Approaches to Evaluate the Impact of a Small-Molecule Binder to a Noncatalytic Site of the Proteasome

Proteasome activity is crucial for cell survival and proliferation. In recent years, small molecules have been discovered that can affect the catalytic activity of the proteasome. Rather than targeting the active sites of the proteasome, it might be possible to affect ubiquitin-dependent degradation of proteins by limiting the association of the 19S regulatory particle (19S RP) with the 20S core particle (20S CP) of the proteasome. We recently described the discovery of TXS-8, a peptoid that binds to Rpn-6. Rpn-6 is a proteasome-associated protein that makes critical contacts with the 19S RP and the 20S CP. Herein, we present a general workflow to evaluate the impact of a small-molecule binder on proteasome activity by using TXS-8 as an example. This workflow contains three steps in which specific probes or overexpressed proteins in cells are used to determine whether the hydrolysis activity of the proteasome is affected. Although, in our case, TXS-8 did not affect proteasome activity, our workflow is highly amenable to studying a variety of small-molecule–proteasome subunit interactions.     

Antiamyloidogenic Activity of Aβ42‐Binding Peptoid in Modulating Amyloid Oligomerization

The oligomerization and aggregation of amyloid β (Aβ) play central role in the pathogenesis of Alzheimer's disease (AD). Molecular binding agents for modulating the formation of Aβ oligomers and fibrils have promising application potential in AD therapies. By screening a peptoid library using surface plasmon resonance imaging, amyloid inhibitory peptoid 1 (AIP1) that has high affinity to Aβ42 is identified. AIP1 is demonstrated to inhibit Aβ42 oligomerization and fibrillation and to rescue Aβ42‐induced cytotoxicity through decreasing the content of Aβ42 oligomers that is related to cell membrane permeability. Molecular docking suggests that the binding sites of AIP1 may be at the N‐terminus of Aβ42. The blood‐brain barrier (BBB) permeability of AIP1 using an in vitro BBB model is also revealed. This work provides a strategy for the design and development of peptoid‐based antiamyloidogenic agents. The obtained amyloid inhibitory peptoid shows prospects in the therapeutic application in AD.     

Peptoid–Peptide Hybrid Backbone Architectures

Peptidomimetic oligomers and foldamers have received considerable attention for over a decade, with β‐peptides and the so‐called peptoids (N‐alkylglycine oligomers) representing prominent examples of such architectures. Lately, hybrid or mixed backbones consisting of both α‐ and β‐amino acids (α/β‐peptides) have been investigated in some detail as well. The present Minireview is a survey of the literature concerning hybrid structures of α‐amino acids and peptoids, including β‐peptoids (N‐alkyl‐β‐alanine oligomers), and is intended to give an overview of this area of research within the field of peptidomimetic science.     

Investigation of the Substrate Specificity of Lacticin 481 Synthetase by Using Nonproteinogenic Amino Acids

One enzyme, many substrates . The substrate specificity of a lantibiotic biosynthetic enzyme, lacticin 481 synthetase, was probed by using synthetic prepeptides containing a variety of nonproteinogenic amino acids, including unnatural α‐amino acids, β‐amino acids, D ‐amino acids, and peptoids.