De-risking Drug Discovery of Intracellular Targeting Peptides: Screening Strategies to Eliminate False-Positive Hits

De-risking Drug Discovery of Intracellular Targeting Peptides: Screening Strategies to Eliminate False-Positive Hits
Title:
De-risking Drug Discovery of Intracellular Targeting Peptides: Screening Strategies to Eliminate False-Positive Hits
Other Titles:
ACS Medicinal Chemistry Letters
Publication Date:
05 May 2020
Citation:
Abstract:
Non-specific promiscuous compounds can mislead researchers and waste significant resources. This phenomenon, though well-documented for small molecules, has not been widely explored for the peptide modality. Here, we demonstrate that two purported peptide-based KRas inhibitors, SAH-SOS1A and cyclorasin 9A5, exemplify false-positive molecules – both in terms of their binding affinities and cellular activities. Through multiple gold-standard biophysical techniques, we unambiguously show that both peptides lack specific binding for KRas and instead induce protein unfolding. Although these peptides inhibited cellular proliferation, the activities appeared to be off-target based on counter-screen with KRas-independent cell lines. We further demonstrate that their cellular activities are derived from membrane disruption. Accordingly, we propose that, to de-risk false-positive molecules, orthogonal binding assays and cellular counter-screens are indispensable.
License type:
PublisherCopyrights
Funding Info:
This research is supported by core funding from the Bioinformatics Institute, ARES.
Description:
This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsmedchemlett.0c00022
ISSN:
1948-5875
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