2. Academic Validation
  3. Generation, optimization and characterization of novel anti-prion compounds

Generation, optimization and characterization of novel anti-prion compounds

  • Bioorg Med Chem. 2020 Nov 1;28(21):115717. doi: 10.1016/j.bmc.2020.115717.
Andrea Altieri 1,  Evgeny A Spiridonov 2,  Semen I Sivtzev 2,  Daisuke Ishibashi 3,  Silvia Biggi 4,  Noriyuki Nishida 5,  Emiliano Biasini 6,  Alexander V Kurkin 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1-3, Moscow 119991, Russian Federation; EDASA Scientific, Via Stingi 37, San Salvo 66050, Italy. Electronic address: [email protected].
  • 2 Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1-3, Moscow 119991, Russian Federation.
  • 3 Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Electronic address: [email protected].
  • 4 Dulbecco Telethon Laboratory of Prions & Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, Trento 38123, Italy.
  • 5 Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
  • 6 Dulbecco Telethon Laboratory of Prions & Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, Trento 38123, Italy. Electronic address: [email protected].
  • 7 Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1-3, Moscow 119991, Russian Federation; A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov St. 28, Moscow, Russian Federation. Electronic address: [email protected].
PMID: 33065443 DOI: 10.1016/j.bmc.2020.115717
Abstract

Prions are misfolded proteins involved in neurodegenerative diseases of high interest in veterinary and public health. In this work, we report the chemical space exploration around the anti-prion compound BB 0300674 in order to gain an understanding of its Structure Activity Relationships (SARs). A series of 43 novel analogues, based on four different chemical clusters, were synthetized and tested against PrPSc and mutant PrP toxicity assays. From this biological screening, two compounds (59 and 65) emerged with a 10-fold improvement in anti-prion activity compared with the initial lead compound, presenting at the same time interesting cell viability.

Keywords

Lead optimization; PrP(C); PrP(Sc); Prion; Screening.

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