Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening

Bibliographic Details
Main Author:	Cooper, Jahan
Language:	English
Published:	The Ohio State University / OhioLINK 2018
Subjects:	Chemistry
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=osu152570020664904

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-osu1525700206649042021-08-03T07:06:47Z Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening Cooper, Jahan Chemistry Intracellular protein-protein interactions (PPIs) are one of the most challenging types of drug targets in pharmaceutical industry and academia today. Cyclic and bicyclic peptides have recently garnered interest as effective inhibitors of PPIs as their unique structures confer advantages in binding to PPI surfaces over traditional small molecule or larger biologic drugs. Screening vast combinatorial libraries of cyclic peptides, including those functionalized to be cell permeable, has proven to be a powerful mechanism for developing lead inhibitors to multiple therapeutically relevant PPIs.Ras proteins are some of the most ubiquitous implicated in cancer and have also proven to be very challenging drug targets. These small GTPases act as molecular switches in critical signaling pathways involved in cell survival and proliferation. Gain-of-function mutants of Ras are present in up to 30% of solid tumors.Work in the Pei Lab has focused on directly targeting Ras-downstream effector interactions, resulting in new classes of monocyclic and bicyclic peptide inhibitors. This work details the continuing effort to optimize the “drug-like” properties of a previously characterized bicyclic ligand against K-Ras G12V, cyclorasin B3, by improving its PPI inhibitory activity, solubility, and cellular effects. Derivatives of B3 included a stem-like linear linker sequence originally meant as a handle for probe conjugation. Fortuitously, we found that this linker may also impact the bicycle’s binding affinity. A second-generation combinatorial peptide library was synthesized and screened to further probe to what extent this external linker contributes to the peptide’s activity and to discover improved binders. Screening this library, which replaced the original linker with a randomized sequence, against mutant K-Ras resulted in only a handful of hits with improved inhibitory activity but confirmed the importance of this small sequence to the function of the peptide as a whole. 2018-10-12 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu152570020664904 http://rave.ohiolink.edu/etdc/view?acc_num=osu152570020664904 restricted--full text unavailable until 2023-08-06 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Chemistry
spellingShingle	Chemistry Cooper, Jahan Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening
author	Cooper, Jahan
author_facet	Cooper, Jahan
author_sort	Cooper, Jahan
title	Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening
title_short	Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening
title_full	Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening
title_fullStr	Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening
title_full_unstemmed	Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening
title_sort	optimizing the potency of a bicyclic peptide inhibitor of the ras-raf protein-protein interaction via combinatorial screening
publisher	The Ohio State University / OhioLINK
publishDate	2018
url	http://rave.ohiolink.edu/etdc/view?acc_num=osu152570020664904
work_keys_str_mv	AT cooperjahan optimizingthepotencyofabicyclicpeptideinhibitoroftherasrafproteinproteininteractionviacombinatorialscreening
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Optimizing the Potency of a Bicyclic Peptide Inhibitor of the Ras-Raf Protein-Protein Interaction via Combinatorial Screening

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