Ukr.Biochem.J. 2016; Volume 88, Issue 6, Nov-Dec, pp. 5-25


Chemical structure and properties of low-molecular furin inhibitors

T. V. Osadchuk1, O. V. Shybyryn1, V. K. Kibirev1,2

1Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine, Kyiv;
2Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;

The review is devoted to the analysis of the relationship between a chemical structure and properties of low-molecular weight inhibitors of furin, the most studied proprotein convertase, which is involved in the development of some pathologies, such as oncologic diseases, viral and bacterial infections, etc. The latest data concerning the influence of peptides, pseudo-peptides, aromatic and heterocyclic compounds, some natural ones such as flavonoids, coumarins, and others on enzyme inactivation are considered. The power of furin inhibition is shown to rise with the increasing number of positively charged groups in the structure of these compounds. Peptidomimetics (Ki = 5-8 pM) are shown to be the most effective furin inhibitors. The synthesized substances, however, have not been used in practical application yet. Nowadays it is very important to find more selective inhibitors, improve their stability, bioavailability and safety for the human organism.

Keywords: , , , , , , , ,


  1. Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66. Review. PubMed, PubMedCentral, CrossRef
  2. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov. 2012 May;11(5):367-83. Review. PubMed, CrossRef
  3. Artenstein AW, Opal SM. Proprotein convertases in health and disease. N Engl J Med. 2011 Dec 29;365(26):2507-18. Review. PubMed, CrossRef
  4. Couture F, D’Anjou F, Day R. On the cutting edge of proprotein convertase pharmacology: from molecular concepts to clinical applications. Biomol Concepts. 2011 Oct 1;2(5):421-438. PubMed, PubMedCentral, CrossRef
  5. Creemers J. Therapeutic potential of furin inhibition. Colloquium Series on Protein Activation and Cancer. Morgan and Claypool Life Sciences, 2013. 32 p.
  6. Basak A. Inhibitors of proprotein convertases. J Mol Med (Berl). 2005 Nov;83(11):844-55. Review. PubMed, CrossRef
  7. Kibirev VK, Osadchuk TV. Structure and properties of proprotein convertase inhibitors. Ukr Biokhim Zhurn. 2012 Mar-Apr;84(2):5-29. Review. (In Russian). PubMed
  8. De UC, Mishra P, Pal PR, Dinda B, Basak A. Non-peptide inhibitors of proprotein convertase subtilisin kexins (PCSKs): An overall review of existing and new data. Colloquium Series on Protein Activation and Cancer. 2012 Sep; 1(3):1-76. CrossRef
  9. Seidah NG, Sadr MS, Chrétien M, Mbikay M. The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J Biol Chem. 2013 Jul 26;288(30):21473-81. Review. PubMed, PubMedCentral, CrossRef
  10. Jean F, Thomas L, Molloy SS, Liu G, Jarvis MA, Nelson JA, Thomas G. A protein-based therapeutic for human cytomegalovirus infection. Proc Natl Acad Sci USA. 2000 Mar 14;97(6):2864-9. PubMed, PubMedCentral, CrossRef
  11. Bennett BD, Denis P, Haniu M, Teplow DB, Kahn S, Louis JC, Citron M, Vassar R. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s beta-secretase. J Biol Chem. 2000 Dec 1;275(48):37712-7.  PubMed, CrossRef
  12. Rostagno A, Tomidokoro Y, Lashley T, Ng D, Plant G, Holton J, Frangione B, Revesz T, Ghiso J. Chromosome 13 dementias. Cell Mol Life Sci. 2005 Aug;62(16):1814-25. Review. PubMed, CrossRef
