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

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. Lane T, Makarov V, Nelson JAE, Meeker RB, Sanna G, Riabova O, Kazakova E, Monakhova N, Tsedilin A, Urbina F, Jones T, Suchy A, Ekins S. N-Phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine as a New Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor. J Med Chem. 2023; 66(9): 6193-6217. DOI: 10.1021/acs.jmedchem.2c02055.

2. Dohme A, Knoblauch M, Egorova A, Makarov V, Bogner E. Broad-spectrum antiviral diazadispiroalkane core molecules block attachment and cell-to-cell spread of herpesviruses. Antiviral Res. 2022; 206: 105402. DOI: 10.1016/j.antiviral.2022.105402.

3. Alimbarova L, Egorova A, Riabova O, Monakhova N, Makarov V. A proof-of-concept study for the efficacy of dispirotripiperazine PDSTP in a rabbit model of herpes simplex epithelial keratitis. Antiviral Res. 2022; 202: 105327. DOI: 10.1016/j.antiviral.2022.105327.

4. Egorova A, Jackson M, Gavrilyuk V, Makarov V. Pipeline of anti-Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities. Med Res Rev. 2021; 41(4): 2350-2387. DOI: 10.1002/med.21798.

5. Adfeldt R, Schmitz J, Kropff B, Thomas M, Monakhova N, Hölper JE, Klupp BG, Mettenleiter TC, Makarov V, Bogner E. Diazadispiroalkane derivatives are new viral entry inhibitors. Antimicrob Agents Chemother. 2021; 65(4): e02103-20. DOI: 10.1128/AAC.02103-20.

6. Egorova A, Kazakova E, Jahn B, Ekins S, Makarov V, Schmidtke M. Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses. Eur J Med Chem. 2020; 188: 112007. DOI: 10.1016/j.ejmech.2019.112007.

7. Lupien A, Foo CS, Savina S, Vocat A, Piton J, Monakhova N, Benjak A, Lamprecht DA, Steyn AJC, Pethe K, Makarov VA, Cole ST. New 2-ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis. PLoS Pathog. 2020; 16(1): e1008270. DOI: 10.1371/journal.ppat.1008270.

8. Wald J, Pasin M, Richter M, Walther C, Mathai N, Kirchmair J, Makarov VA, Goessweiner-Mohr N, Marlovits TC, Zanella I, Real-Hohn A, Verdaguer N, Blaas D, Schmidtke M. Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site. Proc Natl Acad Sci U S A. 2019; 116(38): 19109-19115. DOI: 10.1073/pnas.1904732116.

9. Puhl AC, Garzino Demo A, Makarov VA, Ekins S. New targets for HIV drug discovery. Drug Discov Today. 2019; 24(5): 1139-1147. DOI: 10.1016/j.drudis.2019.03.013

10. Lupien A, Vocat A, Foo CS, Blattes E, Gillon JY, Makarov V, Cole ST. Optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone macozinone (PBTZ169). Antimicrob Agents Chemother. 2018; 62(11): e00840-18. DOI: 10.1128/AAC.00840-18.

11. Scoffone VC, Chiarelli LR, Makarov V, Brackman G, Israyilova A, Azzalin A, Forneris F, Riabova O, Savina S, Coenye T, Riccardi G, Buroni S. Discovery of new diketopiperazines inhibiting Burkholderia cenocepacia quorum sensing in vitro and in vivo. Sci Rep. 2016; 6: 32487. DOI: 10.1038/srep32487.

12. Smith LJ, Bochkareva A, Rolfe MD, Hunt DM, Kahramanoglou C, Braun Y, Rodgers A, Blockley A, Coade S, Lougheed KEA, Hafneh NA, Glenn SM, Crack JC, Le Brun NE, Saldanha JW, Makarov V, Nobeli I, Arnvig K, Mukamolova GV, Buxton RS, Green J. Cmr is a redox-responsive regulator of DosR that contributes to M. tuberculosis virulence. Nucleic Acids Res. 2017; 45(11): 6600-6612. DOI: 10.1093/nar/gkx406.

