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Horton, Douglas A.; Bourne, Gregory T.; Smythe, Mark L.

doi:10.1023/a:1020863921840

Cited by 93 publications

(57 citation statements)

References 83 publications

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“…Among possible peptidomimetic fragments, we focused on the 2,5-diketopiperazine (DKP) scaffold for several reasons: 1) it is synthetically readily accessible and amenable to compound library generation; [28] 2) DKP derivatives have been shown to www.chemmedchem.org modulate protein-protein interactions, [29] to possess neuroprotective activity, [30] and also to cross the blood-brain barrier (BBB); [31] 3) it has been extensively explored in medicinal chemistry. [32] Therefore, it seemed conceivable that DKPs carrying (Z)-alkene units of general structure I (Figure 1) could serve as a template for a diverse array of pharmacophores towards the identification of novel bifunctional structures for the treatment of prion diseases.…”

Section: Design Rationalementioning

confidence: 99%

Discovery of a Class of Diketopiperazines as Antiprion Compounds

et al. 2010

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Prion diseases are fatal neurodegenerative and infectious disorders for which effective pharmacological tools are not yet available. This unmet challenge and the recently proposed interplay between prion diseases and Alzheimer's have led to a more urgent demand for new antiprion agents. Herein, we report the identification of a novel bifunctional diketopiperazine (DKP) derivative 1 d, which exhibits activity in the low micromolar range against prion replication in ScGT1 cells, while showing low cytotoxicity. Supported by properly addressed molecular modeling studies, we hypothesized that a planar conformation is the major determinant for activity in this class of compounds. Moreover, studies aimed at assessing the mechanism-of-action at the molecular level showed that 1 d might interact directly with recombinant prion protein (recPrP) to prevent its conversion to the pathogenic misfolded prion protein (PrP(Sc))-like form. This investigation suggests that DKP based antiprion compounds can serve as a promising lead scaffold in developing new drugs to combat prion diseases.

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Section: Design Rationalementioning

confidence: 99%

Discovery of a Class of Diketopiperazines as Antiprion Compounds

et al. 2010

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“…The constrained structure created by cyclization has been demonstrated to enhance the binding affinity of cyclic peptides [47], to increase intestinal permeability, and to improve resistance to cellular proteases and bioavailability. Cyclization reduces the conformational flexibility of natural and synthetic peptides by inducing a structural constraint, which often makes cyclic peptides and their different chemical derivatives potent bioactive compounds.…”

Section: Anti-amyloidogenic Heterocyclic Peptidesmentioning

confidence: 99%

Anti-amyloidogenic Heterocyclic Peptides

Chemerovski-Glikman

Richman

Rahimipour

2016

Topics in Heterocyclic Chemistry

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The amyloid fibril is a highly ordered proteinous aggregate, originally discovered in the context of the self-assembly of soluble proteins into insoluble extracellular plaques. The molecular structure of amyloidosis, an energetically stable conformation with a thermodynamic local minimum, is of particular interest because of its possible pathogenicity. Amyloidogenic diseases (amyloidoses) are often fatal, widely heterogenic, and caused by sporadic, genetic, or infectious pathogens. Consequently, major effort has been directed in the past few decades to identify and develop agents that decrease the concentration of the pathogenic aggregates either by interfering with the self-assembly of the proteins or by modulating their physiological concentration. Heterocyclic peptides of natural and synthetic origin have gained special attention because of their demonstrated ability to interact with various amyloids. In addition to interfering with the amyloid aggregation process, many of the discovered peptides also inhibit the formation of fibrils, disassemble preformed fibrils, and prevent the pathogenic seeding effect. Others are instrumental candidates for passive vaccination against amyloid deposits. The promising preliminary results described here, together with the broad chemical diversity of heterocyclic peptides and their amenability to largescale production, make these compounds promising for anti-amyloidogenic research and for pharmacological therapy of amyloidoses.

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“…Cyclic peptides are polypeptide chains taking ring structures, typically bind with much higher affinity to target proteins than linear ones, due to a smaller reduction in entropy upon binding, allowing an enhanced binding toward target molecules, or better receptor selectivity [3,4]. The ring structure can be formed by linking one end of the peptide and the other with chemically stable bonds Head-to-tail cyclization is the amide bond formation between amino and carboxyl termini, and many biologically active cyclic peptides are formed by this way.…”

Section: Cyclic Peptidesmentioning

confidence: 99%