Approaching exponential growth with a peptide self-replicator and studies in the dimerization-inhibition of transcription factors E47 and Jun

Roy P Issac, Purdue University

Abstract

In the first part of this thesis, a self-replicating peptide with high catalytic efficiency is described. Based on E1E2, a self-replicating, coiled-coil peptide, RI-26 was designed to avoid product inhibition. The suppression of product inhibition and low uninstructed background reaction rates resulted in near exponential self-replication. From more than one perspective this is an important system. In molecular evolution models, product inhibition leads to inefficient information transfer. In order to develop self-replicating systems that show Darwinian evolution, product inhibition must be solved. RI-26 is such a system that shows turnover and has high catalytic efficiency. From a different perspective, the design of small peptides with enzyme like catalytic efficiency is a well sought after, and considered very difficult goal. In the second part of this thesis, dimerization inhibition of the dimeric interface of E47 and Jun peptides is studied. Against E47, a transcription factor implicated in acute lymphoblastic lymphoma, a seven amino acid beta sheet peptide inhibitor was developed. Shortening the peptide further resulted in the loss of structural features of the beta sheet, and a concomitant loss of inhibitory activity. Dimerization inhibition was used against the Jun onco-protein transcription factor as well. A mutant of Fos-32, a potent inhibitor of Jun dimerization was produced from two inactive fragments, Fos-N15 and Fos-C17 in situ to interrupt Jun dimerization. This is the first time that such a strategy has been used to inhibit protein oligomerization.

Degree

Ph.D.

Advisors

Chmielewski, Purdue University.

Subject Area

Organic chemistry|Biophysics|Biochemistry

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