However, the timing of application was critical in inducing diffe

However, the timing of application was critical in inducing different thermoregulatory responses. These findings provide novel insights on the thermoregulatory role of T-sk during exercise in the heat.”
“Antimicrobial peptides (AMPS) provide protection against a variety of pathogenic bacteria and are, therefore, an important part of the innate immune system. Over the past decade,

there has been considerable interest in developing AMPs as intravenously administered antibiotics. However, despite PS-095760 extensive efforts in the pharmaceutical and biotechnology industry, it has proven difficult to achieve this goal. While researchers have solved some relatively simple problems such as susceptibility to proteolysis, more severe problems have included the expense of the materials, toxicity, poor efficacy, and limited tissue distribution.\n\nIn this Account, we describe our efforts to design and synthesize “foldamers”- short sequence-specific oligomers based on arylamide and beta-amino acid backbones, which fold into well-defined secondary structures- that could act as antimicrobial agents. We reasoned that small “foldamers” would be less expensive to produce than peptides, and

might have better tissue distribution. It should be easier to fine-tune the structures and activities of these molecules to minimize toxicity.\n\nBecause the activities of many AMPS depends primarily on their overall physicochemical properties rather than the fine details of their precise amino add sequences, we have designed and Synthesized very small “coarse-grained” molecules, which are far simpler than naturally produced AMPS. The molecular design of these foldamers epitomizes the positively charged amphiphilic structures believed to be responsible for the activity

of AMPS. The designed oligomers show greater activity than the parent peptides. They have also provided leads for novel small molecule therapeutics AZD1480 price that show excellent potency in animal models for multidrug resistant bacterial infections. In addition, such molecules can serve as relatively simple experimental systems for investigations aimed at understanding the mechanism of action for this class of antimicrobial agents. The foldamers’ specificity for bacterial membranes relative to mammalian membranes appears to arise from differences in membrane composition and physical properties between these cell types.\n\nFurthermore, because experimental coarse-graining provided such outstanding results, we developed computational coarse-grained models to enable molecular dynamic simulations of these molecules with phospholipid membranes. These simulations allow investigation of larger systems for longer times than conventional molecular dynamics simulations, allowing us to investigate how physiologically relevant surface concentrations of AMP mimics affect the bilayer structure and properties.

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