FRIAS Kolloquium - Nibedita Nandi

Microcystin based inhibitors imparting selectivity towards Protein Phosphatase-1 and -2A

Protein phosphatase-1 (PP1) and -2A (PP2A), the two most abundant representatives of the serine/threonine-specific phosphoprotein phosphatase (PPP) family, are supposed to carry out the majority of dephosphorylation of serine/threonine side chains in cellular phosphoproteins. At the molecular level, cyclic peptide based natural toxin Microcystins (MCs) bind irreversibly to inhibit both of these phosphatases with equal potency. Provided that, PP1 and PP2A share about 40% of sequence identity and comparable catalytic functions at the active site, significant efforts have been made to develop compounds that selectively inhibit either of these phosphatases, in order to study their biological roles and assess their therapeutic potential in diseases. However, to date most inhibitors are non-selective or more specific toward PP2A.

To combat this challenge, the primary aim of the project is to synthesize and biochemically evaluate several MC analogues, without the requirement of the complex lipophilic ‘Adda’ group, through an efficient strategy combining solid-and-solution phase approaches. There is a previous report on MC analogues, in which the incorporation of a small lipophilic alkyl chain that is structurally similar to parts of the Adda group, would accommodate closely into the hydrophobic groove of PP2A, and thus enabling to achieve strong selectivity towards PP2A. Through structural and mutational analyses, this project aims to explore the roles of different amino acids or substitutes in different positions of MCs targeting the active centers of PP1 and PP2A. Eventually, this study will provide dynamic insights for a rational design to develop MC based inhibitors selective towards either PP1 or PP2A.