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Peptide-Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration.

ABSTRACT: Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell- and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type?2 diabetes. So far, however, only one of the numerous anti-amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry "tools" to design, develop, and discover peptide-based molecules as anti-amyloid drug candidates. We focus on two major inhibitor rational design strategies: 1)?the oldest and most common strategy, based on molecular recognition elements of amyloid self-assembly, and 2)?a more recent approach, based on cross-amyloid interactions. We discuss why peptide-based amyloid inhibitors, in particular their advanced generations, can be promising leads or candidates for anti-amyloid drugs as well as valuable tools for deciphering amyloid-mediated cell damage and its link to disease pathogenesis.

SUBMITTER: Armiento V

PROVIDER: S-EPMC7064928 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Peptide-Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration.

Armiento Valentina V Spanopoulou Anna A Kapurniotu Aphrodite A

Angewandte Chemie (International ed. in English) 20191128 9

Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell- and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. So far, however, only one of the numerous anti-amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry "tools" to design, develop, and discover peptide-based molecules as anti-amyloid drug candidates. We focus on two major inhibitor rational des ...[more]

PMID: 31529602

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Project description:Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure. Here we demonstrate that electronic configuration and hyperconjugation of the peptide amide bonds ought to be taken into account to advance such a theory. To capture the effect of polarization of peptide linkages on conformational and H-bonding propensity of the polypeptide backbone, we introduce a function of shielding tensors of the Cα atoms. Carrying no information about side chain-side chain interactions, this function nonetheless identifies basic features of the secondary and tertiary structure, establishes sequence correlates of the metamorphic and pH-driven equilibria, relates binding affinities and folding rate constants to secondary structure preferences, and manifests common patterns of backbone density distribution in amyloidogenic regions of Alzheimer's amyloid β and tau, Parkinson's α-synuclein and prions. Based on those findings, a split-intein like mechanism of molecular recognition is proposed to underlie dimerization of Aβ, tau, αS and PrPC, and divergent pathways for subsequent association of dimers are outlined; a related mechanism is proposed to underlie formation of PrPSc fibrils. The model does account for: (i) structural features of paranuclei, off-pathway oligomers, non-fibrillar aggregates and fibrils; (ii) effects of incubation conditions, point mutations, isoform lengths, small-molecule assembly modulators and chirality of solid-liquid interface on the rate and morphology of aggregation; (iii) fibril-surface catalysis of secondary nucleation; and (iv) self-propagation of infectious strains of mammalian prions.

Dataset Information

Peptide-Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration.

Publications

Peptide-Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration.

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