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Antagonists of ribonuclease inhibitor: Small molecules, dendrimers, and peptides
Author(s) -
Ellis Gregory A,
Lavis Luke D.,
Johnson R. Jeremy,
Raines Ronald T.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.651.1
Subject(s) - ribonuclease , peptidomimetic , small molecule , chemistry , peptide , phage display , biochemistry , peptide library , peptide sequence , rna , gene
Recent successes have indicated the feasibility of disrupting protein–protein interactions (PPIs) with small molecules, peptidomimetics, and peptides to modulate cellular processes. Among the tightest of all known PPIs are the interactions between ribonuclease inhibitor (RI) and its ribonuclease ligands, which bind with femtomolar affinity even though these ribonucleases share only ∼30% amino‐acid sequence identity. Due to this high affinity, identifying antagonists of this interaction would be a notable advancement in the area of PPI inhibition. Multiple strategies are currently being used to identify antagonists of RI. Several preliminary antagonists have been identified through screening of small‐molecule libraries. In addition, poly(amidoamine) dendrimers were screened as ribonuclease mimics and demonstrated moderate affinity for RI. Finally, phage display is being conducted to identify peptide antagonists. Ribonucleases that evade RI exhibit selective toxicity for cancer cells, and the lack of affinity for RI is considered a primary determinant of that toxicity. Therefore, it is hypothesized that inhibiting the RI–ribonuclease interaction with antagonists will potentiate the cytotoxic activity of modestly RI‐evasive ribonucleases, possibly leading to extremely potent chemotherapeutics. This work was supported by Grant CA73808 (NIH) and the Wisconsin Alumni Research Foundation.