Chemical Space for Peptide-based Antimicrobials.

Multidrug-resistant (MDR) bacteria represent a global public health threat, and antimicrobial peptides (AMPs), derived from naturally occurring linear or cyclic peptides, can provide the solution. However, most AMPs are sensitive to proteases and have poor pharmacokinetics. The EU-funded ERC Advanced Grant SPACE4AMPS aims to identify new AMPs by applying the concepts of chemical space and ligand-based virtual screening, which are well known for small molecule drug discovery, to the world of peptides.

and urticaria. What we know about its real incidence and management in dermatological settings?

Acute or chronic infections have been described among causes of chronic urticaria (CU). Anisakidosis is a human disease caused by the ingestion of larval nematodes of the family Anisakidae. The infestation is acquired by eating raw seafood or undercooked fish and squid.

Overcoming Protein Orientation Mismatch Enables Efficient Nanoscale Light-Driven ATP Production.

Adenosine triphosphate (ATP)-producing modules energized by light-driven proton pumps are powerful tools for the bottom-up assembly of artificial cell-like systems. However, the maximum efficiency of such modules is prohibited by the random orientation of the proton pumps during the reconstitution process into lipid-surrounded nanocontainers. Here, we overcome this limitation using a versatile approach to uniformly orient the light-driven proton pump proteorhodopsin (pR) in liposomes.

A group of three miRNAs can act as candidate circulating biomarkers in liquid biopsies from melanoma patients.

Background: Staging of melanoma and follow up after melanoma diagnosis aims at predicting risk and detecting progression or recurrence at early stage, respectively in order to timely start and/or change treatment. Tumor thickness according to Breslow, status of the sentinel node and value of the lactate dehydrogenase (LDH) are well-established prognostic markers for metastatic risk, but reliable biomarkers identifying early recurrence or candidates who may benefit best from medical treatment are still warranted. Liquid biopsy has emerged to be a suitable method for identifying biomarkers for early cancer diagnosis, prognosis, therapeutic response prediction, and patient follow-up.

To Fold or Not to Fold: Diastereomeric Optimization of an α-Helical Antimicrobial Peptide.

Membrane disruptive α-helical antimicrobial peptides (AMPs) offer an opportunity to address multidrug resistance; however, most AMPs are toxic and unstable in serum. These limitations can be partly overcome by introducing D-residues, which often confers protease resistance and reduces toxicity without affecting antibacterial activity, presumably due to lowered α-helicity. Here, we investigated 31 diastereomers of the α-helical AMP KKLLKLLKLLL.

Dipropylamine for 9-Fluorenylmethyloxycarbonyl (Fmoc) Deprotection with Reduced Aspartimide Formation in Solid-Phase Peptide Synthesis.

Herein, we report dipropylamine (DPA) as a fluorenylmethyloxycarbonyl (Fmoc) deprotection reagent to strongly reduce aspartimide formation compared to piperidine (PPR) in high-temperature (60 °C) solid-phase peptide synthesis (SPPS). In contrast to PPR, DPA is readily available, inexpensive, low toxicity, and nonstench. DPA also provides good yields in SPPS of non-aspartimide-prone peptides and peptide dendrimers.

An intrinsically disordered antimicrobial peptide dendrimer from stereorandomized virtual screening.

Membrane-disruptive amphiphilic antimicrobial peptides behave as intrinsically disordered proteins by being unordered in water and becoming α-helical in contact with biological membranes. We recently discovered that synthesizing the α-helical antimicrobial peptide dendrimer L- ((KL)(KL)(LL) KLL) using racemic amino acids to form stereorandomized -, an analytically pure mixture of all possible diastereoisomers of L-, preserved antibacterial activity but abolished hemolysis and cytotoxicity, pointing to an intrinsically disordered antibacterial conformation and an α-helical cytotoxic conformation. In this study, to identify non-toxic intrinsically disordered homochiral antimicrobial peptide dendrimers (AMPDs), we surveyed sixty-three -analogs of - selected by virtual screening.

A mixed chirality α-helix in a stapled bicyclic and a linear antimicrobial peptide revealed by X-ray crystallography.

