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New "Unprecedented" Anti Prion Drug

Mike

Well-known member
A Potential Anti-prion Drug With 'Unprecedented' Potency
The urgent search for a medication to treat prion diseases has led scientists in Germany to synthesize a new group of compounds, including one that is 15 times more potent than an approved drug now being tested in clinical trials.


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Their report is scheduled for the Nov. 2 issue of the biweekly ACS Journal of Medicinal Chemistry.

Prions are infectious proteins that cause brain disorders like Mad Cow Disease and Creutzfeldt-Jakob Disease (CJD) in humans. Peter Gmeiner and colleagues note that the recent emergence of a new form of CDJ, linked to consumption of infected beef mainly in Great Britain, intensified the search for anti-prion compounds.

Most potential drugs have proved ineffective, often because they could not enter brain tissue where prions reside. One promising drug, however, is in clinical trials. That drug is quinacrine, already approved for several other medical conditions.

Gmeiner's group describes the chemical synthesis and early laboratory testing of a family of anti-prion compounds that cross into brain tissue and combat prions. One of those compounds has what the report describes as "unprecedented" anti-prion activity, with 15 times greater potency than quinacrine.


Will this be shot down by the USDA as "Unsound Science"?
 

flounder

Well-known member
quinacrine alone was pretty much a failure for cure all for cjd.
just turned the human yellow, but the agent still progressed.
hope this new cocktail works. ...TSS



J. Med. Chem., 49 (22), 6591 -6595, 2006. 10.1021/jm060773j S0022-2623(06)00773-4
Web Release Date: September 29, 2006

Copyright © 2006 American Chemical Society
A Chimeric Ligand Approach Leading to Potent Antiprion Active Acridine Derivatives: Design, Synthesis, and Biological Investigations

Silke Dollinger, Stefan Löber, Ralf Klingenstein, Carsten Korth, and Peter Gmeiner*

Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany, and Institute for Neuropathology, Medical School, Heinrich Heine University Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany

Received June 29, 2006

Abstract:

Human transmissible neurodegenerations including Creutzfeldt-Jakob disease are unique, since they are caused by prions, an infectious agent that replicates without nucleic acids but instead by inducing conversion of a host-resident normal prion protein to a misfolded conformational isoform. For pharmacotherapy of these unusual diseases, tricyclic heterocyclic compounds such as quinacrine have been considered, but with ambiguous success in vivo, so far. On the basis of the synergistic antiprion effects of quinacrine and iminodibenzyl derivatives, we introduce a novel class of potential pharmaceuticals representing structural chimeras of quinacrine and imipramine analogues. We describe the chemical synthesis and bioassays of a focused library of these compounds. The most potent target compound 2a revealed an EC50 value of 20 nM determined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.



http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2006/49/i22/abs/jm060773j.html



Introduction

Prion diseases are transmissible neurodegenerative diseases

of humans and animals.1 The prion agent replicates without a

nucleic acid-encoded genome by converting host-resident normal

prion protein (PrPC)a to a pathogenic and infectious conformational

isoform PrPSc. Human prion diseases such as the most

prevalent Creutzfeldt-Jakob disease (CJD) are rare diseases that

cansuniquelysbe of sporadic, genetic, or infectious origin.

Animal prion diseases are almost exclusively infectious in origin

in the form of scrapie of sheep, bovine spongiform encephalopathy

(BSE) or mad cow disease of cattle, or chronic wasting

disease of American mule deer or elk. The emergence of a new

strain of human prions causing variant CJD (vCJD) through

the consumption of BSE-contaminated material 2 led to 160

deaths, primarily in Great Britain, and to concerns of an epidemy

of vCJD which, so far, has neither happened nor been

completely excluded.3 The new vCJD strain has different

characteristics, such as the occurrence of infectivity in blood

and peripheral organs, which increases the risk of horizontal

transmission, for example, during blood transfusions.4 These

issues have led to a focus on pharmacotherapeutic options of

prion diseases both for symptomatic, curative, and prophylactic

purposes or for decontamination of blood and transplanted

organs.

Although screening for antiprion compounds in scrapieinfected

mouse neuroblastoma cells (ScN2a) as a cell culture

model of prion disease has led to the identification of many

antiprion compounds, most of them proved to be ineffective

when applied to experimentally prion-infected rodents owing

to the lack of blood-brain barrier (BBB) permeability or

toxicity.5 The identification of BBB-permeable heterocyclic

compounds sparked a tremendous effort to enter clinical trials

applying the approved drug quinacrine to patients with CJD.6

Since animal experiments with quinacrine gave only modest or

ambiguous results,7 quinacrine pharmacotherapy could be

improved by introducing a combination of antiprion drugs.8

Structural modifications employing quinacrine as a lead compound

revealed that bis-acridines augmented antiprion activity

around 10-fold in vitro,9 but poor solubility is likely to limit

their in vivo use. The synergistic antiprion effects of quinacrineand

iminodibenzyl-derived antidepressants have prompted us

to synthesize heterodimers incorporating both recognition elements

with a piperazine unit,10 which is known as a privileged

substructure in a great number of bioactive agents, as the linking

element.