  13. Arner EC. Aggrecanase-mediated cartilage degradation. Curr Opin Pharmacol. 2002 Jun;2(3):322-9. Review. PubMed, CrossRef
  14. Stawowy P, Fleck E. Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. J Mol Med (Berl). 2005 Nov;83(11):865-75. Review. PubMed, CrossRef
  15. Remacle AG, Gawlik K, Golubkov VS, Cadwell GW, Liddington RC, Cieplak P, Millis SZ, Desjardins R, Routhier S, Yuan XW, Neugebauer WA, Day R, Strongin AY. Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. Int J Biochem Cell Biol. 2010 Jun;42(6):987-95.
    PubMed, PubMedCentral, CrossRef
  16. Gordon VM, Klimpel KR, Arora N, Henderson MA, Leppla SH. Proteolytic activation of bacterial toxins by eukaryotic cells is performed by furin and by additional cellular proteases. Infect Immun. 1995 Jan;63(1):82-7.
    PubMed, PubMedCentral
  17. Garred O, van Deurs B, Sandvig K. Furin-induced cleavage and activation of Shiga toxin. J Biol Chem. 1995 May 5;270(18):10817-21. PubMed, CrossRef
  18. Matsuzawa T, Fukui A, Kashimoto T, Nagao K, Oka K, Miyake M, Horiguchi Y. Bordetella dermonecrotic toxin undergoes proteolytic processing to be translocated from a dynamin-related endosome into the cytoplasm in an acidification-independent manner. J Biol Chem. 2004 Jan 23;279(4):2866-72. PubMed, CrossRef
  19. Gagnon H, Beauchemin S, Kwiatkowska A, Couture F, D’Anjou F, Levesque C, Dufour F, Desbiens AR, Vaillancourt R, Bernard S, Desjardins R, Malouin F, Dory YL, Day R. Optimization of furin inhibitors to protect against the activation of influenza hemagglutinin H5 and Shiga toxin. J Med Chem. 2014 Jan 9;57(1):29-41. PubMed, CrossRef
  20. Yang HY, Zheng NQ, Li DM, Gu L, Peng XM. Entecavir combined with furin inhibitor simultaneously reduces hepatitis B virus replication and e antigen secretion. Virol J. 2014 Sep 16;11:165. PubMed, PubMedCentral, CrossRef
  21. Pang YJ, Tan XJ, Li DM, Zheng ZH, Lei RX, Peng XM. Therapeutic potential of furin inhibitors for the chronic infection of hepatitis B virus. Liver Int. 2013 Sep;33(8):1230-8. PubMed, CrossRef
  22. Moulard M, Decroly E. Maturation of HIV envelope glycoprotein precursors by cellular endoproteases. Biochim Biophys Acta. 2000 Nov 10;1469(3):121-32. Review. PubMed, CrossRef
  23. Fugère M, Limperis PC, Beaulieu-Audy V, Gagnon F, Lavigne P, Klarskov K, Leduc R, Day R. Inhibitory potency and specificity of subtilase-like pro-protein convertase (SPC) prodomains. J Biol Chem. 2002 Mar 8;277(10):7648-56. PubMed, CrossRef
  24. Bhattacharjya S, Xu P, Wang P, Osborne MJ, Ni F. Conformational analyses of a partially-folded bioactive prodomain of human furin. Biopolymers. 2007 Jul;86(4):329-44. PubMed, CrossRef
  25. Lazure C. The peptidase zymogen proregions: nature’s way of preventing undesired activation and proteolysis. Curr Pharm Des. 2002;8(7):511-31. Review. PubMed, CrossRef
  26. Gawlik K, Shiryaev SA, Zhu W, Motamedchaboki K, Desjardins R, Day R, Remacle AG, Stec B, Strongin AY. Autocatalytic activation of the furin zymogen requires removal of the emerging enzyme’s N-terminus from the active site. PLoS One. 2009;4(4):e5031. PubMed, PubMedCentral, CrossRef
  27. Hosaka M, Nagahama M, Kim WS, Watanabe T, Hatsuzawa K, Ikemizu J, Murakami K, Nakayama K. Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway. J Biol Chem. 1991 Jul 5;266(19):12127-30. PubMed