13. Braun H, Kirchmair J, Williamson MJ, Makarov VA, Riabova OB, Glen RC, Sauerbrei A, Schmidtke M. Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket. Antiviral Res. 2015; 123: 138-145. doi: 10.1016/j.antiviral.2015.09.009.

14. Makarov VA, Braun H, Richter M, Riabova OB, Kirchmair J, Kazakova ES, Seidel N, Wutzler P, Schmidtke M. Pyrazolopyrimidines: potent inhibitors targeting the capsid of rhino- and enteroviruses. ChemMedChem. 2015; 10(10): 1629-1634. DOI: 10.1002/cmdc.201500304.

15. Mori G, Chiarelli LR, Esposito M, Makarov V, Bellinzoni M, Hartkoorn RC, Degiacomi G, Boldrin F, Ekins S, de Jesus Lopes Ribeiro AL, Marino LB, Centárová I, Svetlíková Z, Blaško J, Kazakova E, Lepioshkin A, Barilone N, Zanoni G, Porta A, Fondi M, Fani R, Baulard AR, Mikušová K, Alzari PM, Manganelli R, de Carvalho LP, Riccardi G, Cole ST, Pasca MR. Thiophenecarboxamide derivatives activated by EthA kill Mycobacterium tuberculosis by inhibiting the CTP synthetase PyrG. Chem Biol. 2015; 22(7): 917-927. DOI: 10.1016/j.chembiol.2015.05.016.

16. Turapov O, Glenn S, Kana B, Makarov V, Andrew PW, Mukamolova GV. The in vivo environment accelerates generation of resuscitation-promoting factor-dependent mycobacteria. Am J Respir Crit Care Med. 2014; 190(12): 1455-1457. DOI: 10.1164/rccm.201407-1289LE.

17. Makarov V, Lechartier B, Zhang M, Neres J, van der Sar AM, Raadsen SA, Hartkoorn RC, Ryabova OB, Vocat A, Decosterd LA, Widmer N, Buclin T, Bitter W, Andries K, Pojer F, Dyson PJ, Cole ST. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol Med. 2014; 6(3): 372-383. DOI: 10.1002/emmm.201303575.

18. Trefzer C, Škovierová H, Buroni S, Bobovská A, Nenci S, Molteni E, Pojer F, Pasca MR, Makarov V, Cole ST, Riccardi G, Mikušová K, Johnsson K. Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase DprE1. J Am Chem Soc. 2012; 134(2): 912-915. DOI: 10.1021/ja211042r.

19. Trefzer C, Rengifo-Gonzalez M, Hinner MJ, Schneider P, Makarov V, Cole ST, Johnsson K. Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-D-ribose 2′-epimerase DprE1 of Mycobacterium tuberculosis. J Am Chem Soc. 2010; 132(39): 13663-13665. DOI: 10.1021/ja106357w.

20. Pasca MR, Degiacomi G, Ribeiro AL, Zara F, De Mori P, Heym B, Mirrione M, Brerra R, Pagani L, Pucillo L, Troupioti P, Makarov V, Cole ST, Riccardi G. Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob Agents Chemother. 2010; 54(4): 1616-1618. DOI: 10.1128/AAC.01676-09.

21. Makarov V, Manina G, Mikusova K, Möllmann U, Ryabova O, Saint-Joanis B, Dhar N, Pasca MR, Buroni S, Lucarelli AP, Milano A, De Rossi E, Belanova M, Bobovska A, Dianiskova P, Kordulakova J, Sala C, Fullam E, Schneider P, McKinney JD, Brodin P, Christophe T, Waddell S, Butcher P, Albrethsen J, Rosenkrands I, Brosch R, Nandi V, Bharath S, Gaonkar S, Shandil RK, Balasubramanian V, Balganesh T, Tyagi S, Grosset J, Riccardi G, Cole ST. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science. 2009; 324(5928): 801-804. DOI: 10.1126/science.1171583.

22. Schmidtke M, Wutzler P, Zieger R, Riabova OB, Makarov VA. New pleconaril and [(biphenyloxy)propyl]isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against pleconaril-resistant coxsackievirus B3. Antiviral Res. 2009; 81(1): 56-63. DOI: 10.1016/j.antiviral.2008.09.002.