The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface.

A Perspective of work in our laboratory on the examination of biologically active compounds, especially natural products, is presented. In the context of individual programs and along with a summary of our work, selected cases are presented that illustrate the impact single atom changes can have on the biological properties of the compounds. The examples were chosen to highlight single heavy atom changes that improve activity, rather than those that involve informative alterations that reduce or abolish activity.

The biological and chemical basis for tissue-selective amyloid disease.

Factors controlling the onset and progression of extracellular amyloid diseases remain largely unknown. Central to disease etiology is the efficiency of the endoplasmic reticulum (ER) machinery that targets destabilized mutant proteins for degradation and the enhanced tendency of these variants to aggregate if secreted. We demonstrate that mammalian cells secrete numerous transthyretin (TTR) disease-associated variants with wild-type efficiency in spite of compromised folding energetics.