Laboratory for Biomedicinal Chemistry

Makarov_small_1 Vadim A. Makarov
Dr.Sci. (Pharmacy), Ph.D.
Head of Laboratory
INBI, build. 1, room 342
Телефон +7 (495) 660-34-30 ext. 195
E-Mail makarov@inbi.ras.ru

Leading projects:

Most active in the world for today anti TB compound “PBTZ169” was designed, synthesized and developed by the lab in partnership with Prof. Cole (Global Health Institute, Lausanne). This compound successfully finished 1st clinical trials. Now it is develop by iM4TB non profit foundation in Lausanne, Global Health Institute and TB Alliance. Financial support was from EC (FP6 and FP7).

“PDSTP” – antiviral drug of new generation which protect host cells from broad spectrum of sexually transmitted viruses. Target disease is papilloma and herpes virus infection. It was developed together with Institute of Virology and Antiviral Chemotherapy in Jena, Germany. Preclinical study mostly finished Licensed by Russian Pharma company Niarmedic. Supported by Russian State (Pharma-2020).

A drug for the treatment of diseases associated with damage to the central nervous system neurons (cerebral palsy, senile dementia of various etiologies, stroke, head trauma, depression, multiple sclerosis, autism etc). The MoA of VIN091, apparently associated with the activation of tyrosine hydroxylase in the “blue spot”, which is a pool of “sleeping cells” involved in neurogenesis, and as a result of the unique influence of the drug on the brain as a whole. High efficiency is confirmed by several experiments on mice and rats. The project is under active development.

The drug for the treatment of rhino- and entero- virus infection. We studied interaction between pathogen and host cell by post-genomic technologies and designed small molecule which is blocking this process for a wide range rhino- and entero- viruses. The project is in an advanced stage and has minimum commercial risk and unlimited market about the development of the outer drugform for the treatment and prevention of rhinovirus.

Development of anti HIV drug which is new generation of non nucleoside inhibitor of reverse transcriptase. Already exist lead “drug-like” molecule has nanomolar activity on broad spectrum of HIV strains including wt and MRD strains. The molecule is member of absolutely original group of chemical compounds, very efficient and cheap synthesis developed, the molecule is not cytotoxic, not mutagenic etc. This work done in partnership with University of Cagliari (Italy).

 

Selected publications:

