Helical sulfonyl-γ-AApeptides modulating Aβ oligomerization and cytotoxicity by recognizing Aβ helix.

In contrast to prevalent strategies which make use of β-sheet mimetics to block Aβ fibrillar growth, in this study, we designed a series of sulfonyl-γ-AApeptide helices that targeted the crucial α-helix domain of Aβ13-26 and stabilized Aβ conformation to avoid forming the neurotoxic Aβ oligomeric β-sheets. Biophysical assays such as amyloid kinetics and TEM demonstrated that the Aβ oligomerization and fibrillation could be greatly prevented and even reversed in the presence of sulfonyl-γ-AApeptides in a sequence-specific and dose-dependent manner. The studies based on circular dichroism, Two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) spectra unambiguously suggested that the sulfonyl-γ-AApeptide Ab-6 could bind to the central region of Aβ and induce α-helix conformation in Aβ.

Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions.

Peptidomimetics have gained great attention for their function as protein-protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 α/Sulfono-γ-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 α/Sulfono-γ-AA peptides were shown to bind tightly to MDM2 and MDMX, with of 19.

Aggregation-Induced Emissive and Circularly Polarized Homogeneous Sulfono-γ-AApeptide Foldamers.

Through our continuous effort in developing a new class of foldamers, we have both designed and synthesized homogenous sulfono-γ-AApeptides using tetraphenylethylene (TPE) moieties attached to the backbone as luminogenic sidechains. Based on previous crystal structures, we have found that these foldamers adopted a left-handed 4-helix. Due to the constraint of the helical scaffold, the rotation of the TPE moieties were restricted, leading to fluorescent emissive properties with high quantum yields not only at the aggregate state but also in solution.

Sulfono-γ-AApeptides as Helical Mimetics: Crystal Structures and Applications.

Foldamers have defined and predictable structures, improved resistance to proteolytic degradation, enhanced chemical diversity, and are versatile in their mimicry of biological molecules, making them promising candidates in biomedical and material applications. However, as natural macromolecules exhibit endless folding structures and functions, the exploration of the applications of foldamers remains crucial. As such, it is imperative to continue to discover unnatural foldameric architectures with new frameworks and molecular scaffolds.

Dimeric γ-AApeptides With Potent and Selective Antibacterial Activity.

Over the past few decades, the emergence of antibiotic resistance developed by life-threatening bacteria has become increasingly prevalent. Thus, there is an urgent demand to develop novel antibiotics capable of mitigating this trend. Herein, we report a series of dimeric γ-AApeptide derivatives as potential antibiotic agents with limited toxicity and excellent selectivity against Gram-positive strains.

The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1.

Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies.

Lipidated α/Sulfono-α-AA heterogeneous peptides as antimicrobial agents for MRSA.

Though antibiotics have been used for decades to treat bacterial infections, there is a great need for new treatment methods. Bacteria are becoming resistant to conventional antibiotics, as is the case with Methicillin resistant Staphylococcus aureus (MRSA). Herein we report the design of a series of lipidated α/Sulfono-α-AA heterogeneous peptides as mimics for Host Defense Peptides (HDPs).

De Novo Left-Handed Synthetic Peptidomimetic Foldamers.

The development of peptidomimetic helical foldamers with a wide repertoire of functions is of significant interest. Herein, we report the X-ray crystal structures of a series of homogeneous l-sulfono-γ-AA foldamers and elucidate their folding conformation at the atomic level. Single-crystal X-ray crystallography revealed that this class of oligomers fold into unprecedented dragon-boat-shaped and unexpected left-handed helices, which are stabilized by the 14-hydrogen-bonding pattern present in all sequences.

Genome Sequence of a Newly Isolated F2 Subcluster Mycobacteriophage from the Black Belt Geological Region of Western Alabama.

The bacteriophage Demsculpinboyz was discovered in a soil sample from the Black Belt region of Alabama using mc155 as its host. The genome is 57,437 bp long and contains 116 protein-coding genes. It belongs to the F2 subcluster, which has only five other members.

One-Bead-Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2.

Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides.

Membrane-Active Hydantoin Derivatives as Antibiotic Agents.

Hydantoin (imidazolidinedione) derivatives such as nitrofurantoin are small molecules that have aroused considerable interest recently due to their low rate of bacterial resistance. However, their moderate antimicrobial activity may hamper their application combating antibiotic resistance in the long run. Herein, we report the design of bacterial membrane-active hydantoin derivatives, from which we identified compounds that show much more potent antimicrobial activity than nitrofurantoin against a panel of clinically relevant Gram-positive and Gram-negative bacterial strains.

Right-Handed Helical Foldamers Consisting of De Novo d-AApeptides.

New types of foldamer scaffolds are formidably challenging to design and synthesize, yet highly desirable as structural mimics of peptides/proteins with a wide repertoire of functions. In particular, the development of peptidomimetic helical foldamers holds promise for new biomaterials, catalysts, and drug molecules. Unnatural l-sulfono-γ-AApeptides were recently developed and shown to have potential applications in both biomedical and material sciences.