Formal [4 + 2] combined ionic and radical approach of vinylogous enaminonitriles to access highly substituted sulfonyl pyridazines.

Pyridazine derivatives hold significant interest due to their broad applications in pharmaceuticals and materials science, where they serve as valuable scaffolds for bioactive compounds and functional materials. Here, we report a formal [4 + 2] reaction for the synthesis of 5'-sulfonyl-4'-aryl-3-cyano substituted pyridazine compounds from the reaction between vinylogous enaminonitriles and sulfonyl hydrazides. The key features of our pyridazine synthesis include the transamidation of vinylogous enaminonitriles with sulfonyl hydrazide, radical sulfonylation of the resulting intermediate, and subsequent 6-endo-trig radical cyclization.

Mucosal Penetrative Polymeric Micelle Formulations for Insulin Delivery to the Respiratory Tract.

Purpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers.

Designed Cell-Penetrating Peptide Self-Assembly Featuring Distinctive Tertiary Structure.

Recent attention has focused on the design of proteins, paralleling advancements in biopharmaceuticals. Achieving protein designs with both structure and function poses a significant challenge, particularly considering the importance of quaternary structures, such as oligomers, in protein function. The cell penetration properties of peptides are of particular interest as they involve the penetration of large molecules into cells.

Microwave-Promoted Total Synthesis of Puniceloid D for Modulating the Liver X Receptor.

A growing global health concern is metabolic syndrome, which is defined by low HDL, diabetes, hypertension, and abdominal obesity. Nuclear receptors are attractive targets for treatment of diseases associated with metabolic syndrome. Liver X receptors (LXRs) have become one of the most significant pharmacological targets among nuclear receptors.

Cyclohexylalanine-Containing α-Helical Amphipathic Peptide Targets Cardiolipin, Rescuing Mitochondrial Dysfunction in Kidney Injury.

Mitochondrial dysfunction is linked to degenerative diseases, resulting from cardiolipin (CL)-induced disruption of cristae structure in the inner mitochondrial membrane (IMM); therefore, preserving cristae and preventing CL remodeling offer effective strategies to maintain mitochondrial function. To identify reactive oxygen species (ROS)-blocking agents against mitochondrial dysfunction, a library of cyclohexylamine-containing cell-penetrating α-helical amphipathic "bundle" peptides were screened. Among these, CMP3013 is selectively bound to abnormal mitochondria, preserving the cristae structure impaired by mitochondria-damaging agents.

Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders.

WD40-repeat (WDR) domain proteins play a crucial role in mediating protein-protein interactions that sustain oncogenesis in human cancers. One prominent example is the interaction between the transcription factor MYC and its chromatin co-factor, WD40-repeat domain protein 5 (WDR5), which is essential for oncogenic processes. The MYC family of proteins is frequently overexpressed in various cancers and has been validated as a promising target for anticancer therapies.

Design and Optimization of an α-Helical Bundle Dimer Cell-Penetrating Peptide for Drug Delivery.

To deliver membrane-impermeable drugs into eukaryotic cells, a lot of cell-penetrating peptides (CPPs) were discovered. Previously we designed an amphipathic α-helical peptide which dimerizes itself its two C-residues. This bis-disulfide-linked dimeric bundle, LK-3, has remarkable cell-penetrating ability at nanomolar concentration, which is an essential prerequisite for CPP.

Design, Synthesis, and Cytotoxicity and Topoisomerase I/IIα Inhibition Activity of Pyrazolo[4,3-]quinoline Derivatives.

With the several targets of cancer treatment, inhibition of DNA topoisomerase activity is one of the well-known focuses in cancer chemotherapy. Here, we describe the design and synthesis of a novel series of pyrazolo[4,3-]quinolines with potential anticancer/topoisomerase inhibition activity. Forty newly designed pyrazolo[4,3-]quinoline derivatives were synthesized via inverse imino Diels-Alder reaction.

Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers.

Drug resistance continues to be a major problem associated with cancer treatment. One of the primary causes of anticancer drug resistance is the frequently mutated RAS gene. In particular, considerable efforts have been made to treat KRAS-induced cancers by directly and indirectly controlling the activity of KRAS.

Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases.

Neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and Parkinson's disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry.

One-bead-one-compound screening approach to the identification of cyclic peptoid inhibitors of cyclophilin D as neuroprotective agents from mitochondrial dysfunction.

In an effort designed to discover superior inhibitors of cyclophilin D (CypD), we identified and screened members of a one-bead-one-compound (OBOC) library of cyclic peptoid analogues of cyclosporin A (CsA). The results show that the one member of this cyclic peptoid family, I11, inhibits mitochondrial membrane potential changes mediated by CypD.

Proline Hinged Amphipathic α-Helical Peptide Sensitizes Gram-Negative Bacteria to Various Gram-Positive Antibiotics.

Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides.

An amphipathic cell penetrating peptide aids cell penetration of cyclosporin A and increases its therapeutic effect in an in vivo mouse model for dry eye disease.

Cell penetrating peptide (CPP), LK-3, causes a ca. 10-fold increase in the cell penetration of cyclosporin A (CsA) at nanomolar concentrations. The results of an in vivo dry eye mouse model demonstrated that a 100-fold lower dose of the CsA/LK-3 complex than that of Restasis® is sufficient to cause the same therapeutic effect.

Multimeric Amphipathic α-Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations.

