Abstract
The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg2+ or Mn2+) in the enzyme’s catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1–6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure–activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg2+, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors.
Similar content being viewed by others
References
Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, Zhang Y, Shu Y, Gubareva LV, Cox NJ, Klimov AI (2007) J Infect Dis 196:249–257
Moscona A (2009) N Engl J Med 360:953–956
Memoli MJ, Davis AS, Proudfoot K, Chertow DS, Hrabal RJ, Bristol T, Taubenberger JK (2011) J Infect Dis 203:348–357
Van der Vries E, Schutten M, Fraaij P, Boucher C, Osterhaus A (2013) Adv Pharmacol 67:217–246
Vanderlinden E, Naesens L (2014) Med Res Rev 34:301–339
Honda A, Ishihama A (1997) Biol. Chem 378:483–488
Honda A, Mizumoto K, Ishihama A (2002) Proc Natl Acad Sci USA 99:13166–13171
Das K, Aramini JM, Ma LC, Krug RM, Arnold E (2010) Nat Struct Mol Biol 17:530–538
Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW (2009) Nature 458:914–918
Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, Lv Z, Ge R, Li X, Deng T, Fodor E, Rao Z, Liu Y (2009) Nature 458:909–913
Plotch SJ, Bouloy M, Ulmanen I, Krug RM (1981) Cell 23:847–858
Zhao C, Lou Z, Guo Y, Ma M, Chen Y, Liang S, Zhang L, Chen S, Li X, Liu Y, Bartlam M, Rao Z (2009) J Virol 83:9024–9030
DuBois RM, Slavish PJ, Baughman BM, Yun MK, Bao J, Webby RJ, Webb TR, White SW (2012) PLoS Pathog 8:e1002830
Kowalinski E, Zubieta C, Wolkerstorfer A, Szolar OH, Ruigrok RW, Cusack S (2012) PLoS Pathog 8:e1002831
Doan L, Handa B, Roberts NA, Klumpp K (1999) Biochemistry 38:5612–5629
Xiao S, Klein ML, LeBard DN, Levine BG, Liang H, MacDermaid CM, Alfonso-Prieto M (2014) J Phys Chem B 118:873–889
Rogolino D, Carcelli M, Sechi M, Neamati N (2012) Coord Chem Rev 256:3063–3086
Tomassini JE, Selnick H, Davies ME, Armstrong ME, Baldwin J, Bourgeois M, Hastings J, Hazuda D, Lewis J, McClements W, Ponticello G, Radzilowski E, Smith G, Tebben A, Wolfe A (1994) Antimicrob Agents Chemother 38:2827–2837
Hastings JC, Selnick H, Wolanski B, Tomassini JE (1996) Antimicrob Agents Chemother 40:1304–1307
Stevaert A, Nurra S, Pala N, Carcelli M, Rogolino D, Shepard C, Domaoal RA, Kim B, Alfonso-Prieto M, Marras SAE, Sechi M, Naesens L (2015) Mol Pharmacol 87:323–337
Singh SB (1995) Tetrahedron Lett 36:2009–2012
Carcelli M, Rogolino D, Bacchi A, Rispoli G, Fisicaro E, Compari C, Sechi M, Stevaert A, Naesens L (2014) Mol Pharm 11:304–316
Parkes KEB, Ermert P, Fässler J, Ives J, Martin JA, Merrett JH, Obrecht D, Williams G, Klumpp K (2003) J Med Chem 46:1153–1164
Sagong HY, Parhi A, Bauman JD, Patel D, Vijayan RS, Das K, Arnold E, LaVoie EJ (2013) ACS Med Chem Lett 4:547–550
Knox JJ, Hotte SJ, Kollmannsberger C, Winquist E, Fisher B, Eisenhauer EA (2007) Invest New Drugs 25:471–477
Kang IJ, Wang LW, Hsu TA, Yueh A, Lee CC, Lee YC, Lee CY, Chao YS, Shih SR, Chern JH (2011) Bioorg Med Chem Lett 21:1948–1952
Quenelle DC, Keith KA, Kern ER (2006) Antiv Res 71:24–30
Debebe Z, Ammosova T, Breuer D, Lovejoy DB, Kalinowski DS, Kumar K, Jerebtsova M, Ray P, Kashanchi F, Gordeuk VR, Richardson DR, Nekhai S (2011) Mol Pharmacol 79:185–196
