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.

Ordinary mod p representations of the metaplectic cover of p-adic SL_2

We classify the genuine ordinary mod p representations of the metaplectic group SL(2,F)-tilde, where F is a p-adic field, and compute its genuine mod p spherical and Iwahori Hecke algebras. The motivation is an interest in a possible correspondence between genuine mod p representations of SL(2,F)-tilde and mod p representations of the dual group PGL(2,F), so we also compare the two Hecke algebras to the mod p spherical and Iwahori Hecke algebras of PGL(2,F). We show that the genuine mod p spherical Hecke algebra of SL(2,F)-tilde is isomorphic to the mod p spherical Hecke algebra of PGL(2,F), and that one can choose an isomorphism which is compatible with a natural, though partial, correspondence of unramified ordinary representations via the Hecke action on their spherical vectors. We then show that the genuine mod p Iwahori Hecke algebra of SL(2,F)-tilde is a subquotient of the mod p Iwahori Hecke algebra of PGL(2,F), but that the two algebras are not isomorphic. This is in contrast to the situation in characteristic 0, where by work of Savin one can recover the local Shimura correspondence for representations generated by their Iwahori fixed vectors from an isomorphism of Iwahori Hecke algebras.