An amphipathic leucine (L) and lysine (K)-rich α-helical peptide is multimerized based on helix-loop-helix structures to maximize the penetrating activities. The multimeric LK-based cell penetrating peptides (LK-CPPs) can penetrate cells as protein-fused forms at 100-1000-fold lower concentrations than Tat peptide. The enhanced penetrating activity is increased through multimerization by degrees up to the tetramer level.

Oligomer Formation Propensities of Dimeric Bundle Peptides Correlate with Cell Penetration Abilities.

LK-3, an amphipathic dimeric peptide linked by two disulfide bonds, and related isomeric bundles were synthesized, and their cell penetrating abilities were investigated. The measurements using size exclusion chromatography and dynamic light scattering show that LK-3 and its isomers form cell penetrating oligomers. Calculations, performed for various types of peptide isomers, elucidate a strong correlation between the amphipathic character of dimers and cell penetration ability.

Photoswitching of Cell Penetration of Amphipathic Peptides by Control of α-Helical Conformation.

We stapled an amphipathic peptide mainly consisting of leucine (L) and lysine (K) by an azobenzene (Ab) linker for photocontrol of the secondary structure. The cis- trans isomerization of the Ab moieties could stabilize and destabilize the α-helical conformation of the LK peptide along with dramatic change of associated peptide structures in a reversible manner by UV-vis irradiation. The cell-penetrating activities of the LK peptide can be readily regulated by the photocontrol, as the stabilized cis-Ab-LK peptide showed remarkable increase of cell penetration compared to the destabilized trans-Ab-LK peptide.

Construction of histidine-containing hydrocarbon stapled cell penetrating peptides for and delivery of siRNAs.

A hydrocarbon stapled peptide based strategy was used to develop an optimized cell penetrating peptide for siRNA delivery. Various stapled peptides, having amphipathic Leu- and Lys-rich regions, were prepared and their cell penetrating potentials were evaluated. One peptide, stEK, was found to have high cell penetration and siRNA delivery abilities at low nanomolar concentrations.

Nonhemolytic Cell-Penetrating Peptides: Site Specific Introduction of Glutamine and Lysine Residues into the α-Helical Peptide Causes Deletion of Its Direct Membrane Disrupting Ability but Retention of Its Cell Penetrating Ability.

Cell-penetrating peptides (CPPs) often have cationic and amphipathic characteristics that are commonly associated with α-helical peptides. These features give CPPs both membrane demolishing and penetrating abilities. To make CPPs safe for biomedical applications, their toxicities resulting from their membrane demolishing abilities must be removed while their cell penetrating abilities must be retained.

An Amphiphilic Peptide Induces Apoptosis Through the miR29b-p53 Pathway in Cancer Cells.

Peptides have been in the limelight, as therapeutic agents for cancer treatment through various applications due to their high target selectivity and exceptional ability to penetrate the cell membrane. Recent studies have revealed that synthesized peptides bind to hairpin structures of RNA that affect their activities such as changing the efficacy of microRNA maturation. MicroRNA-mediated p53 activation by the microRNA-29 (miR29) family is one of the most important regulatory pathways in cancer therapeutics.

Screening of Pre-miRNA-155 Binding Peptides for Apoptosis Inducing Activity Using Peptide Microarrays.

MicroRNA-155, one of the most potent miRNAs that suppress apoptosis in human cancer, is overexpressed in numerous cancers, and it displays oncogenic activity. Peptide microarrays, constructed by immobilizing 185 peptides containing the C-terminal hydrazide onto epoxide-derivatized glass slides, were employed to evaluate peptide binding properties of pre-miRNA-155 and to identify its binding peptides. Two peptides, which were identified based on the results of peptide microarray and in vitro Dicer inhibition studies, were found to inhibit generation of mature miRNA-155 catalyzed by Dicer and to enhance expression of miRNA-155 target genes in cells.

Two helices in the third intracellular loop determine anoctamin 1 (TMEM16A) activation by calcium.

Anoctamin 1 (ANO1)/TMEM16A is a Cl(-) channel activated by intracellular Ca(2+) mediating numerous physiological functions. However, little is known of the ANO1 activation mechanism by Ca(2+). Here, we demonstrate that two helices, "reference" and "Ca(2+) sensor" helices in the third intracellular loop face each other with opposite charges.

Apoptosis inducing, conformationally constrained, dimeric peptide analogs of KLA with submicromolar cell penetrating abilities.

The apoptosis inducing KLA peptide, (KLAKLAK)2, possesses an ability to disrupt mitochondrial membranes. However, this peptide has a poor eukaryotic cell penetrating potential and, as a result, it requires the assistance of other cell penetrating peptides for effective translocation in micromolar concentrations. In an effort to improve the cell penetrating potential of KLA, we have created a library in which pairs of residues on its hydrophobic face are replaced by Cys.

Cell-penetrating, dimeric α-helical peptides: nanomolar inhibitors of HIV-1 transcription.

We constructed dimeric α-helical peptide bundles based on leucine (L) and lysine (K) residues for both efficient cell penetration and inhibition of the Tat-TAR interaction. The LK dimers can penetrate nearly quantitatively into eukaryotic cells and effectively inhibit the elongation of the TAR transcript at low nanomolar concentrations. The effective inhibition of HIV-1 replication strongly suggests that the LK dimer has strong potential as an anti-HIV-1 drug.