On the basis of preliminary investigations on the hybrid 1

(Figure 1) displaying a 5-fold improved antiprion potency over

quinacrine,8 we herein describe a novel class of antiprion agents

of type 2 defined by covalently linked acridine and iminodibenzyl

moieties and variations of the particular molecular

subunits. SAR studies led to the discovery of the iminodibenzyl

derivative 2a as the most active antiprion compound yet

described.

Chemistry. ...SNIP...FULL TEXT ;



http://pubs.acs.org/cgi-bin/sample.cgi/jmcmar/2006/49/i22/pdf/jm060773j.pdf



TSS
 

Kathy

Well-known member
Other examples of research to find a treatment for protein-protein related disease interactions.

Biopolymers. 2006 Sep 28; [Epub ahead of print]

Designing allosteric peptide ligands targeting a globular protein.

Selz KA, Samylova TI, Samylov AM, Vodyanoy VJ, Mandell AJ.
Cielo Institute, Asheville, NC, 28804.

Patented signal analytic algorithms applied to hydrophobically transformed, numerical amino acid sequences, have previously been used to design short, protein-targeted, L or D retro-inverso peptides. These peptides have demonstrated allosteric and/or indirect agonist effects on a variety of G-protein and tyrosine kinase coupled membrane receptors with 30% to over 80% hit rates. Here we extend these approaches to a globular protein target. We designed eight peptide ligands targeting an ELISA antibody responsive protein, beta-galactosidase, betaGAL. Three of the eight 14mer peptides allosterically activated betaGAL with ELISA methodology. Using Bayesian statistics, this 38% hit rate would have occurred 2 x 10(-9) by chance. These peptides demonstrated binding site competitive or non-competitive interactions, suggesting allosteric site multiplicity with respect to their betaGAL binding-mediated ELISA signal. Kinetic studies demonstrated the temperature dependence of the betaGAL peptide binding functions. Using the van't Hoff relation, we found evidence for enthalpy-entropy compensation. This relation is often found for hydrophobic interactions in aqueous media, and is consistent with the postulated hydrophobic series encoding underlying our protein-targeted, peptide design methods. It appears that our algorithmic, hydrophobic autocovariance eigenvector template approach to the design of allosteric peptides targeting membrane receptors may also be applicable to the design of peptide ligands targeting non-membrane involved globular proteins. (c) 2006 Wiley Periodicals, Inc. Biopolymers, 2006.

PMID: 17009317


Curr Protein Pept Sci. 2005 Apr;6(2):151-69

Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction

Sillerud LO, Larson RS.

Deparment of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, 915 Camino de Salud N.E., Albuquerque, New Mexico 87131, USA.

Peptides based on the amino acid sequences found at protein-protein interaction sites make excellent leads for antagonist development. A statistical picture of amino acids involved in protein-protein interactions indicates that proteins recognize and interact with one another through the restricted set of specialized interface amino acid residues, Pro, Ile, Tyr, Trp, Asp and Arg. These amino acids represent residues from each of the three classes of amino acids, hydrophobic, aromatic and charged, with one anionic and one cationic residue at neutral pH. The use of peptides as drug leads has been successfully used to search for antagonists of cell-surface receptors. Peptide, peptidomimetic, and non-peptide organic inhibitors of a class of cell surface receptors, the integrins, currently serve as therapeutic and diagnostic imaging agents. In this review, we discuss the structural features of protein-protein interactions as well as the design of peptides, peptidomimetics, and small organic molecules for the inhibition of protein-protein interactions. Information gained from studying inhibitors of integrin functions is now being applied to the design and testing of inhibitors of other protein-protein interactions. Most drug development progress in the past several decades has been made using the enzyme binding-pocket model of drug targets. Small molecules are designed to fit into the substrate-binding pockets of proteins based on a lock-and-key, induced-fit, or conformational ensemble model of the protein binding site. Traditionally, enzymes have been used as therapeutic drug targets because it was easier to develop rapid, sensitive screening assays, and to find low molecular weight inhibitors that blocked the active site. However, for proteins which interact with other proteins, rather than with small substrate molecules, the lack of binding pockets means that this approach will not generally succeed. There exist many diseases in which the inhibition of protein-protein interactions would provide therapeutic benefit, but there are no general methods available to address such problems. The focus of the first part of this review is to discuss the features of protein-protein interactions which may serve as general guidelines for the development and design of inhibitors for protein-protein interactions. In the second part we focus on the design of peptides (lead compounds) and their conversion into peptidomimetics or small organic molecules for the inhibition of protein-protein interactions. We draw examples from the important and emerging area of integrin-based cell adhesion and show how the principles of protein-protein interactions are followed in the discovery, optimization and usage of specific protein interface peptides as drug leads.

PMID: 15853652


J Comput Aided Mol Des. 2006 Feb;20(2):109-30.
Development of small molecules designed to modulate protein-protein interactions.

Che Y, Brooks BR, Marshall GR.
Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. [email protected]

Protein-protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein-protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the "privileged-structure hypothesis" [Che, Ph.D. Thesis, Washington University, 2003] - that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists--to address the challenges inherent in the discovery of small-molecule inhibitors of protein-protein interactions.

PMID: 16622794
 
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