Multivalent Fucosides Targeting ß-Propeller Lectins from Lung Pathogens with Promising Anti-Adhesive Properties.

Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, ß-propeller lectins such as FleA from Aspergillus fumigatus, SapL1 from Scedosporium apiospermum, and BambL from Burkholderia ambifaria have become appealing targets for the design of anti-adhesive agents. In search of novel and cheap anti-infectious agents, we synthesized multivalent compounds that can display up to 20 units of fucose, the natural ligand. We obtained nanomolar inhibitors that are several orders of magnitude stronger than their monovalent analogue according to several biophysical techniques (i.e., fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry). The reason for high affinity might be attributed to a strong aggregating mechanism, which was examined by analytical ultracentrifugation. Notably, the fucosylated inhibitors reduced the adhesion of A. fumigatus spores to lung epithelial cells when administered 1 h before or after the infection of human lung epithelial cells. For this reason, we propose them as promising anti-adhesive drugs for the prevention and treatment of aspergillosis and related microbial lung infections.

Novel Treatment Approach for Aspergilloses by Targeting Germination.

Germination of conidia is an essential process within the Aspergillus life cycle and plays a major role during the infection of hosts. Conidia are able to avoid detection by the majority of leukocytes when dormant. Germination can cause severe health problems, specifically in immunocompromised people. Aspergillosis is most often caused by Aspergillus fumigatus (A. fumigatus) and affects neutropenic patients, as well as people with cystic fibrosis (CF). These patients are often unable to effectively detect and clear the conidia or hyphae and can develop chronic non-invasive and/or invasive infections or allergic inflammatory responses. Current treatments with (tri)azoles can be very effective to combat a variety of fungal infections. However, resistance against current azoles has emerged and has been increasing since 1998. As a consequence, patients infected with resistant A. fumigatus have a reported mortality rate of 88% to 100%. Especially with the growing number of patients that harbor azole-resistant Aspergilli, novel antifungals could provide an alternative. Aspergilloses differ in defining characteristics, but germination of conidia is one of the few common denominators. By specifically targeting conidial germination with novel antifungals, early intervention might be possible. In this review, we propose several morphotypes to disrupt conidial germination, as well as potential targets. Hopefully, new antifungals against such targets could contribute to disturbing the ability of Aspergilli to germinate and grow, resulting in a decreased fungal burden on patients.

Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors.

Divalent inhibitors of the neuraminidase enzyme (NA) of the Influenza A virus were synthesized with vastly different spacers. The spacers varied from 14 to 56 atoms and were relatively rigid by way of the building blocks and their connection by CuAAC. As the ligand for these constructs, a Δ4-ß-d-glucoronide was used, which can be prepared form N-acetyl glucosamine. This ligand showed good NA inhibitory potency but with room for improvement by multivalency enhancement. The synthesized compounds showed modest potency enhancement in NA activity assays but a sizeable potency increase in a 4-day cytopathic effect assay. The demonstration that the compounds can also inhibit hemagglutinin in addition to NA may be the cause of the enhancement.

Stereoselective Protection-Free Modification of 3-Keto-saccharides.

Unprotected 3-keto-saccharides have become readily accessible via site-selective oxidation, but their protection-free functionalization is relatively unexplored. Here we show that protecting groups are obsolete in a variety of stereoselective modifications of our model substrate methyl α-glucopyranoside. This allows the preparation of rare sugars and the installation of click handles and reactive groups. To showcase the applicability of the methodology, maltoheptaose has been converted into a chemical probe, and the rare sugar evalose has been synthesized.

Optical control of GPR40 signalling in pancreatic ß-cells.

Fatty acids activate GPR40 and K+ channels to modulate ß-cell function. Herein, we describe the design and synthesis of FAAzo-10, a light-controllable GPR40 agonist based on Gw-9508. FAAzo-10 is a potent GPR40 agonist in the trans-configuration and can be inactivated on isomerization to cis with UV-A light. Irradiation with blue light reverses this effect, allowing FAAzo-10 activity to be cycled ON and OFF with a high degree of spatiotemporal precision. In dissociated primary mouse ß-cells, FAAzo-10 also inactivates voltage-activated and ATP-sensitive K+ channels, and allows us to control glucose-stimulated Ca2+ oscillations in whole islets with light. As such, FAAzo-10 is a useful tool to study the complex effects, with high specificity, which FA-derivatives such as Gw-9508 exert at multiple targets in mouse ß-cells.