Design and generation of novel modified cyclic peptide inhibitors for the oncogenic mortalin-p53 interaction

Background: There is a pressing need to develop new therapeutic agents to overcome toxicity of current chemotherapeutic agents as well as the emergence of drug resistant cancer cells.

Therefore, there is an intense effort in cancer research to identify and validate new therapeutic targets in cancer cells and to design novel selective chemotherapeutic agents.

Protein p53 is a tumor suppressor that triggers apoptosis via multiple pathways, including cell cycle arrest and the regulation of autophagy through transactivating proapoptotic and repressing antiapoptotic genes.

Mortalin (HSPA9/GRP75/PBP74) is a member of the heat shock protein (HSP) 70 family which also includes the cytosolic heat shock cognate 71 kDa (HSC70/HSPA8) and the endoplasmic reticulum chaperone, BiP/HSPA5.

It is often overexpressed in cancers, including the tumors of colon, liver, brain, breast, and skin, and growing evidence suggests that mortalin is an important regulator of tumor cell growth and survival. Mortalin is a multifunctional protein and is highly expressed in cancers.

It has been shown to interact with tumor suppressor protein-p53 (both wild and mutant types) and inactivates its transcriptional activation and apoptotic functions in cancer cells.

It binds to p53 tumor suppressor protein and sequesters it in the cytoplasm, resulting in an inhibition of the transcriptional activation and control of centrosome duplication functions of p53, thus increasing malignant properties of human cancer cells.

The inhibition of mortalin-p53 interaction has been identified as a key therapeutic target for cancer treatment as it and will result in the restoration of p53 function. Idea of research: I will design modified cyclic peptide inhibitors to the oncogenic mortalin-p53 interaction.

There is a growing evidence that cyclic peptides can inhibit protein-protein interactions (Villar et al. 2014 Nat Chem Biol 10, 723) which are known to be challenging targets for small molecule drugs. The crystal structure of the mortalin nucleotide binding domain (NBD) has been published (protein sci 2014).

A structure-based model on how mortalin-NBD bind with p53 has been presented and will be used in the in-silico design process. Plan of work 1. Structure-based drug design for novel peptides as a lead compounds for P53-Mortalin inhibitors 2. Synthesis of these designed lead peptides using solid phase peptide synthesis, cyclization and purification 3.

Determination of the 3D structure of the generated peptides 4. In vitro biological screening 5. Structure-Activity Relation (SAR) study for enhancing the tested activity