Willis Coupling-Induced Acoustic Radiation Force and Torque Reversal.

Acoustic meta-atoms serve as the building blocks of metamaterials, with linear properties designed to achieve functions such as beam steering, cloaking, and focusing. They have also been used to shape the characteristics of incident acoustic fields, which led to the manipulation of acoustic radiation force and torque for development of acoustic tweezers with improved spatial resolution. However, acoustic radiation force and torque also depend on the shape of the object, which strongly affects its scattering properties. We show that by designing linear properties of an object using metamaterial concepts, the nonlinear acoustic effects of radiation force and torque can be controlled. Trapped objects are typically small compared with the wavelength, and are described as particles, inducing monopole and dipole scattering. We extend such models to a polarizability tensor including Willis coupling terms, as a measure of asymmetry, capturing the significance of geometrical features. We apply our model to a three-dimensional, subwavelength meta-atom with maximal Willis coupling, demonstrating that the force and the torque can be reversed relative to an equivalent symmetrical particle. By considering shape asymmetry in the acoustic radiation force and torque, Gorkov's fundamental theory of acoustophoresis is thereby extended. Asymmetrical shapes influence the acoustic fields by shifting the stable trapping location, highlighting a potential for tunable, shape-dependent particle sorting.

In Vitro Assessment of Putative PD-1/PD-L1 Inhibitors: Suggestions of an Alternative Mode of Action.

The programmed cell death protein 1 (PD-1) signaling axis is among the most important therapeutic targets in modern oncology. Aurigene Discovery Technologies Ltd. (Aurigene) has patented a series of peptidomimetic small molecules derived from the PD-1 protein sequence for use in targeting the interaction between PD-1 and its ligand, PD-L1. We evaluated three of Aurigene's most potent compounds in SPR binding assays. Our results showed that these compounds-each of which is known to be potently effective in a splenocyte recovery assay-do not directly inhibit the PD-1/PD-L1 interaction nor do they appear to bind to either of the constituent proteins, indicating that another mechanism is at play. As a result of these studies and upon consideration of structural features within the PD-1/PD-L1 complex, we hypothesize that the Aurigene molecules may interact with a currently unknown protein capable of regulating the PD-1 axis.

An overview of patented small molecule stearoyl coenzyme-A desaturase inhibitors (2009 - 2013).

INTRODUCTION: Stearoyl coenzyme-A desaturase (SCD) is a critical lipogenic enzyme that converts a range of unsaturated lipids to their corresponding monounsaturated fatty acids. Genetic and enzyme-knockdown experiments have suggested an important role of SCD1 in the regulation of various metabolic disorders. With the prognostication that SCD-inhibition may serve to remediate various metabolic diseases, several pharmaceutical companies have embarked on the development of small-molecule SCD-inhibitors, with over 100 patent applications by 17 companies being reported to date. AREAS COVERED: Recent progress on the development of SCD-inhibitors, including preclinical efficacy and safety are reviewed. Strategies toward overcoming systemic adverse events and the establishment of a suitable therapeutic margin for clinical studies are discussed. EXPERT OPINION: Preclinically, SCD-inhibition leads to reductions in body-weight gain, improvements in glucose clearance and improved liver-lipid profile. However, chronic SCD inhibition in skin and eye-lubricating glands results in undesirable adverse events. Several strategies to overcome these findings have been described, including alternative administration routes for acne or oncology applications, use of potent and rapidly cleared compounds and SCD-inhibitors with a liver-targeted tissue distribution profile. The attainment of sufficient therapeutic margin and robust efficacy for therapeutic applications in humans remains a major frontier for SCD-inhibitors.

Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series.

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.

Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia.

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.

Nickel-catalyzed cross-couplings of organosilicon reagents with unactivated secondary alkyl bromides.

A metal-catalyzed cross-coupling of organosilicon compounds with alkyl halides has been developed. Noteworthy attributes of the method are its scope (secondary electrophiles), its high functional-group compatibility, and the air stability of the catalyst components.