Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice.

Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule.

Structure-Based Design and Synthesis of Covalent Inhibitors for Deubiquitinase and Acetyltransferase ChlaDUB1 of .

Upon infection by an intracellular pathogen, host cells activate apoptotic pathways to limit pathogen replication. Consequently, efficient proliferation of the obligate intracellular pathogen , a major cause of trachoma and sexually transmitted diseases, depends on the suppression of host cell apoptosis. secretes deubiquitinase ChlaDUB1 into the host cell, leading among other interactions to the stabilization of antiapoptotic proteins and, thus, suppression of host cell apoptosis.

Evaluating the antimicrobial and anti-biofilm activity of three synthetic antimicrobial Citropin analogs and their ability to fight against Staphylococcus aureus and Staphylococcus pseudintermedius.

Aims: We developed three new analogs of the antimicrobial peptide (AMP) Citropin 1.1: DAN-1-13, AJP-1-1, and HHX-2-28, and tested their potential antimicrobial and antibiofilm activities against Staphylococcus aureus and S. pseudintermedius.

Enhanced Hydrogen Bonding by Urea Functionalization Tunes the Stability and Biological Properties of Peptide Amphiphiles.

Self-assembled nanostructures such as those formed by peptide amphiphiles (PAs) are of great interest in biological and pharmacological applications. Herein, a simple and widely applicable chemical modification, a urea motif, was included in the PA's molecular structure to stabilize the nanostructures by virtue of intermolecular hydrogen bonds. Since the amino acid residue nearest to the lipid tail is the most relevant for stability, we decided to include the urea modification at that position.

Engineering a nanoantibiotic system displaying dual mechanism of action.

In recent decades, peptide amphiphiles (PAs) have established themselves as promising self-assembling bioinspired materials in a wide range of medical fields. Herein, we report a dual-therapeutic system constituted by an antimicrobial PA and a cylindrical protease inhibitor (LJC) to achieve broad antimicrobial spectrum and to enhance therapeutic efficacy. We studied two strategies: PA-LJC nanostructures () and PA nanostructures + free LJC ().

Structure-Activity Relationship Study to Develop Peptide Amphiphiles as Species-Specific Antimicrobials.

Antimicrobial peptide amphiphiles (PAs) are a promising class of molecules that can disrupt the bacterial membrane or act as drug nanocarriers. In this study, we prepared 33 PAs to establish supramolecular structure-activity relationships. We studied the morphology and activity of the nanostructures against different Gram-positive and Gram-negative bacterial strains (such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii).

Designing peptide amphiphiles as novel antibacterials and antibiotic adjuvants against gram-negative bacteria.

Gram-negative strains are intrinsically resistant to most antibiotics due to the robust and impermeable characteristic of their outer membrane. Self-assembling cationic peptide amphiphiles (PAs) have the ability to disrupt bacteria membranes, constituting an excellent antibacterial alternative to small molecule drugs that can be used alone or as antibiotic adjuvants to overcome bacteria resistance. PA1 (CKHKHK), self-assembled into micelles, which exhibited low antibacterial activity against all strains tested, and showed strong synergistic antibacterial activity in combination with Vancomycin with a Fractional Inhibitory Concentration index (FICi) of 0.

design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain.

Although effective vaccines have been developed against SARS-CoV-2, many regions in the world still have low rates of vaccination and new variants with mutations in the viral spike protein have reduced the effectiveness of most available vaccines and treatments. There is an urgent need for a drug to cure this disease and prevent infection. The SARS-CoV-2 virus enters the host cell through protein-protein interaction between the virus's spike protein and the host's angiotensin converting enzyme (ACE2).

Synthesis and biological evaluation of sulfonylpyridine derivatives as potential anti-chlamydia agents.

Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection in the United States and the world. This pathogen can cause health problems ranging from trachoma (blindness) to damage of the fallopian tubes or ectopic pregnancy, which can be life-threatening if not treated properly. To this day, there is no chlamydia-specific drug on the market.

Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents.

(CT) causes the most prevalent sexually transmitted bacterial disease in the United States. The lack of drug selectivity is one of the main challenges of the current antichlamydial pharmacotherapy. The metabolic needs of CT are controlled, among others, by cylindrical proteases and their chaperones (, ClpX).

The structure of caseinolytic protease subunit ClpP2 reveals a functional model of the caseinolytic protease system from Chlamydia trachomatis.

Chlamydia trachomatis (ct) is the most reported bacterial sexually transmitted infection worldwide and the leading cause of preventable blindness. Caseinolytic proteases (ClpP) from pathogenic bacteria are attractive antibiotic targets, particularly for bacterial species that form persister colonies with phenotypic resistance against common antibiotics. ClpP functions as a multisubunit proteolytic complex, and bacteria are eradicated when ClpP is disrupted.

Pharmacophore modeling, molecular docking, and molecular dynamics studies to identify new 5-HTR antagonists with the potential for design of new atypical antipsychotics.

Some important atypical antipsychotic drugs target the serotonergic receptor 2A (5-HTR). Currently, new therapeutic strategies are needed to offer faster onset of action with fewer side effects and, therefore, greater efficacy in a substantial proportion of patients with neuropsychological disorders such as Autism and Parkinson. The main objective of this work was to use SBDD methods to identify new hit compounds potentially useful as precursors of novel and selective 5-HTR antagonists.

