Multimodal small-molecule screening for human prion protein binders

Reidenbach, Andrew G.; Mesleh, Michael F.; Casalena, Dominick; Vallabh, Sonia M; Dahlin, Jayme L.; Leed, Alison; Chan, Alix I.; Usanov, Dmitry L.; Yehl, Jenna; Lemke, Christopher T.; Campbell, Arthur J.; Shah, Rishi; Shrestha, Om Kumar; Sacher, Joshua R.; Rangel, V.L.; Moroco, Jamie A.; Sathappa, Murugappan; Nonato, Maria Cristina; Nguyen, Kong T.; Wright, S. Kirk; Liu, David R.; Wagner, Florence F.; Kaushik, Virendar K.; Auld, Douglas S.; Schreiber, Stuart L.; Minikel, Eric Vallabh

doi:10.1074/jbc.ra120.014905

Cited by 23 publications

(15 citation statements)

References 91 publications

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“…On the other hand, the four small chemical compounds described to bind PrP and tested here, did not induce increased release. The latter may fit a recent report suggesting that PrP is a difficult-to-target protein, at least with small ligands, and implying that, for PrP ligands to be therapeutically effective, they have to have a certain size and binding characteristics [130]. This, in turn, reinforces the use of nonsmall-molecules, such as antibodies or their derived smaller fragments, which is currently pursued despite obvious difficulties in administration and pharmacokinetics [74].…”

Section: Discussionsupporting

confidence: 62%

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Linsenmeier

Mohammadi

Shafiq

et al. 2021

Preprint

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The cellular prion protein (PrPC) is a central player in neurodegenerative diseases caused by protein misfolding, such as prion diseases or Alzheimer's disease (AD). Expression levels of this GPI-anchored glycoprotein, especially at the neuronal cell surface, critically correlate with various pathomechanistic aspects underlying these diseases, such as templated misfolding (in prion diseases) and neurotoxicity and, hence, with disease progression and severity. In stark contrast to cell-associated PrPC, soluble extracellular forms or fragments of PrP are linked with neuroprotective effects, which is likely due to their ability to interfere with neurotoxic disease-associated protein conformers in the interstitial fluid. Fittingly, the endogenous proteolytic release of PrPC by the metalloprotease ADAM10 ('shedding') was characterized as a protective mechanism. Here, using a recently generated cleavage-site specific antibody, we shed new light on earlier studies by demonstrating that shed PrP (sPrP) negatively correlates with conformational conversion (in prion disease) and is markedly redistributed in murine brain in the presence of prion deposits or AD-associated amyloid plaques indicating a blocking and sequestrating activity. Importantly, we reveal that administration of certain PrP-directed antibodies and other ligands results in increased PrP shedding in cells and organotypic brain slice cultures. We also provide mechanistic and structural insight into this shedding-stimulating effect. In addition, we identified a striking exception to this, as one particular neuroprotective antibody, due to its special binding characteristics, did not cause increased shedding but rather strong surface clustering followed by fast endocytosis and degradation of PrPC. Both mechanisms may contribute to the beneficial action described for some PrP-directed antibodies/ligands and pave the way for new therapeutic strategies against devastating and currently incurable neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 62%

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Linsenmeier

Mohammadi

Shafiq

et al. 2021

Preprint

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“…To investigate whether G418 or puromycin might interact directly with PrP C , we generated recombinant MoPrP (recPrP) and performed differential scanning fluorimetry, a technique capable of detecting shifts in PrP thermal stability upon binding of small molecules ( 50 , 51 ). In the presence of a tenfold molar excess of either puromycin, G418, or quinacrine, a ratio commonly used in protein thermal shift experiments ( 52 ), the melting temperature of recPrP remained unchanged, suggesting that none of these compounds likely act by binding to PrP C and modulating its stability ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The aminoglycoside G418 hinders de novo prion infection in cultured cells

Arshad

Patel

Mehrabian

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…These compounds were assessed for PARP10 inhibition, and they found two compounds with promising results [195]. In another study, Reidenbach et al attempted to identify compounds against Prion disease, a neurodegenerative disease with no therapeutic options; however, the only benzimidazole compounds identified demonstrated low affinities [196]. Whereas, Cuozzo et al screened a DECL library of 225 million compounds, and identified a single compound (X-165) with a high activity against the production of lysophosphatidic acid, and this compound has been approved by the FDA for Phase I Clinical trials [197].…”

Section: Compound Screeningmentioning

confidence: 99%

Microarrays and NGS for Drug Discovery

Pop¹,

Zănoagă²,

Chiroi³

et al. 2021

Drug Design - Novel Advances in the Omics Field and Applications

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Novel technologies and state of the art platforms developed and launched over the last two decades such as microarrays, next-generation sequencing, and droplet PCR have provided the medical field many opportunities to generate and analyze big data from the human genome, particularly of genomes altered by different diseases like cancer, cardiovascular, diabetes and obesity. This knowledge further serves for either new drug discovery or drug repositioning. Designing drugs for specific mutations and genotypes will dramatically modify a patient’s response to treatment. Among other altered mechanisms, drug resistance is of concern, particularly when there is no response to cancer therapy. Once these new platforms for omics data are in place, available information will be used to pursue precision medicine and to establish new therapeutic guidelines. Target identification for new drugs is necessary, and it is of great benefit for critical cases where no alternatives are available. While mutational status is of highest importance as some mutations can be pathogenic, screening of known compounds in different preclinical models offer new and quick strategies to find alternative frameworks for treating more diseases with limited therapeutic options.

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Multimodal small-molecule screening for human prion protein binders

Cited by 23 publications

References 91 publications

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

The aminoglycoside G418 hinders de novo prion infection in cultured cells

Microarrays and NGS for Drug Discovery

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