The peptide α-helix is right-handed when containing amino acids with l-chirality, and left-handed with d-chirality, however mixed chirality peptides generally do not form α-helices unless a helix inducer such as the non-natural residue amino-isobutyric acid is used. Herein we report the first X-ray crystal structures of mixed chirality α-helices in short peptides comprising only natural residues as the example of a stapled bicyclic and a linear membrane disruptive amphiphilic antimicrobial peptide (AMP) containing seven l- and four d-residues, as complexes of fucosylated analogs with the bacterial lectin LecB. The mixed chirality α-helices are superimposable onto the homochiral α-helices and form under similar conditions as shown by CD spectra and MD simulations but non-hemolytic and resistant to proteolysis.

An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate.

Glatiramer acetate (GA) is a random polypeptide drug used to treat multiple sclerosis (MS), a chronic autoimmune disease. With the aim of identifying a precisely defined alternative to GA, we synthesized a library of peptide dendrimers with an amino acid composition similar to GA. We then challenged the dendrimers to trigger the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) from human monocytes, which is one of the effects of GA on immune cells.

Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB-17 Fragment Library.

Solute carrier proteins (SLCs) are membrane proteins controlling fluxes across biological membranes and represent an emerging class of drug targets. Here we searched for inhibitors of divalent metal transporters in a library of 1,676 commercially available 3D-shaped fragment-like molecules from the generated database GDB-17, which lists all possible organic molecules up to 17 atoms of C, N, O, S and halogen following simple criteria for chemical stability and synthetic feasibility. While screening against DMT1 (SLC11A2), an iron transporter associated with hemochromatosis and for which only very few inhibitors are known, only yielded two weak inhibitors, our approach led to the discovery of the first inhibitor of ZIP8 (SLC39A8), a zinc transporter associated with manganese homeostasis and osteoarthritis but with no previously reported pharmacology, demonstrating that this target is druggable.

The antibacterial activity of peptide dendrimers and polymyxin B increases sharply above pH 7.4.

pH-activity profiling reveals that antimicrobial peptide dendrimers (AMPDs) kill Klebsiella pneumoniae and Methicillin-resistant Staphylococcus aureus (MRSA) at pH = 8.0, against which they are inactive at pH = 7.4, due to stronger electrostatic binding to bacterial cells at higher pH.

Stereorandomization as a Method to Probe Peptide Bioactivity.

Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized () peptides, containing up to billions of different stereoisomers, as well-defined single HPLC peaks, single mass products with high yield, which can be used to investigate peptide bioactivity. To exemplify our method, we show that stereorandomization abolishes the membrane-disruptive effect of α-helical amphiphilic antimicrobial peptides but preserves their antibiofilm effect, implying different mechanisms involving folded versus disordered conformations.

Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation.

Solute carrier proteins (SLCs) control fluxes of ions and molecules across biological membranes and represent an emerging class of drug targets. SLC11A2 (hDMT1) mediates intestinal iron uptake and its inhibition might be used to treat iron overload diseases such as hereditary hemochromatosis. Here we report a micromolar (IC = 1.

Synergistic Effect of Propidium Iodide and Small Molecule Antibiotics with the Antimicrobial Peptide Dendrimer G3KL against Gram-Negative Bacteria.

There is an urgent need to develop new antibiotics against multidrug-resistant bacteria. Many antimicrobial peptides (AMPs) are active against such bacteria and often act by destabilizing membranes, a mechanism that can also be used to permeabilize bacteria to other antibiotics, resulting in synergistic effects. We recently showed that , an AMP with a multibranched dendritic topology of the peptide chain, permeabilizes the inner and outer membranes of Gram-negative bacteria including multidrug-resistant strains, leading to efficient bacterial killing.

P53 staining index and zonal staining patterns in actinic keratoses.

Actinic keratoses (AKs) are common dysplastic lesions resulting from chronic excessive ultraviolet exposure. Neither the clinical grade of thickness nor the histological grade of dysplasia seems valid predictors of aggressive potential of AKs. Instead, the mutational status in AKs appears to predict well the clinical course.