Combination of kinetically selected inhibitors in trans leads to highly effective inhibition of amyloid formation.
Summary of "Combination of kinetically selected inhibitors in trans leads to highly effective inhibition of amyloid formation."
Amyloid formation plays a role in over 25 human disorders. A range of strategies have been applied to the problem of developing inhibitors of amyloid formation, but unfortunately, many inhibitors are effective only in molar excess and typically either lengthen the time to the onset of amyloid formation, (the lag time), while having modest effects on the total amount of amyloid fibrils produced, or decrease the amount of amyloid without significantly reducing the lag time. We demonstrate a general strategy whereby two moderate inhibitors of amyloid formation can be rationally selected via kinetic assays and combined in trans to yield a highly effective inhibitor which dramatically delays the time to the appearance of amyloid and drastically reduces the total amount of amyloid formed. A key feature is that the selection of the components of the mixture is based on their effect on the time course of amyloid formation rather than on just the amount of amyloid produced. The approach is validated using inhibitors of amyloid formation by islet amyloid polypeptide, the causative agent of amyloid formation in type 2 diabetes and the Alzheimer's disease Aβ peptide.
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA.
This article was published in the following journal.
Name: Journal of the American Chemical Society
Medical and Biotech [MESH] Definitions
This drug combination has proved to be an effective therapeutic agent with broad-spectrum antibacterial activity against both gram-positive and gram-negative organisms. It is effective in the treatment of many infections, including PNEUMOCYSTIS PNEUMONIA in AIDS.
Ethinyl Estradiol-norgestrel Combination
ETHINYL ESTRADIOL and NORGESTREL given in fixed proportions. It has proved to be an effective contraceptive (CONTRACEPTIVES, ORAL, COMBINED).
One of the CARBONIC ANHYDRASE INHIBITORS that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. (From Smith and Reynard, Textbook of Pharmacology, 1991, p337)
The joining of RNA from two different genes. One type of trans-splicing is the "spliced leader" type (primarily found in protozoans such as trypanosomes and in lower invertebrates such as nematodes) which results in the addition of a capped, noncoding, spliced leader sequence to the 5' end of mRNAs. Another type of trans-splicing is the "discontinuous group II introns" type (found in plant/algal chloroplasts and plant mitochondria) which results in the joining of two independently transcribed coding sequences. Both are mechanistically similar to conventional nuclear pre-mRNA cis-splicing. Mammalian cells are also capable of trans-splicing.
A member of the P450 superfamily, this enzyme catalyzes the first oxidative step of the phenylpropanoid pathway in higher PLANTS by transforming trans-cinnamate into p-coumarate.
Mechanism of phototriggered isomerization of azobenzene and its derivatives is of broad interest. In this paper, the S(0) and S(1) potential energy surfaces of the ethylene-bridged azobenzene (1) that...
Neutral endopeptidase (NEP) plays a key role in the metabolic inactivation of various bioactive peptides such as atrial natriuretic peptide (ANP), endothelins, and enkephalins. Furthermore, NEP is kno...
Efflux pumps are one of the well established mechanisms that contribute to antibiotic resistance in bacteria, such as mycobacteria. As a result, the identification of efflux pump inhibitors is an attr...
Suppression of HIF-prolyl hydroxylase (PHD) activity by small-molecule inhibitors leads to the stabilization of hypoxia inducible factor and has been recognized as promising drug target for the treatm...
The polyphenol trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) is one of the best known plant secondary metabolites. The number of articles devoted to trans-resveratrol has been steadily increasi...
This will be a phase I/II study of 5-azacitidine in combination with vorinostat in patients with relapsed or refractory DLBCL. Combination therapy with methyltransferase inhibitors and hi...
Primary Objective: Determining the maximum tolerated dose (MTD) and pharmacokinetics (PK) of FTS (S-Trans, Trans-Farnesylthiosalicylic Acid) after daily oral administration on Days 1 thro...
The purpose of this study is to confirm that the two forms of the device the Integrated E-TRANS (fentanyl HCl) system and the Separated (Two-Part) E-TRANS (fentanyl HCl) System provide the...
This will be the first prospective study where patients will be selected on the basis of two measures of the EGFR pathway. The study will assess prospectively the efficacy of erlotinib as...
While the deleterious effects of trans fat from industrial sources (iTFA) on cardiovascular health are well established, the impact of TFA from ruminants (rTFA) on cardiovascular risk fact...