A hybrid polymer to target blood group dependence of cholera toxin.

Cholera is a potentially fatal bacterial infection caused by the cholera toxin (CT), an AB5 toxin secreted by Vibrio cholera. GM1 has long been known as the receptor of the cholera toxin in the intestine. However, increasing evidence is pointing towards the role of fucosylated conjugates as additional attachment options of the toxin.

Strong Inhibition of Cholera Toxin B Subunit by Affordable, Polymer-Based Multivalent Inhibitors.

Cholera is a potentially fatal bacterial infection that affects a large number of people in developing countries. It is caused by the cholera toxin (CT), an AB toxin secreted by Vibrio cholera. The toxin comprises a toxic A-subunit and a pentameric B-subunit that bind to the intestinal cell surface.

Orthoester functionalized -guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of β-glucocerebrosidase.

Alkylated guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol bearing an orthoester moiety were prepared using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that one of the compounds prepared displays potent inhibition against human β-glucocerebrosidase (GBA) at pH 7.0 with IC values in the low nanomolar range.

N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol are Potent, Selective, and Stable Inhibitors of β-Glucocerebrosidase.

A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β-glucocerebrosidase with IC values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for β-galactosidase from bovine liver.

Bicyclic isoureas derived from 1-deoxynojirimycin are potent inhibitors of β-glucocerebrosidase.

A series of bicyclic isourea derivatives were prepared from 1-deoxynojirimycin using a concise synthetic protocol proceeding via a guanidino intermediate. Inhibition assays with a panel of glycosidases revealed that these deoxynojirimycin-derived bicyclic isoureas display very potent inhibition against human recombinant β-glucocerebrosidase with IC50 values in the low nanomolar range.

Functional Characterization of Cholera Toxin Inhibitors Using Human Intestinal Organoids.

Preclinical drug testing in primary human cell models that recapitulate disease can significantly reduce animal experimentation and time-to-the-clinic. We used intestinal organoids to quantitatively study the potency of multivalent cholera toxin inhibitors. The method enabled the determination of IC50 values over a wide range of potencies (15 pM to 9 mM).

Head-to-Head Comparison of Anti-Inflammatory Performance of Known Natural Products In Vitro.

Inflammation is an important therapeutic target. Due to their potency, steroidal drugs dominate the current treatment of inflammatory disorders. However, steroidal drugs can also exert a broad range of side effects and appear not always effective.

Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites.

The protein arginine N-methyltransferases (PRMTs) are a family of enzymes that function by specifically transferring a methyl group from the cofactor S-adenosyl-L-methionine (AdoMet) to the guanidine group of arginine residues in target proteins. The most notable is the PRMT-mediated methylation of arginine residues that are present in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases including various forms of cancer.

Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment.

The antimicrobial peptide nisin is a promising template for designing novel peptide-based antibiotics to improve its drug-like properties. First steps in that direction represent the synthesis of hybrid nisin derivatives that contain a native nisin ABC-part and synthesized cross-stapled DE-ring fragments and are described here. The biological activity of the newly synthesized nisin derivatives was evaluated in order to compare the bioactivity of the synthetic DE-ring containing mimic and native lanthionine-bridged DE-ring containing nisin.

Convenient Preparation of Bactericidal Hydrogels by Covalent Attachment of Stabilized Antimicrobial Peptides Using Thiol-ene Click Chemistry.

This report describes the design and synthesis of a bactericidal poly(ethylene glycol)-based (PEG) hydrogel coating with covalently attached antimicrobial peptides (AMP) stabilized against proteolytic degradation. As such, mimics of the highly active AMP HHC10 (H-KRWWKWIRW-NH) were designed for optimal stability in human serum while retaining strong antimicrobial activity against and , the major causative agents of biomaterial associated infection. In order to investigate the selectivity of the AMPs, their hemolytic activity was determined.

Efficient synthesis of protein mimics by sequential native chemical ligation.

