Dataset Information

Transthyretin-derived peptides as ?-amyloid inhibitors.

ABSTRACT: Self-association of ?-amyloid (A?) into soluble oligomers and fibrillar aggregates is associated with Alzheimer's disease pathology, motivating the search for compounds that selectively bind to and inhibit A? oligomerization and/or neurotoxicity. Numerous small-molecule inhibitors of A? aggregation or toxicity have been reported in the literature. However, because of their greater size and complexity, peptides and peptidomimetics may afford improved specificity and affinity as A? aggregation modulators compared to small molecules. Two divergent strategies have been employed in the search for peptides that bind A?: (i) using recognition domains corresponding to sequences in A? itself (such as KLVFF) and (ii) screening random peptide-based libraries. In this study, we propose a third strategy, specifically, designing peptides that mimic binding domains of A?-binding proteins. Transthyretin, a plasma transport protein that is also relatively abundant in cerebrospinal fluid, has been shown to bind to A?, inhibit aggregation, and reduce its toxicity. Previously, we identified strand G of transthyretin as a specific A? binding domain. In this work we further explore and define the necessary features of this binding domain. We demonstrate that peptides derived from transthyretin bind A? and inhibit its toxicity. We also show that, although both transthyretin and transthyretin-derived peptides bind A? and inhibit toxicity, they differ significantly in their effect on A? aggregation.

SUBMITTER: Cho PY

PROVIDER: S-EPMC4102968 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Transthyretin-derived peptides as β-amyloid inhibitors.

Cho Patricia Y PY Joshi Gururaj G Johnson Jeffrey A JA Murphy Regina M RM

ACS chemical neuroscience 20140409 7

Self-association of β-amyloid (Aβ) into soluble oligomers and fibrillar aggregates is associated with Alzheimer's disease pathology, motivating the search for compounds that selectively bind to and inhibit Aβ oligomerization and/or neurotoxicity. Numerous small-molecule inhibitors of Aβ aggregation or toxicity have been reported in the literature. However, because of their greater size and complexity, peptides and peptidomimetics may afford improved specificity and affinity as Aβ aggregation mod ...[more]

PMID: 24689444

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Project description:BACKGROUND:Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. OBJECTIVES:The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. METHODS:Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189). RESULTS:U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival. CONCLUSIONS:In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

Dataset Information

Transthyretin-derived peptides as ?-amyloid inhibitors.

Publications

Transthyretin-derived peptides as β-amyloid inhibitors.

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