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/ange.201609395

Cited by 8 publications

(10 citation statements)

References 48 publications

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“…One way to mitigate these issues could be macrocyclization of the peptide; however, this could also change its shape and function, much like removing the macrocycle from depsidomycin could have changed its function. Because of these issues with peptide-based drugs, many groups have devoted their research to making peptidomimetics, or peptide-like molecules, which includes: β- or γ-peptides [78,79], peptoids [80,81], spiroligomers [82,83], stapled peptides [84,85], and N-amino peptides [86,87] among many others. As there is much work on overcoming the issues associated with peptide-based drugs/therapeutics, it is important to remember new peptide-based therapeutics or diagnostics must possess an inherent ability to circumvent the immune system’s native defenses against foreign peptides or peptide fragments.…”

Section: Extracellular Targetsmentioning

confidence: 99%

Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets

Northrup

Mach

Sellmyer

2019

IJMS

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The discovery of penicillin began the age of antibiotics, which was a turning point in human healthcare. However, to this day, microbial infections are still a concern throughout the world, and the rise of multidrug-resistant organisms is an increasing challenge. To combat this threat, diagnostic imaging tools could be used to verify the causative organism and curb inappropriate use of antimicrobial drugs. Nuclear imaging offers the sensitivity needed to detect small numbers of bacteria in situ. Among nuclear imaging tools, radiolabeled antibiotics traditionally have lacked the sensitivity or specificity necessary to diagnose bacterial infections accurately. One reason for the lack of success is that the antibiotics were often chelated to a radiometal. This was done without addressing the ramifications of how the radiolabeling would impact probe entry to the bacterial cell, or the mechanism of binding to an intracellular target. In this review, we approach bacterial infection imaging through the lens of bacterial specific molecular targets, their intracellular or extracellular location, and discuss radiochemistry strategies to guide future probe development.

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Section: Extracellular Targetsmentioning

confidence: 99%

Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets

Northrup

Mach

Sellmyer

2019

IJMS

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“…We recently described an approach to b-strand stabilization based on peptide backbone N-amination (Figure 1C). 41 The conformational and non-aggregating characteristics of Namino peptides (NAPs) are consistent across distinct models of b-sheet folding and are attributed to cooperative non-covalent interactions involving the Na-NH2 substituent. Here, we describe the design and synthesis of NAPs that block tau fibrilization and spread in a sequence-specific manner.…”

Section: Introductionmentioning

confidence: 96%

From Aggregation to Inhibition: N-Amination Converts Amyloidogenic Tau Peptides into Soluble Antagonists of Cellular Seeding

Makwana¹,

Mp²,

Miao³

et al. 2021

Preprint

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The spread of neurofibrillary tangles resulting from tau protein aggregation is a hallmark of Alzheimer’s and related neurodegenerative diseases. Early oligomerization of tau involves conformational reorganization into parallel b-sheet structures and supramolecular assembly into toxic fibrils. Despite the need for selective inhibitors of tau propagation, b-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 b-strands from the tau R2 and R3 domains. Several N-amino peptides (NAPs) inhibit disease-associated tau aggregation and prevent 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 both monomeric or fibrillar forms of extracellular tau. Peptidomimetic 12 is serum stable, non-toxic to neuronal cells, and selectivity inhibits the aggregation of tau over Ab42. Structural analysis of our lead NAPs shows considerable conformational constraint imposed by the N-amino groups. The enhanced rigidity and full complement of sidechains thus enables NAPs to recognize tau fibrils. 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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“… 30 This problem might be solved by utilizing N -protected electrophilic amination reagents that form hydrazines that are stable under reaction conditions, but this requires a further deprotection step. 25 , 31 , 32 Transformation with commercially available amination reagents that form unprotected hydrazine has practical advantages. Here we report a fast and straightforward method for the preparation of pyrazoles from primary aliphatic and aromatic amines as limiting reagents using bench-stable, commercially available amination reagent.…”

Section: Introductionmentioning

confidence: 99%

Direct Preparation of N-Substituted Pyrazoles from Primary Aliphatic or Aromatic Amines

2021

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Despite a large number of synthesis procedures for pyrazoles known today, those directly employing primary amines as substrates are rare. Herein, we report an original method for the preparation of N -alkyl and N -aryl pyrazoles from primary aliphatic or aromatic amines as a limiting reagent of the reaction. The protocol utilizes no inorganic reagents and requires a short reaction time, mild conditions, and the use of structurally simple and commercially available starting reagents. During this study, pyrazoles containing a wide variety of N -substituents were obtained using the same procedure for both aliphatic and aromatic amines.

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Peptide N‐Amination Supports β‐Sheet Conformations

Cited by 8 publications

References 48 publications

Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets

Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets

From Aggregation to Inhibition: N-Amination Converts Amyloidogenic Tau Peptides into Soluble Antagonists of Cellular Seeding

Direct Preparation of N-Substituted Pyrazoles from Primary Aliphatic or Aromatic Amines

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