  1. Monakhova N., Ryabova S., Makarov V. Synthesis and biological properties of pyrrolo[1,2-a]indoles, Journal of Heterocyclic Chemistry, 2016, 53, 3,  685-709.
  2. Grienke U., Richter M., Walther E., Hoffmann A., Kirchmair J., Makarov V., Nietzsche S., Schmidtke M., Rollinger J. M. Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae, Rep., 2016, 6:27156.
  3. Scoffone V. C., Chiarelli L. R., Makarov V., Brackman G., Israyilova A., Azzalin A., Forneris F., Riabova O., Savina S., Coenye T., Riccardi G., Buroni S., Discovery of new diketopyperazines inhibiting Burkholderia cenocepacia quorum sensingin vitro and in vivo, Sci. Rep., 2016, 6, 32487.
  4. Smith L.J., Bochkareva A., Rolfe M.D., Hunt D.M., Kahramanoglou C., Braun Y., Rodgers A., Blockley A., Coade S.,Lougheed K.E.A., Hafneh N.A., Glenn S.M., Crack J.C., LeBrun N.E., Saldanha J.W., Makarov V., Nobeli I., Arnvig K., Mukamolova G.V., Buxton R.S., Green J. Cmr is a redox-responsive regulator of DosR that contributes 1 to M. tuberculosis virulence, Nucleic Acids Research, 2017, 45(11), 6600-6612.
  5. Rosado LA, Wahni K, Degiacomi G, Pedre B, Young D, G de la Rubia A, Boldrin F, Martens E, Marcos-Pascual L, Sancho-Vaello E, Albesa-Jové D, Provvedi R, Martin C, Makarov V, Versées W, Verniest G, Guerin ME, Mateos LM, Manganelli R, Messens J.The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis, Biol.Chem., 2017, pii: jbc.M117.797837 doi: 10.1074/jbc.M117.797837
  6. Gengenbacher M., Duque-Correa M.A., Kaiser P., Schuerer S., Lazar D., Zedler U., Reece S., Nayyar A., Cole S., Makarov V., Barry C.E. III, Dartois V., Kaufmann S. NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans, Scientific reports, 2017, Sci Rep. 2017, 18, 7(1), 8853.
  7. Chiarelli L.R., Mori G., Orena B.S., Esposito M., Lane T., de Jesus Lopes Ribeiro A.L., Degiacomi G., Zemanová J., Szádocka S., Huszár S., Palčeková Z., Manfredi M., Gosetti F., Lelièvre J., Ballell L., Kazakova E., Makarov V., Marengo E., Mikusova K., Cole S.T., Riccardi G., Ekins S., Pasca M.R. A multitarget approach to drug discovery inhibiting Mycobacterium tuberculosis PyrG and PanK, Sci Rep, 2018, 16, 8, 3187. doi: 10.1038/s41598-018-21614-4.
  8. Salina E.G., Huszár S., Zemanová J., Keruchenko J., Riabova O., Kazakova E., Grigorov A., Azhikina T., Kaprelyants A., Mikušová K., Makarov V. Copper-related toxicity in replicating and dormant Mycobacterium tuberculosis caused by 1-hydroxy-5-R-pyridine-2(1H)-thiones. Metallomics. 2018, 10, 7, 992-1002. doi: 10.1039/c8mt00067k.
  9. Piton J., Vocat A., Lupien F., Foo C., Riabova O., Makarov V., Cole S. Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis, Agents Chemother., 2018, 62, 10, pii: e00681-18. doi: 10.1128/AAC.00681-18
  10. Buroni S., Scoffone V.C., Fumagalli M., Makarov V.,. Cagnone M, Trespidi G., De Rossi E., Forneris F., Riccardi G., Chiarelli L.R. Investigating the mechanism of action of diketopiperazines inhibitors of the Burkholderia cenocepacia quorum sensing synthase CepI: a site-directed mutagenesis study, Frontiers in Pharmacology, 2018, 9, 836. doi: 10.3389/fphar.2018.00836
  11. Lupien A., Vocat A., Foo C., Blattes E., Gillon J., Makarov V., Cole S. An optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone Macozinone (PBTZ169), Agents Chemother., 2018, 62, 11, pii: e00840-18.doi: 10.1128/AAC.00840-18
  12. Hogan A., Scoffone V. C., Makarov V., Gislason A., Tesfu H., Stietz M.,. Brassinga A. K, Domaratzki M., Li X., Azzalin A., Biggiogera M., Riabova O., Monakhova N., Chiarelli L., Riccardi G., Buroni S., Cardona S. Competitive fitness of essential gene knockdowns reveals a broad-spectrum antibacterial inhibitor of the cell division protein FtsZ, Agents Chemother., 2018, 62, 12. pii: e01231-18. doi: 10.1128/AAC.01231-18
  13. Sommer R., Neres J., Piton J., Dhar N., van der Sar A., Mukherjee R., Laroche T., Dyson P.J., McKinney J.D., Bitter W., Makarov V., Cole S.T. Fluorescent benzothiazinone analogs efficiently and selectively label DprE1 in mycobacteria and actinobacteria, ACS Chem. Biol., 2018, 13, 11, 3184-3192. doi: 10.1021/acschembio.8b00790
  14. Salina E.G., Ekins S., Makarov V.A. A Rapid Method for Estimation of the Efficacy of Potential Antimicrobials in Humans and Animals by Agar Diffusion Assay, Biol. & Drug Des., 2019, doi: 10.1111/cbdd.13427
  15. Zorn K.M., Lane T.R., Russo D.P., Clark A.M., Makarov V., Ekins S. Multiple Machine Learning Comparisons of HIV Cell-based and Reverse Transcriptase Data Sets, Mol Pharm., 2019, 16(4):1620-1632. doi: 10.1021/acs.molpharmaceut.8b01297.
  16. Puhl A.C., Garzino Demo, Makarov V.A., Ekins S. New targets for HIV drug discovery, Drug Discovery Today, 2019, doi.org/10.1016/j.drudis.2019.03.013