  28. Shiryaev SA, Chernov AV, Golubkov VS, Thomsen ER, Chudin E, Chee MS, Kozlov IA, Strongin AY, Cieplak P. High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome. PLoS One. 2013;8(1):e54290. PubMed, PubMedCentral, CrossRef
  29. Zhu J, Declercq J, Roucourt B, Ghassabeh GH, Meulemans S, Kinne J, David G, Vermorken AJ, Van de Ven WJ, Lindberg I, Muyldermans S, Creemers JW. Generation and characterization of non-competitive furin-inhibiting nanobodies. Biochem J. 2012 Nov 15;448(1):73-82.  PubMed, PubMedCentral, CrossRef
  30. Cameron A, Appel J, Houghten RA, Lindberg I. Polyarginines are potent furin inhibitors. J Biol Chem. 2000 Nov 24;275(47):36741-9. PubMed, CrossRef
  31. Kacprzak MM, Peinado JR, Than ME, Appel J, Henrich S, Lipkind G, Houghten RA, Bode W, Lindberg I. Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine. J Biol Chem. 2004 Aug 27;279(35):36788-94.  PubMed, CrossRef
  32. Ramos-Molina B, Lick AN, Nasrolahi Shirazi A, Oh D, Tiwari R, El-Sayed NS, Parang K, Lindberg I. Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors. PLoS One. 2015 Jun 25;10(6):e0130417.  PubMed, PubMedCentral, CrossRef
  33. Becker GL, Sielaff F, Than ME, Lindberg I, Routhier S, Day R, Lu Y, Garten W, Steinmetzer T. Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J Med Chem. 2010 Feb 11;53(3):1067-75.  PubMed, PubMedCentral, CrossRef
  34. Becker GL, Hardes K, Steinmetzer T. New substrate analogue furin inhibitors derived from 4-amidinobenzylamide. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4695-7. PubMed, CrossRef
  35. Becker GL, Lu Y, Hardes K, Strehlow B, Levesque C, Lindberg I, Sandvig K, Bakowsky U, Day R, Garten W, Steinmetzer T. Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. J Biol Chem. 2012 Jun 22;287(26):21992-2003.  PubMed, PubMedCentral, CrossRef
  36. Hardes K, Becker GL, Lu Y, Dahms SO, Köhler S, Beyer W, Sandvig K, Yamamoto H, Lindberg I, Walz L, von Messling V, Than ME, Garten W, Steinmetzer T. Novel Furin Inhibitors with Potent Anti-infectious Activity. Chem Med Chem. 2015 Jul;10(7):1218-31. PubMed, CrossRef
  37. Basak A, Cooper S, Roberge AG, Banik UK, Chrétien M, Seidah NG. Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters. Biochem J. 1999 Feb 15;338 (Pt 1):107-13. PubMed, PubMedCentral, CrossRef
  38. Jiao GS, Cregar L, Wang J, Millis SZ, Tang C, O’Malley S, Johnson AT, Sareth S, Larson J, Thomas G.  Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine. Proc Natl Acad Sci USA. 2006 Dec 26;103(52):19707-12.  PubMed, PubMedCentral, CrossRef
  39. López-Vallejo F, Martínez-Mayorga K. Furin inhibitors: importance of the positive formal charge and beyond. Bioorg Med Chem. 2012 Jul 15;20(14):4462-71. PubMed, CrossRef
  40. Ramos-Molina B, Lick AN, Blanco EH, Posada-Salgado JA, Martinez-Mayorga K, Johnson AT, Jiao GS, Lindberg I. Identification of potent and compartment-selective small molecule furin inhibitors using cell-based assays. Biochem Pharmacol. 2015 Jul 15;96(2):107-18.  PubMed, PubMedCentral, CrossRef
  41. Kowalska D, Liu J, Appel JR, Ozawa A, Nefzi A, Mackin RB, Houghten RA, Lindberg I. Synthetic small-molecule prohormone convertase 2 inhibitors. Mol Pharmacol. 2009 Mar;75(3):617-25. PubMed, PubMedCentral, CrossRef
