Linda Quarles van Ufford

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.

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.

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. Also reported is an extension of the utility of 7-HC in the generation of a protected building block suitable for use in solid phase peptide synthesis. The building block was successfully incorporated at various positions in a series of model peptides, including analogues of the cell penetrating HIV-Tat peptide, further illustrating the utility of this unique amino acid.

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). The results indicate for the first time that an organoid-based swelling assay is a useful preclinical method to evaluate inhibitor potencies of drugs that target pathogen-derived toxins.

Multiple pathway assessment to predict anti-atherogenic efficacy of drugs targeting macrophages in atherosclerotic plaques

BACKGROUND Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages. METHODS AND RESULTS We evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti-inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti-atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery. CONCLUSION This dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.

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 IC50 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. No inhibition of human recombinant β‐glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).

The antimicrobial activity and microbiological safety of stingless bee honeys from Costa Rica

Summary Stingless bee honeys from Costa Rica possess etnopharmacological value mainly as a wound dressing. The microbiological study by APHA methods reported that 83 % of the honeys analysed had microbial counts that comply with European Pharmacopoeias acceptance criteria for microbiological quality of non-sterile substances for pharmaceutical use. All samples reported the absence of Clostridium botuiinum spores by PCR. Over 90 % of Tetragonisca angustula and Melipona beecheii honeys inhibited Pseudomonas aeruginosa and Staphylococcus aureus at minimum inhibitory concentrations lower than MedihoneyTM. Under the conditions tested, MedihoneyTM was not active against Candida albicans, whereas 53 % of T angustula honeys rendered inhibition. The melissopalynological analyses reported a homogeneous (monofloral) botanical composition for the Meliponini honeys, which emphasizes the contribution of nectar constituents to the antimicrobial activity and provides foundation to the standardization of a desired inhibitory effect. The traditional use of Costa Rican stingless bee honey as a dressing for burns and wounds reveals the application of a proficient antiseptic agent with low health associated risks.

In-Vitro Assays for Activity-Guided Enrichment of Immunomodulatory Plant Constituents

It has been known for ages or even millennia that certain plants or plant preparations may be used successfully to selectively treat immunological disorders. In the course of the last centuries, it has become clear that the active ?rinciple(s) of such ‘immunomodulatory’ plants/plant preparations may be single chemical entities or more complex mixtures of related substances that can either enhance or suppress deranged immunological reactions. Depending on their mode of action, plant-derived ‘immunomodulators’ can be used to stimulate the immune system of immunocompromised individuals (patients with congenital or acquired immunodeficiencies, young children, or elderly people) or, alternatively, to suppress the immune system of hyperreactive subjects (patients with allergic, autoimmune, and/or rheumatic diseases) or transplantation patients. There are even examples of plant derived substances with more or less selective anti-lymphoproliferative effects.