Development of piperazine-based hydroxamic acid inhibitors against falcilysin, an essential malarial protease.

The human parasite Plasmodium falciparum kills an estimated 445,000 people a year, with the most fatalities occurring in African children. Previous studies identified falcilysin (FLN) as a malarial metalloprotease essential for parasite development in the human host. Despite its essentiality, the biological roles of this protease are not well understood. Here we describe the optimization of a piperazine-based hydroxamic acid scaffold to develop the first reported inhibitors of FLN. Inhibitors were tested against cultured parasites, and parasiticidal activity correlated with potency against FLN. This suggests these compounds kill P. falciparum by blocking FLN, and that FLN is a druggable target. These compounds represent an important step towards validating FLN as a therapeutic target and towards the development of chemical tools to investigate the function of this protease.

Covalent Bonding of Thermoplastics to Rubbers for Printable, Reel-to-Reel Processing in Soft Robotics and Microfluidics.

The lamination of mechanically stiff structures to elastic materials is prevalent in biological systems and popular in many emerging synthetic systems, such as soft robotics, microfluidics, stretchable electronics, and pop-up assemblies. The disparate mechanical and chemical properties of these materials have made it challenging to develop universal synthetic procedures capable of reliably adhering to these classes of materials together. Herein, a simple and scalable procedure is described that is capable of covalently laminating a variety of commodity ("off-the-shelf") thermoplastic sheets to silicone rubber films. When combined with laser printing, the nonbonding sites can be "printed" onto the thermoplastic sheets, enabling the direct fabrication of microfluidic systems for actuation and liquid handling applications. The versatility of this approach in generating thin, multifunctional laminates is demonstrated through the fabrication of milliscale soft actuators and grippers with hinged articulation and microfluidic channels with built-in optical filtering and pressure-dependent geometries. This method of fabrication offers several advantages, including technical simplicity, process scalability, design versatility, and material diversity. The concepts and strategies presented herein are broadly applicable to the soft robotics, microfluidics, and advanced and additive manufacturing communities where hybrid rubber/plastic structures are prevalent.