The design and synthesis of peptidomimetic serine-based prodrugs as 14-3-3 inhibitors

Eric Drake Jones, Purdue University

Abstract

This work describes the design and synthesis of peptidomimetics for the inhibition of the protein-protein interactions (PPI) with 14-3-3. This protein is a promiscuous binder of other proteins with a variety of key functions such as the regulation of proapoptotic proteins (e.g. FOXO, BAD), suppression of tumor growth, and sensitizing cells to other drugs. The promiscuous binding is the result of PPIs being shallow binding sites which accept many proteins and modify their activity. Compounds which inhibit 14-3-3 include peptides which induce cellular apoptosis. As a result, this interaction has been identified as a potential drug target for future cancer therapeutics, however the 7 isoforms are not perfectly redundant adding additional selectivity development as an eventual direction. The Borch lab has a long standing interest in phosphoramidate prodrugs, here incorporated into peptidomimetics, to improve the cellular permeability of charged phosphate compounds. The previous work by Kim et al utilized these prodrugs to develop a modified version of the peptidomimetic produced by Shao Q. Yao. The original compound 1 had an IC50 of 2.6±0.4 µM with molecular interactions, while the prodrug analogue 2, which included the difluoromethylene phosphonate analogue of the phosphate, had an IC50 near 5 µM in cells. The exact results were unable to be determined as they resulted in cytotoxicity presumably from 14-3-3 activation. The peptidomimetics designed herein were modeled in comparison with the compounds produced by Kim et al. In this process two prospective binding modes were identified. One involved a linear binding method while another has a bent orientation. The compounds previously produced bind in a bent method while those found in the linear method more closely resembled the orientation of several peptides designated consensus sequences. Unsurprisingly those which more closely resemble the crystallized consensus sequences produced higher G-scores. The goal of this work was then to produce these compounds for initial confirmation of increased activity by these trial runs.

Degree

M.S.

Advisors

Borch, Purdue University.

Subject Area

Organic chemistry|Pharmacy sciences

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