Pelosi G, Bisceglie F, Bignami F, Ronzi P, Schiavone P, Re MC, Casoli C, Pilotti E (2010) J Med Chem 53:8765–8769
Torti SV, Torti FM (2013) Nat Rev Cancer 13:342–355
Pelosi G (2010) Open Crystallogr J 3:16–28
Sacconi L (1954) Z Anorg Allg Chem 275:249–256
Dolomanov OV, Bourhis LJ, Gildea RJ, Howard JAK, Puschmann H (2009) J Appl Cryst 42:339–341
Burla MC, Caliandro R, Camalli M, Carrozzini B, Cascarano GL, De Caro L, Giacovazzo C, Polidori G, Siliqi D, Spagna R (2007) J Appl Cryst 40:609–613
Sheldrick GM (2008) Acta Cryst A64:112–122
Nardelli M (1995) J Appl Cryst 28:659
Allen FH, Kennard O, Taylor R (1983) Acc Chem Res 16:146–153
Bruno IJ, Cole JC, Edgington PR, Kessler M, Macrae CF, McCabe P, Pearson J, Taylor R (2002) Acta Crystallogr B 58:389–397
Meneghesso S, Vanderlinden E, Stevaert A, McGuigan C, Balzarini J, Naesens L (2012) Antiviral Res 94:35–43
Stevaert A, Dallocchio R, Dessì R, Pala N, Rogolino D, Sechi M, Naesens L (2013) J Virol 87:10524–10538
Kim M, Kim SY, Lee HW, Shin JS, Kim P, Jung YS, Jeong HS, Hyun JK, Lee CK (2013) Antiviral Res 100:460–472
Reed LJ, Muench H (1938) Am J Epidemiol 27:493–497
Vanderlinden E, Göktas F, Cesur Z, Froeyen M, Reed ML, Russell CJ, Cesur N, Naesens L (2010) J Virol 84:4277–4288
Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727
Gong Q, Menon L, Ilina T, Miller LG, Ahn J, Parniak MA, Ishima R (2011) Chem Biol Drug Des 77:39–47
Enyedy ÉA, Zsigó É, Nagy NV, Kowol CR, Roller A, Keppler BK, Kiss T (2012) Eur J Inorg Chem 2012(25):4036–4047
Lobana TS, Kumari P, Hundal G, Butcher RJ (2010) Polyhedron 29:1130–1136
Chellan P, Stringer T, Shokar A, Dornbush PJ, Vazquez-Anaya G, Land KM, Chibale K, Smith GS (2011) J Inorg Biochem 105:1562–1568
Ramachandran E, Kalaivani P, Prabhakaran R, Rath NP, Brinda S, Poornima P, Padma VV, Natarajan K (2012) Metallomics 4:218–227
Kalaivani P, Prabhakaran R, Dallemer F, Poornima P, Vaishnavi E, Ramachandran E, Padma VV, Renganathan R, Natarajan K (2012) Metallomics 4:101–113
West DX, Salberg MM, Bain GA, Liberta AE, Valdés-Martínez J, Hernández Ortega S (1996) Transit Met. Chem. 21:206–212
Sahadev RKS, Sindhwani SK (1992) Thermochim Acta 202:291–299
Laskowski RA, Swindells MB (2011) J Chem Inf Mod 51:2778
Yang ZF, Bai LP, Huang WB, Li XZ, Zhao SS, Zhong NS, Jiang ZH (2014) Fitoterapia 93:47–53
Martin DP, Blachly PG, McCammon JA, Cohen SM (2014) J Med Chem 57:7126–7135
Rogolino D, Carcelli M, Bacchi A, Compari C, Contardi L, Fisicaro E, Gatti A, Sechi M, Stevaert A, Naesens L (2015) J Inorg Biochem 150:9–17
Acknowledgments
The authors thank the “Centro Interfacoltà Misure Giuseppe Casnati” of the University of Parma for facilities. L. Naesens and A. Stevaert acknowledge financial support from the Geconcerteerde Onderzoeksacties—KU Leuven (GOA/15/019/TBA) and the technical assistance from Wim van Dam, Leentje Persoons en Ria Van Berwaer.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rogolino, D., Bacchi, A., De Luca, L. et al. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease. J Biol Inorg Chem 20, 1109–1121 (2015). https://doi.org/10.1007/s00775-015-1292-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-015-1292-0