Improving the biological activity of pyrrole-imidazole polyamides

DNA is nature’s blueprint, holding within it the genetic code that defines the structure and function of an organism. A complex network of DNA-binding proteins called transcription factors can largely control the flow of information from DNA, so modulating the function of transcription factors is a promising approach for treating many diseases. Pyrrole-imidazole (Py-Im) polyamides are a class of DNA-binding oligomers, which can be synthetically programmed to bind a target sequence of DNA. Due to their unique shape complementarity and a series of favorable hydrogen bonding interactions that occur upon DNA-binding, Py-Im polyamides can bind to the minor groove of DNA with affinities comparable to transcription factors. Previous studies have demonstrated that these cell-permeable small molecules can enter cell nuclei and disrupt the transcription factor-DNA interface, thereby repressing transcription. As the use of Py-Im polyamides has significant potential as a type of modular therapeutic platform, the need for polyamides with extremely favorable biological properties and high potency will be essential. Described herein, a variety of studies have been performed aimed at improving the biological activity of Py-Im polyamides. To improve the biological potency and cellular uptake of these compounds, we have developed a next-generation class of polyamides bearing aryl-turn moieties, a simple structural modification that allows significant improvements in cellular uptake. This strategy was also applied to a panel of high-affinity cyclic Py-Im polyamides, again demonstrating the remarkable effect minor structural changes can have on biological activity. The solubility properties of Py-Im polyamides and use of formulating reagents with their treatment have also been examined. Finally, we describe the study of Py-Im polyamides as a potential artificial transcription factor.

The Voting Rights Act, Shelby County, and Redistricting: Improving Estimates of Racially Polarized Voting in a Multiple-Election Context

The Supreme Court’s decision in Shelby County has severely limited the power of the Voting Rights Act. I argue that Congressional attempts to pass a new coverage formula are unlikely to gain the necessary Republican support. Instead, I propose a new strategy that takes a “carrot and stick” approach. As the stick, I suggest amending Section 3 to eliminate the need to prove that discrimination was intentional. For the carrot, I envision a competitive grant program similar to the highly successful Race to the Top education grants. I argue that this plan could pass the currently divided Congress.

Without Congressional action, Section 2 is more important than ever before. A successful Section 2 suit requires evidence that voting in the jurisdiction is racially polarized. Accurately and objectively assessing the level of polarization has been and continues to be a challenge for experts. Existing ecological inference methods require estimating polarization levels in individual elections. This is a problem because the Courts want to see a history of polarization across elections.

I propose a new 2-step method to estimate racially polarized voting in a multi-election context. The procedure builds upon the Rosen, Jiang, King, and Tanner (2001) multinomial-Dirichlet model. After obtaining election-specific estimates, I suggest regressing those results on election-specific variables, namely candidate quality, incumbency, and ethnicity of the minority candidate of choice. This allows researchers to estimate the baseline level of support for candidates of choice and test whether the ethnicity of the candidates affected how voters cast their ballots.