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Small GTPases - Ras and Rho

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:

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Related Experiment Video

Updated: Apr 17, 2026

Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library

Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library

Published on: September 30, 2019

Phage Display Driven Identification and Computational Mapping of Macrocyclic Peptides Targeting RhoA G17V.

Sebin Abraham¹, Chaoyang Zhu¹, Lai Hoang Son Le¹

¹Texas A&M Drug Discovery Center and Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.

|April 15, 2026

Summary

Researchers developed macrocyclic peptides to target the undruggable mutant RhoA G17V, a key driver of T-cell lymphoma. This approach successfully identified high-affinity peptide binders, offering a new therapeutic strategy for challenging oncogenic GTPases.

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Last Updated: Apr 17, 2026

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Peptide-based Identification of Functional Motifs and their Binding Partners

Peptide-based Identification of Functional Motifs and their Binding Partners

Published on: June 30, 2013

Area of Science:

Oncology
Molecular Biology
Drug Discovery

Background:

Mutant RhoA G17V is a clinically significant oncogenic GTPase driving angioimmunoblastic T-cell lymphoma.
Its structure presents challenges for conventional small-molecule drug development.
There is a critical need for alternative therapeutic modalities targeting this oncogene.

Purpose of the Study:

To develop a novel therapeutic strategy targeting the undruggable mutant RhoA G17V.
To discover high-affinity macrocyclic peptides against RhoA G17V using phage display.
To establish macrocyclic peptides as a viable platform for targeting challenging mutant GTPases.

Main Methods:

Systematic biopanning of two complementary phage-displayed cyclic peptide libraries (10-mer and 12-mer) against recombinant RhoA G17V.
High-throughput screening and affinity determination of peptide binders.
Computational docking, molecular dynamics simulations, and alanine scanning mutagenesis for validation.

Main Results:

Discovery of Z1, a macrocyclic peptide with submicromolar affinity (K_D = 136 nM) for RhoA G17V, the highest reported to date.
Identification of key hydrophobic and electrostatic interactions stabilizing the peptide-protein complex.
Experimental validation of binding determinants through alanine scanning mutagenesis.

Conclusions:

Macrocyclic phage display is a powerful platform for discovering high-affinity ligands against challenging mutant GTPases like RhoA G17V.
This work provides a foundation for developing precision peptide-based therapeutics for RhoA G17V-driven cancers.
The strategy is generalizable for targeting other difficult-to-drug mutant GTPases.