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Affinity selection methods are applied to the identification of the structural form of the parnafungins responsible for binding to polyadenosine polymerase (PAP). The study has shown the potential of applying affinity selection for the identification of novel natural products that binds to a biologically relevant protein as well as to solve the problems in chemical biology.

The article explains the structure and the isolation of parnafungins, the antifungal natural products that inhibit mRNA polyadenylation. The fungal polyadenosine polymerase is shown to act as the biochemical target of these natural products.

Polymer based carriers that aid in endosomal escape have proven to be efficacious siRNA delivery agents in vitro and in vivo; however, most suffer from cytotoxicity due in part to a lack of selectivity for endosomal versus cell membrane lysis. For polymer based carriers to move beyond the laboratory and into the clinic, it is critical to find carriers that are not only efficacious, but also have margins that are clinically relevant. In this paper we report three distinct categories of polymer conjugates that improve the selectivity of endosomal membrane lysis by relying on the change in pH associated with endosomal trafficking, including incorporation of low pKa heterocycles, acid cleavable amino side chains, or carboxylic acid pH sensitive charge switches. Additionally, we determine the therapeutic index of our polymer conjugates in vivo and demonstrate that the incorporation of pH responsive elements dramatically expands the therapeutic index to 10-15, beyond that of the therapeutic index (less than 3), for polymer conjugates previously reported.