2. Academic Validation
  3. Identification of novel fluorescent probes preventing PrPSc replication in prion diseases

Identification of novel fluorescent probes preventing PrPSc replication in prion diseases

  • Eur J Med Chem. 2017 Feb 15;127:859-873. doi: 10.1016/j.ejmech.2016.10.064.
Ludovica Zaccagnini 1,  Simone Brogi 2,  Margherita Brindisi 2,  Sandra Gemma 3,  Giulia Chemi 2,  Giuseppe Legname 4,  Giuseppe Campiani 2,  Stefania Butini 2
Affiliations

Affiliations

  • 1 Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, 34136 Trieste, Italy.
  • 2 European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.
  • 3 European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy. Electronic address: gemma@unisi.it.
  • 4 Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: legname@sissa.it.
PMID: 27842893 DOI: 10.1016/j.ejmech.2016.10.064
Abstract

Prion diseases are serious, not curable neurodegenerative disorders caused by the accumulation of the misfolded protein PrPSc that represents the pathological variant of the normally folded cellular protein PrPC. Molecules that bind the cellular isoform PrPC preventing its misfolding, could arrest the progression of pathological conditions related to the abnormal PrP protein. In this context, by combining 3D-QSAR model, derived from pharmacophore-based alignment, with molecular docking procedures and physico-chemical properties prediction we have developed a virtual screening protocol to find novel chemicals able to prevent PrPC misfolding. We identified different hits characterized by low toxicity and able to inhibit PrPSc accumulation in vitro in prion-infected neuroblastoma cell lines (ScN2a). In this assay, the pyrroloquinoxaline hydrazone 96 showed the higest potency with an IC50 value of 1.6 μM. Pyrroloquinoxaline 96 was demonstrated also to bind PrPSc aggregates in infected ScN2a cells with a fluorescence pattern comparable to that found for Thioflavin-T. In consideration of its satisfactory physico-chemical properties, including predicted blood brain barrier permeability, 96 could represent an interesting prototypic hit for the development of diagnostic and therapeutic probes for prion diseases.

Keywords

3D-QSAR; Anti-Prion agents; Pharmacophore modeling; Prion; Theranostic tools.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z