  42. Podsiadlo P, Komiyama T, Fuller RS, Blum O. Furin inhibition by compounds of copper and zinc. J Biol Chem. 2004 Aug 27;279(35):36219-27. PubMed, CrossRef
  43. Basak A, Khatib AM, Mohottalage D, Basak S, Kolajova M, Bag SS, Basak A. A novel enediynyl peptide inhibitor of furin that blocks processing of proPDGF-A, B and proVEGF-C. PLoS One. 2009 Nov 26;4(11):e7700. PubMed, PubMedCentral, CrossRef
  44. Basak A, Mandal S, Bag SS. Chelation-controlled Bergman cyclization: synthesis and reactivity of enediynyl ligands. Chem Rev. 2003 Oct;103(10):4077-94. Review. PubMed, CrossRef
  45. Majumdar S, Mohanta BC, Chowdhury DR, Banik R, Dinda B, Basak A. Proprotein convertase inhibitory activities of flavonoids isolated from Oroxylum indicum. Curr Med Chem. 2010;17(19):2049-58. PubMed, CrossRef
  46. Lalou C, Basak A, Mishra P, Mohanta BC, Banik R, Dinda B, Khatib AM. Inhibition of tumor cells proliferation and migration by the flavonoid furin inhibitor isolated from Oroxylum indicum. Curr Med Chem. 2013;20(4):583-91. PubMed, CrossRef
  47. Kibirev VK, Osadchuk TV, Vadziuk OB, Garazd MM. New non-peptide inhibitors of furin. Ukr Biokhim Zhurn. 2010 Mar-Apr;82(2):15-21. (In Russian). PubMed
  48. Komiyama T, Coppola JM, Larsen MJ, van Dort ME, Ross BD, Day R, Rehemtulla A, Fuller RS. Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J Biol Chem. 2009 Jun 5;284(23):15729-38. PubMed, PubMedCentral, CrossRef
  49. Dahms SO, Hardes K, Becker GL, Steinmetzer T, Brandstetter H, Than ME. X-ray structures of human furin in complex with competitive inhibitors. ACS Chem Biol. 2014 May 16;9(5):1113-8. PubMed, PubMedCentral, CrossRef
  50. Henrich S, Cameron A, Bourenkov GP, Kiefersauer R, Huber R, Lindberg I, Bode W, Than ME. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Biol. 2003 Jul;10(7):520-6. PubMed, CrossRef
  51. Sielaff F, Than ME, Bevec D, Lindberg I, Steinmetzer T. New furin inhibitors based on weakly basic amidinohydrazones. Bioorg Med Chem Lett. 2011 Jan 15;21(2):836-40. PubMed, PubMedCentral, CrossRef
  52. Kibirev VK, Osadchuk TV, Kozachenko AP, Vadziuk OB, Brovarets VS. Non-peptide furin inhibitors based on amidinohydrazones of diarylaldehydes. Ukr Biokhim Zhurn. 2013 Jan-Feb;85(1):22-32. (In Russian). PubMed, CrossRef
  53.  Kibirev VK, Osadchuk TV, Kozachenko OP, Kholodovych V, Fedoryak OD, Brovarets VS. Synthesis, biological evaluation and docking of novel bisamidino-hydrazones as non-peptide inhibitors of furin. Ukr Biochem J. 2015 Jan-Feb;87(1):55-63. PubMed, CrossRef
  54. Coppola JM, Hamilton CA, Bhojani MS, Larsen MJ, Ross BD, Rehemtulla A. Identification of inhibitors using a cell-based assay for monitoring Golgi-resident protease activity. Anal Biochem. 2007 May 1;364(1):19-29.  PubMed, PubMedCentral, CrossRef
  55. Kibirev VK, Osadchuk TV, Rodik RV, Kalchenko VI. Furin inhibitors based on the derivatives of calix[4]arene CX3im. Ukr Biochem J. 2015 May-Jun;87(3):31-6. PubMed, CrossRef
  56. Jean F, Stella K, Thomas L, Liu G, Xiang Y, Reason AJ, Thomas G. alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc Natl Acad Sci USA. 1998 Jun 23;95(13):7293-8. PubMed, PubMedCentral, CrossRef
  57. Couture F, Kwiatkowska A, Dory YL, Day R. Therapeutic uses of furin and its inhibitors: a patent review. Expert Opin Ther Pat. 2015 Apr;25(4):379-96. Review. PubMed, CrossRef

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