal complementary TIR interactions with the mRNA coding region. Russ. J. Bioorganic Chem. 25 (7), 487–491
  38. Antonov KV, Backinowsky LV, Grzeszczyk B, Brade L, Holst O, Zamojski A (1998). Synthesis and serological characterization of L-glycero-α-D-manno-heptopyranose-containing di- and tri-saccharides of the non-reducing terminus of the Escherichia coli K-12 LPS core oligosaccharide. Carbohydr Res 314 (12), 85–93
  39. Patrushev LI, Zykova ES, Kayushin AL, Korosteleva MD, Miroshnikov AI, Bokarew IN, Leontev SG, Koshkin VM, Severin ES (1998). New DNA diagnostic system for detection of factor V leiden. Thromb Res 92 (6), 251–259
  40. Fonina LA, Guryanov SA, Efremov MA, Smirnova OV (1998). Myelopeptides: Isolation and structure. Russ. J. Bioorganic Chem. 24 (6), 353–356
  41. Patrushev LI, Zykova ES, Kayushin AL, Korosteleva MD, Miroshnikov AI (1998). A new DNA-diagnostic system for revealing and identifying homozygous and heterozygous point mutations. Russ. J. Bioorganic Chem. 24 (3), 173–178
  42. Shpakovski GV, Proshkin SA, Kayushin AL, Korosteleva MD, Lebedenko EN (1998). Structural and functional characterization of the rpb8+gene of schizosaccharomyces pombe encoding a subunit of RNA polymerases I-III only specific for eukaryotes. Russ. J. Bioorganic Chem. 24 (2), 105–111
  43. Antonov KV, Konstantinova ID, Miroshnikov AI (1998). New approach to the synthesis of 2',3',-dideoxyadenosine and 2',3'- dideoxyinosine. Nucleosides Nucleotides 17 (13), 153–159
  44. Esipov RS, Gurevich AI, Kayushin AL, Korosteleva MD, Miroshnikov AI, Shevchenko LV, Pluzhnikov KA, Grishin EV (1997). Recombinant proteins containing amino acid sequences of two ectatomin chains. Russ. J. Bioorganic Chem. 23 (12), 839–842
  45. Kryukov VI, Antonov KV, Miroshnikov AI (1997). Formylation of nucleosides with formic acid. Russ. J. Bioorganic Chem. 23 (11), 803–805
  46. Gurevich AI, Esipov RS, Kachalina TA, Kayushin AL, Korosteleva MD (1997). Relation between the expression level of an Escherichia coli gene and the structure of the Transcription Initiation Region (TIR). III. Sites of complementary interaction of TIR with 16S rRNA. Russ. J. Bioorganic Chem. 23 (11), 790–795
  47. Gurevich AI, Esipov RS, Kayushin AL, Korosteleva MD (1997). Synthesis of artificial genes by PCR on a synthetic template. Russ. J. Bioorganic Chem. 23 (6), 457–460
  48. Zykova ES, Patrushev LI, Kayushin AL, Korosteleva MD, Miroshnikov AI, Bokarev IN, Leontev SG, Koshkin VM, Severin ES (1997). New allele-specific primers for detecting the Leiden mutation in exon 10 of the factor V gene in thrombophilia. Russ. J. Bioorganic Chem. 23 (3), 184–189
  49. Kayushin AL, Korosteleva MD, Miroshnikov AI, Kosch W, Zubov D, Piel N (1996). A convenient approach to the synthesis of trinucleotide phosphoramidites-synthons for the generation of oligonucleotide/peptide libraries. Nucleic Acids Res 24 (19), 3748–3755
  50. Gurevich AI, Kachalina TA, Kayushin AL, Korosteleva MD, Maltsev KV, Mirgorodskaya OA, Miroshnikov AI (1996). Recombinant proteins containing oligomeric sequences of oxytocin. Russ. J. Bioorganic Chem. 22 (1), 12–16
  51. Khodorov BI, Yelin EA, Zaborovskaya LD, Maksudov MZ, Tikhomirova OB, Leonov VN (1992). Comparative analysis of the effects of synthetic derivatives of batrachotoxin on sodium currents in frog node of Ranvier. Cell Mol Neurobiol 12 (1), 59–81
  52. Ананченко СН, Леонов ВН, Платонова АВ, Торгов ИВ (1960). Новый путь синтеза стероидных соединений. Полный синтез dl-эстрона. 135 (1), 73–76

Anatoliy Miroshnikov

  • Russia, Moscow, Ul. Miklukho-Maklaya 16/10 — On the map
  • IBCh RAS, build. 53, office. 6601
  • Phone: +7(495)995-55-57#2005
  • E-mail: aiv@ibch.ru