Synthetic mimics of protein surfaces have the potential to become inhibitors of protein-protein interactions or even synthetic vaccines. However, the synthesis of these complicated molecular constructs is still difficult. Here we describe an efficient and versatile synthesis of protein mimics containing up to three different cyclic peptides.

Oseltamivir analogues bearing N-substituted guanidines as potent neuraminidase inhibitors.

A series of oseltamivir analogues bearing an N-substituted guanidine unit were prepared and evaluated as inhibitors of neuraminidases from four strains of influenza. The two most potent analogues identified contain relatively small N-guanidine substituents (N-methyl and N-hydroxyl) and display enhanced inhibition with IC50 values in the low nanomolar range against neuraminidases from wild-type and oseltamivir-resistant strains. Potential advantages of including the N-hydroxyguanidine moiety in neuraminidase inhibitors are also discussed.

Improving the biological activity of the antimicrobial peptide anoplin by membrane anchoring through a lipophilic amino acid derivative.

The lipophilic amino acid, (S)-2-aminoundecanoic acid, was synthesized and incorporated at a number of specific positions within the peptide sequence of anoplin. These lipophilic anoplin analogs showed to be more active against Escherichia coli and Staphylococcus aureus compared to native anoplin, while the EC50-value of hemolysis was at least one order of magnitude lower than the MIC values. This was in sharp contrast to the N-acylated anoplin derivative, where a gain in activity also led to a complete loss of selectivity.

Scaffold optimization in discontinuous epitope containing protein mimics of gp120 using smart libraries.

A diversity of protein surface discontinuous epitope mimics is now rapidly and efficiently accessible. Despite the important role of protein-protein interactions involving discontinuous epitopes in a wide range of diseases, mimicry of discontinuous epitopes using peptide-based molecules remains a major challenge. Using copper(I) catalyzed azide-alkyne cycloaddition (CuAAC), we have developed a general and efficient method for the synthesis of collections of discontinuous epitope mimics.

A concise preparation of the fluorescent amino acid L-(7-hydroxycoumarin-4-yl) ethylglycine and extension of its utility in solid phase peptide synthesis.

Incorporation of the unnatural amino acid L-(7-hydroxycoumarin-4-yl)ethylglycine (7-HC) is a powerful and reliable approach for the preparation of fluorescently labeled proteins. The growing popularity of this valuable amino acid prompted us to pursue an improved protocol for its synthetic preparation. The optimized procedure here described provides ready access to multi-gram quantities of 7-HC.

Chalcones from the seed of Cedrelopsis grevei (Ptaeroxylaceae).

The seed of Cedrelopsis grevei (Ptaeroxylaceae) has yielded the known compounds uvangoletin, 5,7-dimethylpinocembrin, cardamonin, flavokawin B, 2'-methoxyhelikrausichalcone, and the novel prenylated chalcones, cedreprenone and cedrediprenone. Cedridiprenone has been shown to exhibit superoxide scavenging properties.

Coumarins from Cedrelopsis grevei (Ptaeroxylaceae).

The stem bark of Cedrelopsis grevei Baill. has yielded the first reported examples of 5-prenylated coumarins, cedrecoumarin A and B as well as the known coumarins, cedrelopsin, scoparone, O-methylcedrelopsin and norbraylin, and the known chromones ptaeroglycol and ptaeroxylinol.

Bioactive constituents of Cedrelopsis microfoliata.

The stem bark of Cedrelopsis microfoliata has yielded the new compounds microfolian (1), microfolione (2), and microfolicoumarin (6) along with the known compounds agrandol (3), cedrecoumarin A (4), obliquin (5), and sesquichamaenol (7). Compounds 2-4 were found to show agonistic activity on both alpha- and beta-estrogenic receptors, and compounds 1, 3, and 4 were shown to inhibit the chemiluminescence of reactive oxygen metabolites and showed superoxide scavenging activity.