4m5o Citations

Crystallographic Fragment Screening and Structure-Based Optimization Yields a New Class of Influenza Endonuclease Inhibitors.

ACS Chem. Biol. (2013)
Related entries: 4m4q, 4m5v, 4m5r, 4m5q, 4ln7, 4mk5, 4mk1, 4mk2

Cited: 26 times
EuropePMC logo PMID: 23978130


Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity, was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 μM against PR8 H1N1 influenza A in MDCK cells.

Reviews citing this publication (9)

  1. The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design. Stevaert A, Naesens L. Med Res Rev 36 1127-1173 (2016)
  2. Structural biology in antiviral drug discovery. Bassetto M, Massarotti A, Coluccia A, Brancale A. Curr Opin Pharmacol 30 116-130 (2016)
  3. Antiviral therapies on the horizon for influenza. Naesens L, Stevaert A, Vanderlinden E. Curr Opin Pharmacol 30 106-115 (2016)
  4. Learning from structure-based drug design and new antivirals targeting the ribonucleoprotein complex for the treatment of influenza. Monod A, Swale C, Tarus B, Tissot A, Delmas B, Ruigrok RW, Crépin T, Slama-Schwok A. Expert Opin Drug Discov 10 345-371 (2015)
  5. Supramolecular Hydrogelators and Hydrogels: From Soft Matter to Molecular Biomaterials. Du X, Zhou J, Shi J, Xu B. Chem. Rev. 115 13165-13307 (2015)
  6. Successful generation of structural information for fragment-based drug discovery. Öster L, Tapani S, Xue Y, Käck H. Drug Discov. Today 20 1104-1111 (2015)
  7. Antiviral strategies against influenza virus: towards new therapeutic approaches. Loregian A, Mercorelli B, Nannetti G, Compagnin C, Palù G. Cell. Mol. Life Sci. 71 3659-3683 (2014)
  8. Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery. Patel D, Bauman JD, Arnold E. Prog. Biophys. Mol. Biol. 116 92-100 (2014)
  9. Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part II: Future compounds against influenza virus. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. J Prev Med Hyg 55 109-129 (2014)

Articles citing this publication (17)

  1. Influenza A and B virus intertypic reassortment through compatible viral packaging signals. Baker SF, Nogales A, Finch C, Tuffy KM, Domm W, Perez DR, Topham DJ, Martínez-Sobrido L. J. Virol. 88 10778-10791 (2014)
  2. Phenyl substituted 4-hydroxypyridazin-3(2H)-ones and 5-hydroxypyrimidin-4(3H)-ones: inhibitors of influenza A endonuclease. Sagong HY, Bauman JD, Patel D, Das K, Arnold E, LaVoie EJ. J. Med. Chem. 57 8086-8098 (2014)
  3. Replication-competent influenza A viruses expressing a red fluorescent protein. Nogales A, Baker SF, Martínez-Sobrido L. Virology 476 206-216 (2015)
  4. Structural and functional studies of MutS2 from Deinococcus radiodurans. Zhang H, Xu Q, Lu M, Xu X, Wang Y, Wang L, Zhao Y, Hua Y. DNA Repair (Amst.) 21 111-119 (2014)
  5. Functional Constraint Profiling of a Viral Protein Reveals Discordance of Evolutionary Conservation and Functionality. Wu NC, Olson CA, Du Y, Le S, Tran K, Remenyi R, Gong D, Al-Mawsawi LQ, Qi H, Wu TT, Sun R. PLoS Genet. 11 e1005310 (2015)
  6. Replication-competent fluorescent-expressing influenza B virus. Nogales A, Rodríguez-Sánchez I, Monte K, Lenschow DJ, Perez DR, Martínez-Sobrido L. Virus Res. 213 69-81 (2016)
  7. Exploring the influence of the protein environment on metal-binding pharmacophores. Martin DP, Blachly PG, McCammon JA, Cohen SM. J. Med. Chem. 57 7126-7135 (2014)
  8. LEADOPT: an automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors. Li GB, Ji S, Yang LL, Zhang RJ, Chen K, Zhong L, Ma S, Yang SY. Eur J Med Chem 93 523-538 (2015)
  9. Virtual Screening and Biological Validation of Novel Influenza Virus PA Endonuclease Inhibitors. Pala N, Stevaert A, Dallocchio R, Dessì A, Rogolino D, Carcelli M, Sanna V, Sechi M, Naesens L. ACS Med Chem Lett 6 866-871 (2015)
  10. Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1. Moen SO, Abendroth J, Fairman JW, Baydo RO, Bullen J, Kirkwood JL, Barnes SR, Raymond AC, Begley DW, Henkel G, McCormack K, Tam VC, Phan I, Staker BL, Stacy R, Myler PJ, Lorimer D, Edwards TE. Sci Rep 4 5944 (2014)
  11. Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF. Chapman TM, Gillen KJ, Wallace C, Lee MT, Bakrania P, Khurana P, Coombs PJ, Stennett L, Fox S, Bureau EA, Brownlees J, Melton DW, Saxty B. Bioorg. Med. Chem. Lett. 25 4097-4103 (2015)
  12. Global geno-proteomic analysis reveals cross-continental sequence conservation and druggable sites among influenza virus polymerases. Babar MM, Zaidi NU, Tahir M. Antiviral Res. 112 120-131 (2014)
  13. N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes. Carcelli M, Rogolino D, Gatti A, De Luca L, Sechi M, Kumar G, White SW, Stevaert A, Naesens L. Sci Rep 6 31500 (2016)
  14. Tuned by metals: the TET peptidase activity is controlled by 3 metal binding sites. Colombo M, Girard E, Franzetti B. Sci Rep 6 20876 (2016)
  15. Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library. Huschmann FU, Linnik J, Sparta K, Ühlein M, Wang X, Metz A, Schiebel J, Heine A, Klebe G, Weiss MS, Mueller U. Acta Crystallogr F Struct Biol Commun 72 346-355 (2016)
  16. Fragment-Based Identification of Influenza Endonuclease Inhibitors. Credille CV, Chen Y, Cohen SM. J. Med. Chem. 59 6444-6454 (2016)
  17. Pandemic 2009 H1N1 Influenza Venus reporter virus reveals broad diversity of MHC class II-positive antigen-bearing cells following infection in vivo. DiPiazza A, Nogales A, Poulton N, Wilson PC, Martínez-Sobrido L, Sant AJ. Sci Rep 7 10857 (2017)