Laboratory for Biomedicinal Chemistry

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


Our main research projects:

  • Drug candidate for the therapy of dementia associated with ageing, Parkinson’s or Alzheimer’s diseases, major depressive disorder

The goal of this project is to discover an original compound from the eburnamine-vincamine alkaloid class for the treatment of cognitive impairment associated with ageing or CNS diseases. Preliminary efficacy was confirmed in behavioural testing on mice and rats. This project is actively under development with the participation of the Russian pharmaceutical company R-Pharm.

  • Drug candidate for the treatment of HIV infections

Available non-nucleoside reverse transcriptase inhibitors (NNRTIs) are known to have CNS toxicity, and the side effects of efavirenz and nevirapine have been well studied. The goal of our research project was to discover novel NNRTIs with enhanced potency and reduced CNS toxicity. The molecule with the developmental code 12126065 demonstrated in vitro activity against HIV-1 strains and favourable in vivo toxicity and pharmacokinetic profiles. It lacks the neuronal toxicity compared to the standard efavirenz. Efficacy studies are currently in progress.

  • Drug candidate for the treatment of rhino- and enterovirus infection

The pyrazolo[3,4-d]pyrimidine-core molecule with the developmental code OBR-5-340 was discovered as a potent inhibitor of a wide range of rhino- and enteroviruses through rigorous medicinal chemistry efforts. The compound has favourable in vitro ADME-T and in vivo pharmacokinetics in mice. Acute and chronic toxicological studies revealed no toxicity in mice. The efficacy of the compound was demonstrated in a mouse model of Coxsackievirus B3-caused chronic myocarditis, where the treatment with the molecule reduced tissue damage as well as inflammation in the heart and pancreas of infected mice. The compound targets a pocket located in the VP1 of the rhino- or enterovirus capsids differently from well-known capsid-binding agents (pleconaril, vapendavir).

  • Drug candidate for the treatment of herpes simplex virus infections

PDSTP, a pyrimidinodispirotripiperazine, inhibits a panel of distinct viruses known to use heparan sulfate for early interaction with host cell, such as herpes simplex virus and cytomegalovirus. The compound demonstrated efficacy in several preclinical animal models, including a rabbit model of herpes simplex epithelial keratitis, a mouse model of herpes simplex-1-induced encephalitis, and a guinea pig model of genital herpes infection. These studies were conducted by the company Niarmedic and supported by the Pharma-2020 program.

  • Drug candidate for the treatment of multidrug-resistant tuberculosis

Macozinone (INN; developmental code PBTZ169·HCl) was designed, synthesized, and developed by our lab in partnership with Dr. Stewart T. Cole (at the time affiliated with the Global Health Institute, Ecole Polytechnique Fédérale de Lausanne) and with the support of FP6 and FP7. This compound, belonging to the chemical class of benzothiazinones, is the result of the structural optimization of BTZ043, which was previously developed in our lab. Macozinone works by inhibiting the synthesis of the mycobacterial cell wall through the covalent targeting of the essential enzyme decaprenylphosphoryl-β-D-ribose-2’-epimerase (DprE1). The agent successfully completed Phase I (a and b) and Phase IIa of clinical trials.

Some other achievements:

  • A facile synthetic method for the 3rd generation antiarrhythmic agent niferedil (trade name Refralon), was successfully introduced into production at the pilot plant of the National Medical Research Center of Cardiology;
  • Design and development of the first nucleotide HIV reverse transcriptase inhibitor INDOPY-1.

The results of our research projects are presented in more than 150 peer-reviewed high-quality journals and more than 10 patents.

 

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.