Urea-Modified Self-Assembling Peptide Amphiphiles That Form Well-Defined Nanostructures and Hydrogels for Biomedical Applications.

Hydrogen bonding plays a critical role in the self-assembly of peptide amphiphiles (PAs). Herein, we studied the effect of replacing the amide linkage between the peptide and lipid portions of the PA with a urea group, which possesses an additional hydrogen bond donor. We prepared three PAs with the peptide sequence Phe-Phe-Glu-Glu (FFEE): two are amide-linked with hydrophobic tails of different lengths and the other possesses an alkylated urea group.

and Activity of (Trifluoromethyl)pyridines as Anti- Agents.

is the leading pathogen in sexually transmitted bacterial infections across the globe. The development of a selective treatment against this pathogen could be an attractive therapeutic option that will reduce the overuse of broad-spectrum antibiotics. Previously, we reported some sulfonylpyridine-based compounds that showed selectivity against .

Scission energies of surfactant wormlike micelles loaded with nonpolar additives.

Hypothesis: The previously observed effects of nonpolar additives on the scission energy and rheological properties of surfactant wormlike micelles can be explained in terms of the spatial distribution of the additive within the micelles. The dependence of the scission energy with the molecular organization of the system can be analyzed with a molecular theory capable of describing the thermodynamics and structure of the micelles.

Theory: A new theoretical method to determine the scission energy of surfactant wormlike micelles is introduced.

Control of Peptide Amphiphile Supramolecular Nanostructures by Isosteric Replacements.

Supramolecular nanostructures with tunable properties can have applications in medicine, pharmacy, and biotechnology. In this work, we show that the self-assembly behavior of peptide amphiphiles (PAs) can be effectively tuned by replacing the carboxylic acids exposed to the aqueous media with isosteres, functionalities that share key physical or chemical properties with another chemical group. Transmission electron microscopy, atomic force microscopy, and small-angle X-ray scattering studies indicated that the nanostructure's morphologies are responsive to the ionization states of the side chains, which are related to their p values.

Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a pandemic of unprecedented scale. This coronavirus enters cells by the interaction of the receptor binding domain (RBD) with the human angiotensin-converting enzyme 2 receptor (hACE2). In this study, we employed a rational structure-based design to propose 22-mer stapled peptides using the structure of the hACE2 α1 helix as a template.

Molecular Basis for the Morphological Transitions of Surfactant Wormlike Micelles Triggered by Encapsulated Nonpolar Molecules.

Surfactant wormlike micelles are prone to experience morphological changes, including the transition to spherical micelles, upon the addition of nonpolar additives. These morphological transitions have profound implications in diverse technological areas, such as the oil and personal-care industries. In this work, additive-induced morphological transitions in wormlike micelles were studied using a molecular theory that predicts the equilibrium morphology and internal molecular organization of the micelles as a function of their composition and the molecular properties of their components.

The ClpX and ClpP2 Orthologs of Chlamydia trachomatis Perform Discrete and Essential Functions in Organism Growth and Development.

is an obligate intracellular bacterium that undergoes a complex developmental cycle in which the bacterium differentiates between two functionally and morphologically distinct forms, the elementary body (EB) and reticulate body (RB), each of which expresses its own specialized repertoire of proteins. Both primary (EB to RB) and secondary (RB to EB) differentiations require protein turnover, and we hypothesize that proteases are critical for mediating differentiation. The Clp protease system is well conserved in bacteria and important for protein turnover.

Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases.

is the most common sexually transmitted bacterial disease globally and the leading cause of infertility and preventable infectious blindness (trachoma) in the world. Unfortunately, there is no FDA-approved treatment specific for chlamydial infections. We recently reported two sulfonylpyridines that halt the growth of the pathogen.

Twisting of Charged Nanoribbons to Helicoids Driven by Electrostatics.

Charged amphiphiles in solution usually self-assemble into flat nanoribbons that spontaneously twist into different shapes. The role of electrostatics in this process is still under strong debate. This work studies the electrostatic free energy of twisting a nanoribbon at the level of the nonlinear Poisson-Boltzmann approximation.

Protecting Groups in Peptide Synthesis.

The protection of amino acid reactive functionalities including the α-amino group, the side chain (amines, carboxylic acids, alcohols, and thiols), or the carboxylic acid terminus is an essential strategy in peptide chemistry. This is mandatory to prevent polymerization of the amino acids and to minimize undesirable side reactions during the synthetic process. Proper protecting group manipulation strategies can maximize the yield of the desired product or allow the construction of complex peptide-based structures.

Identification of an Anti-MRSA Cyclic Lipodepsipeptide, WBP-29479A1, by Genome Mining of .

are ubiquitous in the environment but remain largely underexplored, although the bacteria are considered "peptide specialists". Here, we identified a new cyclic lipodepsipeptide, WBP-29479A1 (), through genome mining of ATCC 29479. is biosynthesized by a large NRPS gene cluster, and its structure, including the six nonproteinogenic residues and 3-hydroxy fatty acid, was determined by extensive spectroscopic analyses and chemical derivatization.