Phage Display Driven Identification and Computational Mapping of Macrocyclic Peptides Targeting RhoA G17V
= 136 nM), representing the highest-affinity peptide reported for RhoA G17V to date. Computational docking combined with long-timescale molecular dynamics simulations revealed a stable peptide-protein interaction governed by cooperative hydrophobic and electrostatic interactions. Systematic alanine scanning mutagenesis experimentally validated the predicted binding determinants, confirming the key residues within the macrocycle. Collectively, this work establishes macrocyclic phage display as a powerful and generalizable platform for discovering high-affinity ligands against challenging mutant GTPases and lays a foundation for the development of precision peptide-based therapeutics.
Authors
- Joshua Trae Hampton (ORCID: https://orcid.org/0000-0001-5562-162X)
- Yugendar R. Alugubelli
- Yubin Zhou (ORCID: https://orcid.org/0000-0001-7962-0517)
- Sebin Abraham
- Wenshe Ray Liu (ORCID: https://orcid.org/0000-0002-7078-6534)
- Lai Hoang Son Le (ORCID: https://orcid.org/0000-0002-2473-6309)
- Chaoyang Zhu (ORCID: https://orcid.org/0000-0003-3930-9024)
- Yun Huang
Institutions
- Mitchell Institute (US)
- Drug Discovery Laboratory (Norway) (NO)
- Pediatrics and Genetics (US)
- Texas A&M University (US)
Publication Details
- Journal
- Biochemistry
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1021/acs.biochem.6c00058
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Welch Foundation
- Leukemia and Lymphoma Society
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences