The elucidation of the cause of Alzheimer's disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY-based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 (VQIVYK) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Aβ-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly cost-effective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood-brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Aβ plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost-effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging.

Rapid change and zoonotic transmission to humans have enhanced the virulence of the influenza A virus (IAV). Neutralizing antibodies fail to provide lasting protection from seasonal epidemics. Furthermore, the effectiveness of anti-influenza neuraminidase inhibitors has declined because of drug resistance. Drugs that can block viral attachment and cell entry independent of antigenic evolution or drug resistance might address these problems. We show that multivalent 6'-sialyllactose-polyamidoamine (6SL-PAMAM) conjugates, when designed to have well-defined ligand valencies and spacings, can effectively inhibit IAV infection. Generation 4 (G4) 6SL-PAMAM conjugates with a spacing of around 3 nm between 6SL ligands (S3-G4) showed the strongest binding to a hemagglutinin trimer (dissociation constant of 1.6 × 10 M) and afforded the best inhibition of H1N1 infection. S3-G4 conjugates were resistant to hydrolysis by H1N1 neuraminidase. These conjugates protected 75% of mice from a lethal challenge with H1N1 and prevented weight loss in infected animals. The structure-based design of multivalent nanomaterials, involving modulation of nanoscale backbone structures and number and spacing between ligands, resulted in optimal inhibition of IAV infection. This approach may be broadly applicable for designing effective and enduring therapeutic protection against human or avian influenza viruses.

Activatable (turn‐on) probes that permit the rapid, sensitive, selective, and accurate identification of cancer‐associated biomarkers can help drive advances in cancer research. Herein, a NAD(P)H:quinone oxidoreductase‐1 (NQO1)‐specific chemiluminescent probe 1 is reported that allows the differentiation between cancer subtypes. Probe 1 incorporates an NQO1‐specific trimethyl‐locked quinone trigger moiety covalently tethered to a phenoxy‐dioxetane moiety through a para‐aminobenzyl alcohol linker. Bio‐reduction of the quinone to the corresponding hydroquinone results in a chemiluminescent signal. As inferred from a combination of in vitro cell culture analyses and in vivo mice studies, the probe is safe, cell permeable, and capable of producing a “turn‐on” luminescence response in an NQO1‐positive A549 lung cancer model. On this basis, probe 1 can be used to identify cancerous cells and tissues characterized by elevated NQO1 levels.

Eleven new briarane-type diterpene lactones, designated milolides (1--8, 10--12), together with four known diterpene lactones (9, 13--15), were isolated from the Micronesian octocoral Briareum stechei collected at Yap, Federated States of Micronesia. One aspect of the stereochemistry of one of the known compounds, solenolide C (9), is revised. Structures of the new compounds were determined from spectral data.