Peptide N‐Amination Supports β‐Sheet Conformations

Sarnowski, Matthew P.; Kang, Chang Won; Elbatrawi, Yassin M.; Wojtas, Łukasz; Valle, Juan R. Del

doi:10.1002/anie.201609395

Cited by 38 publications

(60 citation statements)

References 49 publications

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“…We previously showed that Boc-protected hydrazino acids can be chemoselectively condensed with amines at their C-termini without protection of N. 17 The N-terminus can then be acylated with a variety of protected amino acid chlorides to provide backbone aminated peptide derivatives.…”

Section: Letter Synlettmentioning

confidence: 99%

Diastereoselective Synthesis of (3R,5R)-γ-Hydroxypiperazic Acid

Gerrein¹,

Elbatrawi²,

Valle³

2021

Synlett

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We report an asymmetric synthesis of the (3R,5R)-γ-hydroxypiperazic acid (γ-OHPiz) residue encountered in several bioactive nonribosomal peptides. Our strategy relies on a diastereoselective enolate hydroxylation reaction and electrophilic N-amination to provide the acyclic γ-OHPiz precursor. This orthogonally protected α-hydrazino acid intermediate is amenable to late-stage diazinane ring formation following incorporation into a peptide chain. We determined the N-terminal amide rotamer propensity of the γ-OHPiz residue and showed that the γ-OH substituent enhances trans-amide bias relative to piperazic acid.

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Section: Letter Synlettmentioning

confidence: 99%

Diastereoselective Synthesis of (3R,5R)-γ-Hydroxypiperazic Acid

Gerrein¹,

Elbatrawi²,

Valle³

2021

Synlett

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“…The smallest β‐sheet template reported to date involves the use of N‐aminated amino acids to replace the C5 hydrogen bond . Applied to the model β‐hairpin GB1 at non‐hydrogen bonding positions, this strategy preserves all side chains for molecular recognition but has not been used in such applications yet.…”

Section: β‐Sheet Peptide Mimeticsmentioning

confidence: 99%

Bent into shape: Folded peptides to mimic protein structure and modulate protein function

2020

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“…47,48 We recently described an approach to β-strand stabilization based on peptide backbone N-amination (Figure 1C). 42 The conformational and non-aggregating characteristics of N-amino peptides (NAPs) are consistent across distinct models of βsheet folding and are attributed to cooperative non-covalent interactions involving the Nα-NH 2 substituent. These qualities distinguish NAPs from N-alkylated peptides that do not readily adopt or stabilize β-strand conformations.…”

Section: ■ Introductionmentioning

confidence: 99%

N-Amination Converts Amyloidogenic Tau Peptides into Soluble Antagonists of Cellular Seeding

Makwana

Sarnowski

Miao

et al. 2021

ACS Chem. Neurosci.

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The spread of neurofibrillary tangles composed of tau protein aggregates is a hallmark of Alzheimer’s and related neurodegenerative diseases. Early oligomerization of tau involves conformational reorganization into parallel β-sheet structures and supramolecular assembly into toxic fibrils. Despite the need for selective inhibitors of tau propagation, β-rich protein assemblies are inherently difficult to target with small molecules. Here, we describe a minimalist approach to mimic the aggregation-prone modules within tau. We carried out a backbone residue scan and show that amide N-amination completely abolishes the tendency of these peptides to self-aggregate, rendering them soluble mimics of ordered β-strands from the tau R2 and R3 domains. Several N-amino peptides (NAPs) inhibit tau fibril formation in vitro. We further demonstrate that NAPs 12 and 13 are effective at blocking the cellular seeding of endogenous tau by interacting with monomeric or fibrillar forms of extracellular tau. Peptidomimetic 12 is serum stable, non-toxic to neuronal cells, and selectivity inhibits the fibrilization of tau over Aβ42. Structural analysis of our lead NAPs shows considerable conformational constraint imposed by the N-amino groups. The described backbone N-amination approach provides a rational basis for the mimicry of other aggregation-prone peptides that drive pathogenic protein assembly.

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Peptide N‐Amination Supports β‐Sheet Conformations

Cited by 38 publications

References 49 publications

Diastereoselective Synthesis of (3R,5R)-γ-Hydroxypiperazic Acid

Diastereoselective Synthesis of (3R,5R)-γ-Hydroxypiperazic Acid

Bent into shape: Folded peptides to mimic protein structure and modulate protein function

N-Amination Converts Amyloidogenic Tau Peptides into Soluble Antagonists of Cellular Seeding

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